Search

Rationale: Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g., Ritalin®). One potential limitation of increased l-MPH was indicated in a preclinical study showing l-MPH may attenuate effects of d-MPH., Objectives: The objective of the study was to investigate the interactive effects of MPH enantiomers by (1) assessing drug effects via a preclinical model of "impulsivity" and (2) performing a quantitative dose equivalence analysis of MPH enantiomer interactions., Methods: Sprague-Dawley rats were trained to emit either of two responses, one producing an immediate food pellet, the other producing four pellets delivered at increasing delays (0, 8, and 32 s). The percent selection of the larger food amount was graphed as a function of delay with the area under the curve (AUC) assessed. Increases in AUC are consistent with decreases in "impulsivity" (i.e., selection of the smaller, immediate over the larger, delayed reinforcer)., Results: Systemic administration of dl-MPH and d-MPH dose-dependently increased AUC, while l-MPH, morphine, and pentobarbital did not alter AUC. An analysis based upon dose equivalence indicated that dl-MPH produced additive effects that were not different from that predicted from effects of the enantiomers administered alone., Conclusions: The present results indicate pharmacologically selective effects in that only drugs prescribed for the treatment of ADHD symptoms decreased a measure of "impulsivity" and that l-MPH likely does not attenuate or enhance the effects of d-MPH in the current delay-discounting task.

New designer drugs such as K2, Spice, and "bath salts" present a formidable challenge for law enforcement and public health officials. The following report summarizes a three-year study of 1320 law enforcement cases involving over 3000 products described as vegetable material, powders, capsules, tablets, blotter paper, or drug paraphernalia. All items were seized in Arkansas from January 2010 through December 2012 and submitted to the Arkansas State Crime Laboratory for analysis. The geographical distribution of these seizures co-localized in areas with higher population, colleges, and universities. Validated forensic testing procedures confirmed the presence of 26 synthetic cannabinoids, 12 designer stimulants, and 5 hallucinogenic-like drugs regulated by the Synthetic Drug Prevention Act of 2012 and other state statutes. Analysis of paraphernalia suggests that these drugs are commonly used concomitantly with other drugs of abuse including marijuana, MDMA, and methamphetamine. Exact designer drug compositions were unpredictable and often formulated with multiple agents, but overall, the synthetic cannabinoids were significantly more prevalent than all the other designer drugs detected. The synthetic cannabinoids JWH-018, AM2201, JWH-122, JWH-210, and XLR11 were most commonly detected in green vegetable material and powder products. The designer stimulants methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxy-N-methylcathinone (methylone), and α-methylamino-valerophenone (pentedrone) were commonly detected in tablets, capsules, and powders. Hallucinogenic drugs were rarely detected, but generally found on blotter paper products. Emerging designer drug products remain a significant problem and continued surveillance is needed to protect public health., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Caffeine is a central nervous system stimulant that is consumed by large numbers of people on a routine basis, usually in the form of coffee or tea. However, if consumed in high doses, this xanthine alkaloid is profoundly toxic and can result in death. Increasingly being sold as a dietary supplement, many people, particularly those in the health and fitness community, where it is touted as a fitness and muscle building aid, are consuming caffeine anhydrous on a daily basis. We report a case of fatal caffeine overdose in a 39-year-old man resulting from the self-administered ingestion of approximately 12 g of pure caffeine anhydrous. Autopsy blood caffeine levels were 350 mg/L. We recommend mandated labeling of pure caffeine anhydrous, highlighting the toxicity risk of ingesting this chemical; and we recommend ensuring that caffeine levels are included in the comprehensive forensic toxicology panel performed on all cases.

From 2005 to 2012, 236 new substances have been officially notified in European Union via the Early Warning System with an increasing trend from year by year. In October 2009, 4-methylamphetamine (4-MA), an amphetamine derivative, was detected in Belgium and on 14 December 2009 this stimulant was notified to the European Monitoring Centre for Drugs and Drug Addiction. Since its appearance within the recreational drug market, some cases of severe intoxication and deaths have been signaled across Europe. In this paper we summarized the chemical, pharmacological and toxicological information about this new potential recreational drug.

Objective: To elaborate a clinical and X-ray classification of osteonecrosis of the low jaw in people with desomorphine or pervitin addiction., Material and Methods: Ninety-two patients with drug addiction who had undergone orthopantomography, direct frontal X-ray of the skull, and multislice computed tomography, followed by multiplanar and three-dimensional imaging reconstruction were examined. One hundred thirty four X-ray films and 74 computed tomographic images were analyzed., Results: The authors proposed a clinical and X-ray classification of osteonecrosis of the low jaw in people with desomorphine or pervitin addiction and elaborated recommendations for surgical interventions on the basis of the developed classification., Conclusion: The developed clinical and X-ray classification and recommendations for surgical interventions may be used to treat osteonecroses of various etiology.

Bath salts are designer drugs with stimulant properties that are a growing medical and psychiatric concern due to their widespread availability and use. Although the chemical compounds in the mixtures referred to as "bath salts" vary, many are derivatives of cathinone, a monoamine alkaloid. Cathinones have an affinity for dopamine, serotonin, and norepinephrine synapses in the brain. Because of the strong selection for these neurotransmitters, these drugs induce stimulating effects similar to those of methamphetamines, cocaine, and 3,4-methylenedioxy-N-methylamphetamine (MDMA). Much of the emerging information about bath salts is from emergency department evaluation and treatment of severe medical and neuropsychiatric adverse outcomes. This review consists of a compilation of case reports and describes the emergent literature that illustrates the chemical composition of bath salts, patterns of use, administration methods, medical and neuropsychiatric effects, and treatments of patients with bath salt toxicity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the "high" it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories., Objective and Methods: A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated., Results: Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence., Conclusions: With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact.

Using bioluminescence resonance energy transfer and proximity ligation assays, we obtained the first direct evidence that adenosine A₁ receptors (A₁Rs) form homomers not only in cell cultures but also in brain cortex. By radioligand binding experiments in the absence or in the presence of the A₁Rs allosteric modulator, adenosine deaminase, and by using the two-state dimer receptor model to fit binding data, we demonstrated that the protomer-protomer interactions in the A₁R homomers account for some of the pharmacological characteristics of agonist and antagonist binding to A₁Rs. These pharmacological properties include the appearance of cooperativity in agonist binding, the change from a biphasic saturation curve to a monophasic curve in self-competition experiments and the molecular cross-talk detected when two different specific molecules bind to the receptor. In this last case, we discovered that caffeine binding to one protomer increases the agonist affinity for the other protomer in the A₁R homomer, a pharmacological characteristic that correlates with the low caffeine concentrations-induced activation of agonist-promoted A₁R signaling. This pharmacological property can explain the biphasic effects reported at low and high concentration of caffeine on locomotor activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In Australia and increasingly worldwide, methamphetamine is one of the most commonly seized drugs analysed by forensic chemists. The current well-established GC/MS methods used to identify and quantify methamphetamine are lengthy, expensive processes, but often rapid analysis is requested by undercover police leading to an interest in developing this new analytical technique. Ninety six illicit drug seizures containing methamphetamine (0.1%-78.6%) were analysed using Fourier Transform Infrared Spectroscopy with an Attenuated Total Reflectance attachment and Chemometrics. Two Partial Least Squares models were developed, one using the principal Infrared Spectroscopy peaks of methamphetamine and the other a Hierarchical Partial Least Squares model. Both of these models were refined to choose the variables that were most closely associated with the methamphetamine % vector. Both of the models were excellent, with the principal peaks in the Partial Least Squares model having Root Mean Square Error of Prediction 3.8, R(2) 0.9779 and lower limit of quantification 7% methamphetamine. The Hierarchical Partial Least Squares model had lower limit of quantification 0.3% methamphetamine, Root Mean Square Error of Prediction 5.2 and R(2) 0.9637. Such models offer rapid and effective methods for screening illicit drug samples to determine the percentage of methamphetamine they contain.

Objective: In the past 25-30 years, a large number of synthetic and non-synthetic drugs have appeared on the recreational scene, but with the exception of 4-methylmethcathinone (mephedrone), none of these substances reached the popularity of ecstasy [3,4-methylenedioxy-N-methylamphetamine, (MDMA)]. Authors aimed to determine the subjective effects of mephedrone in order to understand how mephedrone can serve as a potential substitute for entactogens, such as MDMA., Methods: One hundred forty-five mephedrone users--recruited by snowball method--filled out a questionnaire on their patterns of use and experienced subjective effects of mephedrone., Results: Factor analysis revealed six factors of mephedrone-induced subjective effects: positive emotions, sensibility, adverse somatic effects, adverse psychological effects, stimulant effects, and psychedelic effects. A preference list of subjective effects indicates that mephedrone is popular primarily for its psychostimulant and entactogen effects. Latent class analysis identified two classes of mephedrone users, with closely parallel profiles. The two classes differed in severity of subjective experience in a way that was consistent across the six dimensions., Conclusions: By having similar subjective effects as MDMA and other entactogens, mephedrone seems able to substitute other enactogenic stimulants., (Copyright © 2013 John Wiley & Sons, Ltd.)

The multiequilibrium system of reactions of cyanidin 3-glucoside at acidic and mildly acidic pH values was studied in the presence of caffeine as a copigment. The thermodynamic and kinetic constants were determined using the so-called direct and reverse pH jump experiments that were followed by conventional UV-vis spectroscopy or stopped flow coupled to a UV-vis detector, depending on the rate of the monitored process. Compared with that of free anthocyanin, the copigmentation with caffeine extends the domain of the flavylium cation up to less acidic pH values, while in a moderately acidic medium, the quinoidal base becomes more stabilized. As a consequence, the hydration to give the colorless hemiketal is difficult over the entire range of pH values. At pH 1, two adducts were found for the flavylium cation-caffeine interaction, with stoichiometries of 1:1 and 1:2 and association constants of 161 M⁻¹ (K₁) and 21 M⁻¹ (K₂), respectively.

New groups of synthetic "designer drugs" have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as "legal" highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.

Rationale: Psychoactive "bath salts" represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated., Materials and Methods: Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes., Results: Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine., Conclusions: Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine.

4-Methylethcathinone (4-MEC) is a designer drug that is structurally similar to mephedrone. This substance was identified in many drug seizures analyzed in the Institute of Forensic Research (IFR). This paper describes three of the first cases in which both powders and biological material were secured at the same time and delivered to the IFR for toxicological analysis. The first case concerned a man who died in a car crash. The second case describes a death associated with multiple-drug intake, including 4-MEC. In this case, however, the death was the result of an overdose of para-methoxyamphetamine (PMA). In the third case, the man was arrested for possession of illicit drugs. Analysis of powders was carried out using gas chromatography-mass spectrometry (GC-MS) and high pressure liquid chromatography with diode array detection (HPLC-DAD). The purity of 4-MEC found in powder samples was 51% and 78%. Analyses of biological material were carried out using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 4-MEC was found in blood samples at concentrations of 46, 56 and 152 ng/mL., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

5-(2-Aminopropyl)benzofuran (5-APB), a 'research chemical' that was first reported by UK authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2010, is anecdotally reported to produce a combination of stimulant and entactogenic effects. More recently, in 2011, 6-(2-aminopropyl)benzofuran (6-APB) was identified by Hungarian authorities. To confirm positional isomer identity in Internet purchased products, 4- 5- 6- and 7-APBs were synthesized and found to be separable by gas chromatography (as heptafluorobutyramide derivatives) and liquid chromatography. The analyses of products purchased from online vendors of 'research chemicals' identified the presence of 5- or 6-APBs. These findings were further confirmed by liquid chromatography-mass spectrometry and (1) H nuclear magnetic resonance spectroscopy. In products containing 6-APB, the 4- positional isomer was also identified and this may have arisen during the manufacturing process., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Vaccines have treatment potential for methamphetamine (MA) addiction. We tested whether a conjugate vaccine against MA (succinyl-methamphetamine-keyhole limpet hemocyanin carrier protein; SMA-KLH) would generate MA antibodies and alter MA-induced behaviors., Methods: Mice were injected with SMA-KLH and received booster administrations 3 and 20 weeks later. Serum antibody titers reached peak levels by 4-6 weeks, remained at a modest level through 18 weeks, peaked again at 22 weeks after the second boost, and were still elevated at 35 weeks. At 7 weeks, groups of vaccinated and non-vaccinated mice were administered one of three MA doses (1, 2 or 3 mg/kg) to assess locomotor activity., Results: Non-vaccinated mice showed dose-dependent effects of MA with hypolocomotion at the lowest dose and elevated activity levels at the highest dose. Both dose effects were reduced in SMA-KLH groups, particularly low dose-induced hypolocomotion at later times post MA administration. Separate groups of vaccinated and non-vaccinated mice were trained in MA place conditioning at 30 weeks with either 0 (vehicle) or 0.5mg/kg MA. Although times spent in the MA-paired side did not differ between groups on test vs. baseline sessions, SMA-KLH mice conditioned with MA showed reduced conditioned approach behaviors and decreased conditioned activity levels compared to control groups., Conclusion: These data suggest SMA-KLH attenuates the ability of MA to support place conditioning and reduces or delays its locomotor effects. Overall, results support SMA-KLH as a candidate MA vaccine., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: This study examines whether Mexico's controls on ephedrine and pseudoephedrine, the two precursor chemicals that yield the most potent form of methamphetamine, d-methamphetamine, impacted the prevalence/availability of less potent types of methamphetamine in the United States-types associated with the alternative precursor chemical P2P., Method: Using ARIMA-intervention time series analysis of monthly drug exhibits (a prevalence/availability indicator) from the System to Retrieve Information from Drug Evidence (STRIDE), we tested whether Mexico's controls, which began in 2005, were associated with growth/decline in d-methamphetamine and growth/decline in P2P-associated, less potent l-methamphetamine, racemic methamphetamine (a 50:50 ratio of d- and l-isomers), and mixed isomer methamphetamine (an unequal ratio of d- and l-isomers). Heroin, cocaine and marijuana exhibits were used for quasi-control (01/2000-04/2011)., Results: Mixed-isomer exhibits constituted about 4% of the methamphetamine exhibits before Mexico's controls, then rose sharply in association with them and remained elevated, constituting about 37% of methamphetamine exhibits in 2010. d-Methamphetamine exhibits dropped sharply; l-methamphetamine and racemic methamphetamine exhibits had small rises. d-Methamphetamine exhibits partially recovered in the US West, but little recovery occurred in the US Central/South. Quasi-control series were generally unaffected., Conclusion: The US methamphetamine market changed. Widespread emergence of less potent methamphetamine occurred in conjunction with Mexico's controls. And prevalence/availability of the most potent type of the drug, d-methamphetamine, declined, a partial recovery in the West notwithstanding. Granting that lower potency drugs typically engender less dependence and attendant problems, these findings suggest that, following Mexico's controls, the potential harm of a sizeable amount of the US methamphetamine supply decreased., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

N-Methyl-3-phenyl-norbornan-2-amine (N-methyl-3-phenylbicyclo[2.2.1]heptan-2-amine, Camfetamine(™) ) is available from a number of online legal highs/research chemicals' vendors. Although it was developed as an analeptic by Merck in the early 1960s, it was never commercialized. However, the Association of Independent Research Chemical Retailers (AIRCR), an umbrella organization for a number of online vendors, has redeveloped it for use as a recreational drug. N-Methyl-3-phenyl-norbornan-2-amine is closely related to fencamfamine which has been widely used as a central nervous system (CNS) stimulant and appetite suppressant. In this paper we describe the synthesis of N-methyl-3-phenyl-norbornan-2-amine, its characterization and interpretations of its electron impact, and electrospray ionization mass spectra., (Copyright © 2012 John Wiley & Sons, Ltd.)

A number of methods of clandestine manufacture of methylamphetamine involve the extraction and subsequent reaction of pseudoephedrine hydrochloride with other essential chemicals. The precursor can be easily extracted from over-the-counter medication widely available in the UK and elsewhere. Essential chemicals such as iodine and red phosphorous are also readily available and can be extracted from iodine tinctures and matchboxes, respectively. This work reports the repetitive preparation of methylamphetamine using two popular routes (the Moscow and Hypophosphorous synthesis). The focus was on the extraction solvent used for isolation of the precursor chemical and any consequential isotopic variation which may arise in the final product. Six batches of methylamphetamine were prepared under precisely controlled conditions for each synthetic route and for each of three different precursor extraction solvents. Synthesis of the final product from laboratory grade precursor using the synthetic methods described was used as a template for comparison. The resultant IRMS data from all 48 prepared samples suggests some underlying trends in the identification of the synthetic route which may aid in the interpretation of IRMS data derived from clandestine samples.

Bath salts are new designer drugs with stimulant effects on the central nervous system. White or brown powder sold online and in mini-marts under different brand names, bath salts can be used by injecting, snorting, smoking, or ingesting with food or drink. The case of a 30-year-old Caucasian male who developed acute psychosis within a few hours of injecting himself with bath salts is described. The patient was hospitalized with a complaint of hearing voices. The drug also induced in the patient a state of euphoria, increased energy level, along with decreased need for sleep and decreased appetite. The psychological effects of the bath salts subsided within a few hours of injection and his reality testing remained consistently intact over the next 3 days of hospitalization. This case brings to attention the fact that bath salts were legal throughout the United States until recently and is still not completely controlled. This report informs clinicians of harmful effects of bath salts, including severe agitation with possible rhabdomyolysis, psychosis, suicidal ideation, hypertension, tachycardia, and death., (© 2013 American Academy of Forensic Sciences.)

The rise in popularity of "bath salts" as safe alternatives to MDMA (3,4-methylenedioxymethamphetamine), methamphetamine, and other illicit substances has resulted in increased scrutiny of the contents and toxicology associated with these products. We report a case of sudden death related to the synthetic cathinone methylone (3,4-methylenedioxy-N-methylcathinonmethylone) in a previously healthy 19-year-old man. Although several fatal case reports have been published involving methylone and other synthetic cathinones, this is the first reported case of sudden cardiac death associated with methylone use. Although lack of published data prevented a comparison of blood methylone concentrations between our case and existing reports, the amount of methylone we detected postmortem (0.07 mg/dL) is below those reported in MDMA-related fatalities. Our report suggests that methylone toxicity has been greatly underestimated by users of this synthetic cathinone.

The illicit consumption of psychoactive compounds may cause short and long-term health problems and addiction. This is also true for amphetamines and cocaine, which target monoamine transporters. In the recent past, an increasing number of new compounds with amphetamine-like structure such as mephedrone or 3,4-methylenedioxypyrovalerone (MDPV) entered the market of illicit drugs. Subtle structural changes circumvent legal restrictions placed on the parent compound. These novel drugs are effectively marketed "designer drugs" (also called "research chemicals") without any knowledge of the underlying pharmacology, the potential harm or a registration of the manufacturing process. Accordingly new entrants and their byproducts are identified postmarketing by chemical analysis and their pharmacological properties inferred by comparison to compounds of known structure. However, such a heuristic approach fails, if the structures diverge substantially from a known derivative. In addition, the understanding of structure-activity relations is too rudimentary to predict detailed pharmacological activity. Here, we tested a combined approach by examining the composition of street drugs using mass spectrometry and by assessing the functional activity of their constituents at the neuronal transporters for dopamine, serotonin, and norepinephrine. We show that this approach is superior to mere chemical analysis in recognizing novel and potentially harmful street drugs.

Chiral molecules need special attention in drug design. In this sense, the R and S configurations of a series of thirty-four amphetamines were evaluated by quantitative structure-activity relationship (QSAR). This class of compounds has antidepressant, anti-Parkinson and anti-Alzheimer effects against the enzyme monoamine oxidase A (MAO A). A set of thirty-eight descriptors, including electronic, steric and hydrophobic ones, were calculated. Variable selection was performed through the correlation coefficients followed by the ordered predictor selection (OPS) algorithm. Six descriptors (CHELPG atomic charges C3, C4 and C5, electrophilicity, molecular surface area and logP) were selected for both configurations and a satisfactory model was obtained by PLS regression with three latent variables with R(2)=0.73 and Q(2)=0.60, with external predictability Q(2)=0.68, and R(2)=0.76 and Q(2)=0.67 with external predictability Q(2)=0.50, for R and S configurations, respectively. To confirm the robustness of each model, leave-N-out cross validation (LNO) was carried out and the y-randomization test was used to check if these models present chance correlation. Moreover, both automated or a manual molecular docking indicate that the reaction of ligands with the enzyme occurs via pi-pi stacking interaction with Tyr407, inclined face-to-face interaction with Tyr444, while aromatic hydrogen-hydrogen interactions with Tyr197 are preferable for R instead of S configurations., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Synthetic beta-cathinone derivatives belong to the novel group of psychostimulant "designer drugs". They show significant structural similarity to catecholamines and exogenous central nervous system (CNS) stimulating agents such as amphetamine, methamphetamine, ephedrine, 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy), and act as dopamine, noradrenaline and serotonin reuptake inhibitors. Popular synthetic beta-cathinones include e.g. mephedrone (4-methylmethcathinone, 4-MMC), naphyrone (naphthylpyrovalerone) and MDPV (3,4-methylenedioxypyrovalerone). Ingestion of synthetic cathinones produces effects of CNS stimulation, often comparable to those evoked by cocaine, amphetamine and MDMA. Chronic abuse of beta-cathinone derivatives leads to the development of tolerance, psychic and physical dependence. This paper discusses pharmacological properties of the most commonly used beta-cathinone derivatives as well as risks associated with their abuse. Special emphasis is given to neurological, psychiatric, cardiovascular and hematologic disturbances. Authors also present cases of fatalities caused by acute beta-cathinone intoxication or resulting from the drug-related accidents and crimes.

Purpose: Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products., Methods: A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC., Results: The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased., Conclusions: PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.

Background and Purpose: Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied., Experimental Approach: Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors., Key Results: Butylone, mephedrone and methylone (5-25 mg·kg(-1) ) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]dopamine uptake with IC(50) values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA., Conclusions and Implications: Butylone and methylone induced hyperlocomotion through activating 5-HT(2A) receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Abuse of the psychoactive "designer drug" methylenedioxypyrovalerone (MDPV) has become a serious international public health concern because of the severity of its physical and behavioral toxicities. MDPV is the primary ingredient in so-called "bath salts," labeled as such to avoid criminal prosecution and has only been classified recently as a controlled substance in the United States and some other countries. However, it remains a danger because of illegal sources, including the Internet. MDPV is a synthetic, cathinone-derivative, central nervous system stimulant and is taken to produce a cocaine- or methamphetamine-like high. Administered via oral ingestion, nasal insufflation, smoking, intravenous or intramuscular methods, or the rectum, the intoxication lasts 6 to 8 hours and has high addictive potential. Overdoses are characterized by profound toxicities, causing increased attention by emergency department and law enforcement personnel. Physical manifestations range from tachycardia, hypertension, arrhythmias, hyperthermia, sweating, rhabdomyolysis, and seizures to those as severe as stroke, cerebral edema, cardiorespiratory collapse, myocardial infarction, and death. Behavioral effects include panic attacks, anxiety, agitation, severe paranoia, hallucinations, psychosis, suicidal ideation, self-mutilation, and behavior that is aggressive, violent, and self-destructive. Treatment is principally supportive and focuses on counteracting the sympathetic overstimulation, including sedation with intravenous benzodiazepines, seizure-prevention measures, intravenous fluids, close (eg, intensive care unit) monitoring, and restraints to prevent harm to self or others. Clinical presentation is often complicated by coingestion of other psychoactive substances that may alter the treatment approach. Clinicians need to be especially vigilant in that MDPV is not detected by routine drug screens and overdoses can be life-threatening., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood-brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines-amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

Impurity profiling and classification of abused drugs using chiral analytical techniques is of particular interest and importance because of the additional information obtained from this approach. When these methods are applied to the synthesis of illicitly used substances, they can supply valuable information about the conditions/chemicals used in the synthesis. We have applied GC and NMR methods to the study of intermediates found in methylamphetamine manufacture with the aim of linking the intermediates to the ephedrine/pseudoephedrine starting materials. Therefore, determination of the stereochemical makeup within samples of forensic interest is important giving further specific information to the analyst. This study investigates the stereochemical course of the Emde synthesis of methylamphetamine with particular focus on intermediate formation via the chlorination of ephedrine and pseudoephedrine enantiomers. The configurations of these chloro-phenethylamines were determined by 1D and 2D NMR analysis, and thereafter, the GC/MS analysis was carried out. We have shown here that chlorination of the ephedrine/pseudoephedrine compounds occurs via inversion (S(N)2) and retention (S(N)i) of configuration around the α carbon and mixture of diastereoisomers (chloroephedrine and chloropseudoephedrine) were formed, with the ratio of the resulting compounds dependent on the precursors used. The preparation and analytical properties of these intermediate standards provide data for laboratories interested in the stereochemical analysis of methylamphetamine intermediates such as forensic/law enforcement, and illustrate the value of using a combination of analytical methodology.

The synthesis of methylamphetamine hydrochloride from l-ephedrine or d-pseudoephedrine hydrochloride via reduction with hydriodic acid and red phosphorus was investigated. Eighteen batches of methylamphetamine hydrochloride were synthesized in six replicate batches using three different reaction times. This allowed the investigation of the variation of impurities in the final product with reaction time. The results obtained have resolved previously conflicting impurity profile data reported in the literature for this synthesis route. The impurity profile was shown to change with reaction time, and all previously reported impurity components were identified but not in all batches. Additionally, 20 batches of methylamphetamine hydrochloride were synthesized from either from l-ephedrine or d-pseudoephedrine hydrochloride in reactions which were allowed to proceed for 24 h. The impurities present in the resulting batches were investigated, and route-specific impurities present in all batches were identified. Batch-to-batch fluctuations in the resultant chromatographic impurity profile, despite careful synthetic monitoring and control, were also noted.

Various "legal high" products were tested for synthetic cannabinoids and synthetic stimulants to qualitatively determine the active ingredient(s). Ultra-performance liquid chromatography with accurate mass time-of-flight mass spectrometry (UPLC-TOF) was used to monitor the non-biological specimens utilizing a customized panel of 65+ compounds comprised of synthetic cannabinoids, synthetic stimulants and other related drugs. Over the past year, the United States Drug Enforcement Agency has controlled five synthetic cannabinoid compounds (JWH-018, JWH-073, JWH-200, CP-47,497 and CP-47,497-C8) and three synthetic stimulant compounds (3,4-methylenedioxypyrovalerone, mephedrone and methylone) that were previously reported to be detected in these legal high products. Through our analyses of first and second generation products, it was shown that many of these banned substances are no longer used and have been replaced by other derivatives that are federally legal. Since enactment of the federal bans on synthetic cannabinoids and synthetic stimulants, 4.9% of the products analyzed at our facility contained at least one controlled substance. The remaining 95.1% of products contained only uncontrolled drugs. We demonstrate the UPLC-TOF methodology to be a powerful tool in the qualitative identification of these designer drugs, thus enabling a laboratory to keep current with the drugs that are being sold as these designer products.

A study was performed on the detection, separation and quantification of isomers from the new designer drugs named fluoroamphetamines (FAs) in forensic cases in eastern Denmark. The drugs were detected in whole blood extracts by ultraperformance liquid chromatography with time of flight mass spectrometer (UPLC-TOF-MS) and thereafter verified and quantified by UPLC tandem mass spectrometer (MS/MS). The quantitative method involved liquid–liquid extraction of FAs from whole blood, evaporation of organic solvent, and reconstitution with a mobile phase mixture. Identification of the FAs was achieved by the retention time, multiple reaction monitoring (MRM) traces [154 > 109 (quantifier); 154 > 137], and ion ratio of the two transitions. For all FAs, LOQ was 0.002 mg/kg with linear ranges from 0.002 to 1.0 mg/kg whole blood. Since 2008, a total of 15 forensic investigations, mainly driving under the influence of drugs (DUID) cases, involving 4-fluoroamphetamine (4-FA) have been observed with whole blood concentrations ranging from 0.006 to 0.58 mg/kg. One autopsy case involved 4-FA; however, it was determined to be a combined intoxication. In 2010, ortho-fluoroamphetamine (2-FA) was discovered in forensic samples by the same UPLC/MS/MS method and MRM functions because of variation in retention time and ion ratio. Up to now, three eastern Danish DUID cases have involved 2-FA. The whole blood concentrations of 2-FA were 0.028, 0.041 and 0.37 mg/kg, respectively. Thirteen cases with 4-FA and the three cases with 2-FA also contained amphetamine, but no correlation was observed between the amount of FA and amphetamine. So far, 3-FA has not been observed in any cases, and although it co-elutes with 4-FA, 3-FA will be identified by its variation in ion ratio. To our knowledge, this study has confirmed 2-FA in blood from DUID cases for the first time, and provides typical whole blood concentrations of FAs in forensic cases.

In urine drug testing, enantiomer analysis is used to determine whether a positive methamphetamine result could be due to use of an over-the-counter (OTC) nasal inhaler containing L-methamphetamine. D-methamphetamine at more than 20% of the total is considered indicative of a source other than an OTC product. This interpretation is based on a 1991 Department of Health and Human Services (HHS) Technical Advisory. We performed studies to verify the methamphetamine enantiomer content of current OTC nasal inhalers and to evaluate current laboratory testing capabilities. This study demonstrated that OTC inhalers contain less than 1% D-methamphetamine. A proficiency testing (PT) set for HHS-certified laboratories performing methamphetamine enantiomer testing found D-methamphetamine percentages that were consistently 1 to 3% higher than theoretical due to optical impurity of the derivatizing reagent N-trifluoroacetyl-L-prolyl chloride (L-TPC). The PT results also demonstrate that laboratories can accurately determine 20% D-methamphetamine in samples with total methamphetamine concentrations down to 250 ng/mL. Based on these studies, the guideline of >20% D-methamphetamine is appropriate for interpreting results obtained using current laboratory methods.

In recent years, derivatives of cathinone, a naturally occurring beta-keto phenylethylamine, have entered the illicit drug market. These compounds have been marketed over the internet or in so-called head shops as "legal highs" and have gained popularity among drug users. Numerous fatalities due to the abuse of these drugs in recent years have increased the need for their detection in human blood samples. For detection and determination of 25 designer cathinones and their related ephedrines in blood samples, a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed using only 100 µL of blood. The blood was extracted using liquid-liquid extraction with 1 mL of 1-chlorobutane containing 10% of isopropanol. The final extract was analyzed using a Shimadzu 8030 LC-MS-MS system operated in electrospray positive ionization multiple reaction monitoring mode. The method has been validated according to international guidelines and was found to be selective for all tested compounds. Calibration for all 25 studied analytes was satisfactory from 10-1,000 ng/mL. Accuracy data were within the acceptance interval of ±15% [±20% at the lower limit of quantification (LLOQ)] of the nominal values for all drugs. Within-day (repeatability) and intermediate precision data were within the required limits of 15% relative standard deviation (RSD) (20% RSD at LLOQ).

Synthetic cannabinoids sprayed on herbal mixtures have been abused as a new designer drug all over the world since 2004. In 2008, the first compounds, CP 47,497 and JWH-018, were identified as active ingredients in these mixtures. Most of the compounds have been synthesized for research purposes and are potent CB1 and/or CB2 receptor agonists. To investigate the presence of synthetic cannabinoids in blood samples, a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed using only 100 µL of blood. After the addition of 0.2 mL of trizma buffer, the blood was extracted using liquid-liquid extraction with 1 mL of 1-chlorobutane containing 10% of isopropanol for 5 min on a shaker at 1,500 rpm. After centrifugation at 12,000 rpm for 1 min, the separated solvent layer was transferred to an autosampler vial and evaporated to dryness under N₂. The residue was reconstituted in methanol and injected into a Shimadzu 8030 LC-MS-MS system to separate and detect 25 synthetic cannabinoids. The method has been validated according to international guidelines and was found to be selective for all tested compounds. Calibration was satisfactory from 0.5-100 ng/mL, and from 5.0-500 ng/mL. for HU-210, CP 47,497 and the CP 47,497 C-8 homolog, respectively. The extraction efficiencies ranged from 30-101% and the matrix effects from 67-112%. Accuracy data were within the acceptance interval of ±15% (±20% at the lower limit of quantification) of the nominal values for all drugs.

Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

During a 6 month period (July 2010-January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as "Death", is occasionally found in street drugs offered as "ecstasy" or "amphetamine". The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non-fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15-50) with 67% males; in non-fatal cases 27 years (20-47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17-3.30), which is in the reported lethal range of 0.6-3.1 mg/L in peripheral blood and 1.2-15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01-0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58-3.30), 2.56 (1.52-3.23) and 0.52 mg/L (0.17-1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal "ecstasy" or "speed" drugs., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Although plant-derived essential oils (EOs) have been used to treat various mental disorders, their central nervous system (CNS) acting effects have not been clarified. The present study compared the effects of 20 kinds of EOs with the effects of already-known CNS acting drugs to examine whether the EOs exhibited CNS stimulant-like effects, CNS depressant-like effects, or neither. All agents were tested using a discrete shuttle-type conditioned avoidance task in mice. Essential oils of peppermint and chamomile exhibited CNS stimulant-like effects; that is, they increased the response rate (number of shuttlings/min) of the avoidance response. Linden also increased the response rate, however, the effect was not dose-dependent. In contrast, EOs of orange, grapefruit, and cypress exhibited CNS depressant-like effects; that is, they decreased the response rate of the avoidance response. Essential oils of eucalyptus and rose decreased the avoidance rate (number of avoidance responses/number of avoidance trials) without affecting the response rate, indicating that they may exhibit some CNS acting effects. Essential oils of 12 other plants, including juniper, patchouli, geranium, jasmine, clary sage, neroli, lavender, lemon, ylang-ylang, niaouli, vetivert and frankincense had no effect on the avoidance response in mice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Cathinone derivatives display a wide range of pharmacological activities and uses; some of them are used as prescription medicines, while others are encountered within a recreational context and are available without a prescription over the Internet and in retail shops around the world. One of the difficulties involved in the unambiguous identification of these new psychoactive substances is the lack of suitable reference standards, particularly when dealing with unreported derivatives and positional isomers. In order to address this need, three trifluoromethyl analogues of the psychostimulant methcathinone, with a CF(3) substituent at the 2-, 3- and 4-position of the phenyl ring (2-TFMAP 1, 3-TFMAP 2 and 4-TFMAP 3), have been prepared for analytical characterization using ATR-FTIR, (1)H and (13) C NMR, and GC-(EI/CI)-ion trap-MS. Differentiation among isomers was feasible by IR, for example when assessing the carbonyl stretch at 1711 (1), 1693 (2) and 1688 (3) cm(-1) , respectively. In addition to the expected iminium base peak at m/z 58, EI-MS displayed key ions at m/z 173, 145, 125, 95, and 75. Separation of isomers was possible under GC conditions. A characteristic feature under CI conditions was the loss of water from the [M + H](+) yielding m/z 214 in addition to m/z 58. Studies currently underway show that the three CF(3) -methcathinone analogues have central nervous system effects and that the 4-CF(3) isomer 3 is more potent as a serotonin uptake inhibitor and releasing agent than the 3-CF(3) and 2-CF(3) counterparts., (Copyright © 2012 John Wiley & Sons, Ltd.)

Five acylation reagents have been compared for use as derivatizing agents for the analysis of amphetamine-type stimulants (ATS) in urine by gas chromatography-mass spectrometry (GC-MS). The evaluated reagents were heptafluorobutyric anhydride, pentafluoropropionic anhydride, trifluoroacetic anhydride, acetic anhydride (AA) and N-methyl-bis(trifluoroacetamide). The ATS included amphetamine, methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA). A mixture of the ATS was added to urine (1 mL) followed by KOH solution and saturated NaHCO(3) solution. The sample was then extracted with dichloromethane and the derivatizing agent and 2 µL were injected into the GC-MS instrument. The derivatizing agents were compared with reference to the signal-to-noise (S/N) ratios, peak area values, relative standard deviations (RSDs), linearities, limits of detection (LODs) and selectivities. The acetic anhydride proved to be the best according to the S/N ratio and peak area results for amphetamine, MA, MDMA and MDEA. The best RSD values of peak areas and of S/N ratios at 3 µg/mL were also given by AA in cases of MDA, MDMA and MDEA. At 20 µg/mL, the lowest RSD values of peak areas for MDA and the lowest RSD values of S/N ratios for MA, MDA, MDMA and MDEA were again given by AA. Additionally, the highest correlation coefficients for MA, MDA, MDMA and MDEA and the lowest LOD results for MA, MDMA and MDEA were produced by AA.

Mephedrone is a synthetic derivative of cathinone which is becoming more common on the recreational drug market. Several intoxications following mephedrone abuse have been reported though published papers have focused essentially on analytical approaches for biological fluids and only one has involved a hair sample. After the development and validation of a new method, the first series of positive results for mephedrone in hair specimens is reported here. After decontamination of the hair strand in methylene chloride, hair segments were cut into small pieces with scissors, weighed and incubated overnight in Soerensen buffer pH 7.0 in the presence of deuterated 3,4-methylenedioxymethamphetamine (MDMA) at 40°C. The incubation medium was extracted using ethyl acetate after alkalinisation with 1N sodium hydroxide (NaOH). Before injection, the dry extract was derivatized using a mixture of heptafluorobutyric anhydride/ethyl acetate (100:50, v/v), evaporated and dissolved in ethyl acetate (25μl). After introduction of 1μl of the extract onto a splitless injector, chromatographic separation was achieved on a HP 6890 gas chromatograph equipped with a 5-MS capillary column. Detection was achieved in single ion monitoring mode (m/z 254-119-210 for mephedrone, m/z 258-213 for MDMA-d5) using a 5973 MSD operating in electron impact mode. Sixty-seven hair specimens were tested for mephedrone. Thirteen of them were found positive for mephedrone with concentrations ranging from 0.2 to 313.2ng/mg with a mean concentration of 26.8ng/mg. It was difficult to compare our findings due to a lack of reference data, nevertheless mephedrone seems well incorporated into hair (concentrations in the ng/mg range) like other stimulant drugs such as amphetamines or cocaine. The aim of this work was to develop a specific and accurate method for mephedrone analysis in hair specimens and its application to a large number of samples (n=67). The developed analytical method appears sensitive enough to reveal occasional to regular use of mephedrone., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Conventional chemical profiling of methylamphetamine has long been employed by national forensic laboratories to determine the synthetic route and where possible the precursor chemicals used in its manufacture. This laboratory has been studying the use of stable isotope ratio mass spectrometry (IRMS) analysis as a complementary technique to conventional chemical profiling of fully synthetic illicit drugs such as methylamphetamine. As part of these investigations the stable carbon (δ(13) C), nitrogen (δ(15) N), and hydrogen (δ(2) H) isotope values in the precursor chemicals of ephedrine and pseudoephedrine and the resulting methylamphetamine end-products have been measured to determine the synthetic origins of methylamphetamine. In this study, results are presented for δ(13) C, δ(15) N, and δ(2) H values in methylamphetamine synthesized from ephedrine and pseudoephedrine by two synthetic routes with varying experimental parameters. It was demonstrated that varying parameters, such as stoichiometry, reaction temperature, reaction time, and reaction pressure, had no effect on the δ(13) C, δ(15) N, and δ(2) H isotope values of the final methylamphetamine product, within measurement uncertainty. Therefore the value of the IRMS technique in identifying the synthetic origin of precursors, such as ephedrine and pseudoephedrine, is not compromised by the potential variation in synthetic method that is expected from one batch to the next, especially in clandestine laboratories where manufacture can occur without stringent quality control of reactions., (Copyright © 2011 John Wiley & Sons, Ltd.)

Rationale: The synthesis of a novel chiral derivatisation reagent, (S)-(-)-N-(pentafluorobenzylcarbamoyl)prolyl chloride is described which is preferably useful for negative-ion chemical ionisation mass spectrometry., Methods: Preparation of the reagent followed a general strategy used to prepare enantioselective reagents based on the N-substitution of L-proline. Pentafluorobenzyl chloroformate smoothly reacted with L-proline to give the desired derivatisation reagent after conversion into the acyl chloride. The product was sufficiently pure to be used in the following steps without any additional purification., Results: The reagent was tested against selected chiral and non-chiral analytical targets. Chromatographic enantioseparation was at least equal to the commonly used (S)-(-)-N-(heptafluorobutyryl)prolyl derivatives. The derivatives exhibit excellent mass spectral properties under negative ion chemical ionisation, i.e. reduced fragmentation and thus high ion current for the targeted m/z during analysis. With electron ionisation, the fragmentation that occurs is mainly directed by the introduced group. Enantioseparation with gas chromatography/negative-ion chemical ionisation mass spectrometry of the derivatives was demonstrated for the enantiomers of amphetamine, α-aminocaprylic acid methyl ester and threo-methylphenidate., Conclusions: The new derivatisation reagent shows highly improved mass spectral properties for negative-ion chemical ionisation mass spectrometry and is thus suitable for sensitive chiral detection of amino compounds. The reagent extends the applicability of dissociative resonance electron capture using pentafluorobenzyl derivatives to chiral analysis., (Copyright © 2012 John Wiley & Sons, Ltd.)

Introduction: The use of oral fluid for monitoring drug consumption on roads has many advantages over conventional biological fluids; therefore, several immunoassays have been developed for this purpose. In this work, the ability of 3 commercial immunoassays to detect amphetamine-type stimulants (ATSs) in oral fluid was assessed. In addition, it was reviewed the main controlled ATSs available worldwide, as well as the oral fluid immunological screening tests that have been used for identifying ATSs in drivers., Materials and Methods: The analytical specificity of amphetamine direct enzyme-linked immunosorbent assay (ELISA), methamphetamine direct ELISA (Immunalysis Corporation), and Oral-View saliva multidrug of abuse test (Alfa Scientific Designs) was evaluated using ATS-spiked oral fluid. Legislation and published articles that report the use of immunological screening tests to detect ATS consumption in conductors were reviewed, including the kit's technical information, project reports, police and drug databases., Results and Discussion: Even at high concentrations, the tested assays were not able to detect methylphenidate, fenproporex, or diethylpropion, controlled ATSs legally marketed in many countries., Conclusions: This evidences the need to develop new kits that enable one to control the misuse of prescription ATSs on roads through oral fluid immunoassays.

Human liver microsomes (HLMs) are used to simulate human xenobiotic metabolism in vitro. In forensic and clinical toxicology, HLMs are popularly used to study the metabolism of new designer drugs for example. In this work, we present an automated online extraction system we developed for HLM experiments, which was compared to a classical offline approach. Furthermore, we present studies on the metabolism of 11 cathinones; for eight of these, the metabolism has not previously been reported. Metabolites were identified based on MS(2) and MS(3) scans. Fifty-three substances encompassing various classes of drugs were employed to compare the established offline and the new online methods. The metabolism of each of the following 11 cathinones was studied using the new method: 3,4-methylenedioxy-N-benzylcathinone, benzedrone, butylone, dimethylcathinone, ethylone, flephedrone, methedrone, methylone, methylethylcathinone, naphyrone, and pentylone. The agreement between the offline and the online methods was good; a total of 158 metabolites were identified. Using only the offline method, 156 (98.7%) metabolites were identified, while 151 (95.6%) were identified using only the online method. The metabolic pathways identified for the 11 cathinones included the reduction of the keto group, desalkylation, hydroxylation, and desmethylenation in cathinones containing a methylenedioxy moiety. Our method provides a straightforward approach to identifying metabolites which can then be added to the library utilized by our clinical toxicological screening method. The performance of our method compares well with that of an established offline HLM procedure, but is as automated as possible.