New Designer Drugs.

In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana.

From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC.

Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment.

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

Reinforcing and discriminative-stimulus effects of two pyrrolidine-containing synthetic cathinone derivatives in rats.

The molecular and behavioral aspects of α-pyrrolidinopentiophenone (α-PVP) have been characterized; however, how the structural modification of α-PVP affects its abuse potential is still unknown. In this study, we investigated the abuse potential of two pyrrolidinylated second-generation cathinones:4-chloro-α-pyrrolidinopentiophenone (4cl-α-PVP) and 4-chloro-α-pyrrolidinopropiophenone (4cl-α-PPP). Male Sprague-Dawley rats were trained to self-administer methamphetamine (METH, 0.05 mg·kg-1·infusion-1), α-PVP (0.05 mg·kg-1·infusion-1), 4cl-α-PVP (0.05 mg·kg-1·infusion-1), and 4cl-α-PPP (0.5 mg·kg-1·infusion-1) under a fixed ratio (FR) 1 reinforcement schedule for 10 sessions. The discriminative-stimulus effect of METH (0.8 mg/kg) from saline was tested under an FR10 schedule of food delivery. α-PVP, 4cl-α-PVP and 4cl-α-PPP produced reinforcement behaviors and presented an inverted U-shaped dose effect. The reinforcing potency was displayed with a rank order of α-PVP (0.029 mg·kg-1·infusion-1) > METH (0.040 mg·kg-1·infusion-1) > 4cl-α-PVP (0.094 mg·kg-1·infusion-1) > 4cl-α-PPP (0.51 mg·kg-1·infusion-1). All three drugs were fully substituted for the discriminative-stimulus effects of METH in rats. The substitution potency for discriminative-stimulus effects of α-PVP (ED50 = 0.4 mg/kg) was approximately equal to that of METH (ED50 = 0.3 mg/kg), while the discriminative potency of 4cl-α-PVP (ED50 = 1.0 mg/kg) and 4cl-α-PPP (ED50 = 5 mg/kg) was approximately 3 and 16-fold less than that of METH. The rank order of potency was α-PVP ≈ METH >4cl-α-PVP > 4cl-α-PPP. The present data demonstrated that 4cl-α-PVP and 4cl-α-PPP produced reinforcing effects and fully and dose-dependently substituted for the subjective effects of METH, suggesting that both 4cl-α-PVP and 4cl-α-PPP have abuse potential that may be similar to METH.

MDPV self-administration in female rats: influence of reinforcement history.

RATIONALE: A subset of male rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) have unusually high levels of drug intake; however, factor(s) that influence this behavior (e.g., reinforcement history and sex) are unknown. OBJECTIVES: Characterize the reinforcing potency and effectiveness of MDPV in female rats to determine whether (1) a subset of females also develop high levels of MDPV self-administration (i.e., a high-responder phenotype) and (2) the degree to which the high-responder phenotype is influenced by various reinforcement histories (i.e., responding for cocaine or food). METHODS: Female Sprague Dawley rats initially responded for MDPV (0.032 mg/kg/infusion), cocaine (0.32 mg/kg/infusion), or food (45-mg grain pellet) under fixed ratio (FR) 1 and FR5 schedules of reinforcement. After 20 sessions, the cocaine- and food-history rats responded for MDPV for 20 additional sessions. Dose-response curves for MDPV were generated under FR5 and progressive ratio (PR) schedules of reinforcement. RESULTS: A subset of rats responding for MDPV developed high levels of MDPV intake. A history of responding for cocaine, but not food, inhibited the development of high levels of MDPV intake. Large individual differences were observed in the level of self-administration when MDPV was available under an FR5, but not PR, schedule of reinforcement. CONCLUSIONS: MDPV functions as a powerful reinforcer in female rats, as has been previously reported in male rats. The substantial variability in MDPV self-administration between subjects may be related to individual differences in human drug-taking behavior.

Urinary excretion profile of methiopropamine in mice following intraperitoneal administration: A liquid chromatography-tandem mass spectrometry investigation.

We have considered the urinary excretion profile of methiopropamine (MPA), a thiophene ring-based structural analog of methamphetamine with similar stimulant effects, with the aim of selecting the most appropriate marker(s) of intake that may be useful in forensic analysis. For this purpose, in vitro studies were preliminarily performed on human liver microsomes for tracing the phase I metabolic pathways of MPA, preselecting the best candidates as potential target analytes, and designing the optimal experimental strategy. In vivo studies were then conducted on mice, after the intraperitoneal administration of a 10-mg/kg dose. Urine samples were collected every 3 h in the first 9 h and, subsequently, from 24 to 36 h, and stored at -80°C until further analysis. The measurements were performed using a targeted procedure based on liquid/liquid extraction followed by liquid chromatography-tandem mass spectrometry analysis. Our results show that in the time interval 0-9 h after administration, MPA was extensively oxidized mainly to nor-MPA, oxo-MPA, and two hydroxylated metabolites (ie, hydroxy-aryl-methiopropamine and hydroxy-alkyl-methiopropamine). All phase I metabolites underwent phase II metabolism, with the formation of nor-hydroxy-methiopropamine only in phase II, confirmed by the results obtained after enzymatic hydrolysis with ß-glucuronidase and arylsulfatase. In the time interval 24-36 h after administration, only unchanged MPA and nor-MPA were detected, suggesting that these two markers are those endowed with the highest diagnostic value. The method was validated for these two principal markers, proving to be fit for anti-doping, toxicological, and forensic analyses.

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or Compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools commonly-used to manipulate brain activity. The most widely-used synthetic DREADD ligand, clozapine-N-oxide (CNO), is back-metabolized to clozapine which can itself activate endogenous receptors. Studies in non-DREADD-expressing rodents suggest CNO or a DREADD agonist that lacks active metabolites, such as Compound 21 (C21), change rodent behavior (e.g. decrease locomotion), but chronic injection of CNO does not change locomotion. However, it is unknown if chronic CNO changes behaviors relevant to locomotion, exploration, anxiety, and depression, or if chronic C21 changes any aspect of mouse behavior. Here non-DREADD-expressing mice received i.p. Vehicle (Veh), CNO, or C21 (1 mg/kg) 5 days/week for 16 weeks and behaviors were assessed over time. Veh, CNO, and C21 mice had similar weight gain over the 16-week-experiment. During the 3rd injection week, CNO and C21 mice explored more than Veh mice in a novel context and had more open field center entries; however, groups were similar in other measures of locomotion and anxiety. During the 14th-16th injection weeks, Veh, CNO, and C21 mice had similar locomotion and anxiety-like behaviors. We interpret these data as showing chronic Veh, CNO, and C21 injections given to male non-DREADD-expressing mice largely lack behavioral effects. These data may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists.

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes.

The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neuronal activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for CNS drug delivery and clearance of CNS waste products, including Aß, and for understanding how neuronal activity can modulate diurnal processes.

Designers Drugs-A New Challenge to Emergency Departments-An Observational Study in Poland.

Background and Objective: In the last decade, the phenomenon of using new psychoactive substances (NPS), called designer drugs, has been on rise. Though their production and marketing in Poland is prohibited, reports of the Supreme Audit Office noted that young people are increasingly reaching for new intoxication agents in the form of designer drugs. There is a significant increase in the number of patients with NPS abuse admitted to the emergency departments. As NPS cannot be detected by standard tests for the presence of psychoactive substances, it is difficult to choose the appropriate therapeutic intervention. Therefore, the aim of the present study was to evaluate the patient characteristics in the population of adults and children suspected of using NPS and formulate the protocol for diagnosis and treatment. Materials and Method: The paper is based on a retrospective analysis of medical records of hospitalized patients in the Clinical Emergency Department of The Regional Specialist Hospital in Olsztyn (SKOR WSS, emergency department (ED)) and the Pediatric Emergency Department of the Provincial Specialist Children's Hospital in Olsztyn (SORD WSSD, pediatric emergency department (PED)) between years 2013 to 2018. The patient records related to their general symptoms at admission, mental state and laboratory diagnostic tests were evaluated. Results: The majority of patients hospitalized due to the suspected use of NPS were adolescents in 2013-2016 and a reversal of this trend was observed in 2017-2018 when number of adults admitted to the emergency department (ED) due to NPS use was higher. The NPS abuse was significantly higher among male patients, alcoholics, people using other psychoactive substances, patients suffering from mental disorders and teenagers in difficult socio-economic family situations. Whereas, the most common symptoms among pediatric patients were co-ordination disorder and aggression, in adults mainly tachycardia and aggression was observed. The laboratory tests in significant number of adult patients showed leukocytosis and ketonuria. Conclusions: In the present study, no unambiguous toxidrome or biochemical pattern characteristic for using NPS was observed. However, evaluation of blood morphology, coagulation parameters, liver and kidney function can be helpful in the diagnostic and therapeutic process. Symptomatic treatment of patients, fluid therapy and sedation was sufficient in most cases to resolve the patient symptoms in 48 h.

Analysis of 4-fluoroamphetamine in cerumen after controlled oral application.

Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner. METHODS: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). RESULTS AND DISCUSSION: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen. CONCLUSIONS: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used.

Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice.

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a ß-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.

4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels.

RATIONALE: A high number of synthetic dissociative drugs continue to be available through online stores, leading to their misuse. Recent inclusions in this category are 4-MeO-PCP and 3-MeO-PCMo, analogs of phencyclidine. Although the dissociative effects of these drugs and their recreational use have been reported, no studies have investigated their abuse potential. OBJECTIVES: To examine their rewarding and reinforcing effects and explore the mechanistic correlations. METHODS: We used conditioned place preference (CPP), self-administration, and locomotor sensitization tests to assess the rewarding and reinforcing effects of the drugs. We explored their mechanism of action by pretreating dopamine receptor (DR) D1 antagonist SCH23390 and DRD2 antagonist haloperidol during CPP test and investigated the effects of 4-MeO-PCP and 3-MeO-PCMo on dopamine-related proteins in the ventral tegmental area and nucleus accumbens. We also measured the levels of dopamine, phosphorylated cyclic-AMP response element-binding (p-CREB) protein, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens. Additionally, we examined the effects of both drugs on brain wave activity using electroencephalography. RESULTS: While both 4-MeO-PCP and 3-MeO-PCMo induced CPP and self-administration, only 4-MeO-PCP elicited locomotor sensitization. SCH23390 and haloperidol inhibited the acquisition of drug CPP. 4-MeO-PCP and 3-MeO-PCMo altered the levels of tyrosine hydroxylase, DRD1, DRD2, and dopamine, as well as that of p-CREB, deltaFosB, and BDNF. All drugs increased the delta and gamma wave activity, whereas pretreatment with SCH23390 and haloperidol inhibited it. CONCLUSION: Our results indicate that 4-MeO-PCP and 3-MeO-PCMo induce rewarding and reinforcing effects that are probably mediated by the mesolimbic dopamine system, suggesting an abuse liability in humans.

Self-administration of the synthetic cathinones 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopentiophenone (α-PVP) in rhesus monkeys.

RATIONALE: The availability and abuse of synthetic analogues of cathinone have increased dramatically around the world. Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone [MDPV] and α-pyrrolidinopentiophenone [α-PVP], are cocaine-like inhibitors of monoamine transporters and common constituents of "bath salts" or "flakka" preparations. Studies in rats suggest that MDPV and α-PVP are 3 to 4-fold more effective reinforcers than cocaine; however, comparisons of the relative reinforcing effectiveness of MDPV and α-PVP have not been reported in other species. OBJECTIVES: Accordingly, in the present study, 4 adult male rhesus monkeys responding under a progressive ratio schedule of reinforcement were used to characterize the reinforcing effects of MDPV and α-PVP and to compare directly these effects with those of cocaine and methamphetamine. RESULTS: MDPV was the most potent reinforcer, followed by α-PVP, methamphetamine, and cocaine. α-PVP was the most effective reinforcer, followed by MDPV, cocaine, and methamphetamine. In addition to making more responses to obtain MDPV and α-PVP, monkeys also responded for longer periods of time when MDPV or α-PVP was available compared with when either cocaine or methamphetamine was available for infusion. CONCLUSIONS: These studies confirm recent reports from rodents and provide strong evidence that the synthetic cathinones MDPV and α-PVP are capable of maintaining high levels of responding for prolonged periods of time, and that they function as more effective reinforcers than either cocaine or methamphetamine. The relative strength of these reinforcing effects may account for the high rates of "bath salts" use reported in humans.

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1-butanoyl-d-lysergic acid diethylamide (1B-LSD).

The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One recent addition to this series of LSD analogs is 1-butanoyl-LSD (1B-LSD), a constitutional isomer of 1-propanoyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B-LSD employing nuclear magnetic resonance spectroscopy (NMR), low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B-LSD from 1P-ETH-LAD was straightforward. LSD and other serotonergic hallucinogens induce the head-twitch response (HTR) in rats and mice, which is believed to be mediated largely by 5-HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B-LSD has LSD-like behavioral effects. 1B-LSD produced a dose-dependent increase in HTR counts, acting with ~14% (ED50  = 976.7 nmol/kg) of the potency of LSD (ED50  = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B-LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B-LSD serves as a pro-drug for LSD. Further investigations are warranted to confirm whether 1B-LSD produces LSD-like psychoactive effects in humans.

Pharmacokinetic properties of 4-fluoroamphetamine in serum and oral fluid after oral ingestion.

INTRODUCTION: Each year, synthetic drugs occur in high numbers on the illicit drug market. But data on their pharmacology and toxicology are scarce. Therefore, a controlled study was performed to evaluate pharmacokinetic parameters of 4-fluoroamphetamine (4-FA) in humans and to compare it with effects. METHODS: Twelve subjects ingested 100 mg and five subjects also received 150 mg 4-FA in a bitter lemon drink. Blood and oral fluid samples were taken during the following 12 hours and analyzed for 4-FA and traces of amphetamine as impurity by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: For 12 hours after ingestion, the concentration-time course of 4-FA was similar to that of amphetamine with maximal concentrations appearing in serum after about 2 hours (in median 195 ng/mL after the 100 mg dose, range 155-316 ng/mL). The elimination half-life was approximately 8-9 hours and shorter than that of amphetamine but it exhibited a marked variation (5.5-16.8 hours). In oral fluid, 4-FA could also be detected for 12 hours and concentrations were higher than in serum. During the first 3 hours after ingestion concentrations were higher, most probably due to oral contamination. Serum concentrations in forensic cases were in the range of those observed in the present study suggesting dosages in recreational use in the range of those tested here. CONCLUSIONS: The pharmacokinetic properties of 4-FA are similar to that of amphetamine including a marked variation in elimination. However, recreational dosages may already exhibit prominent adverse effects and may even have life-threatening consequences.

Practical Considerations for the Use of DREADD and Other Chemogenetic Receptors to Regulate Neuronal Activity in the Mammalian Brain.

Chemogenetics is the process of genetically expressing a macromolecule receptor capable of modulating the activity of the cell in response to selective chemical ligand. This chapter will cover the chemogenetic technologies that are available to date, focusing on the commonly available engineered or otherwise modified ligand-gated ion channels and G-protein-coupled receptors in the context of neuromodulation. First, we will give a brief overview of each chemogenetic approach as well as in vitro/in vivo applications, then we will list their strengths and weaknesses. Finally, we will provide tips for ligand application in each case.Each technology has specific limitations that make them more or less suitable for different applications in neuroscience although we will focus mainly on the most commonly used and versatile family named designer receptors exclusively activated by designer drugs or DREADDs. We here describe the most common cases where these can be implemented and provide tips on how and where these technologies can be applied in the field of neuroscience.

"Not for Human Consumption": A Descriptive Investigation into User Characteristics, Motives, and Consequences Associated with Bath Salt Use.

Synthetic cathinones, commonly referred to as "bath salts," are recreational designer drugs that recently emerged as a drug of abuse. However, little is known about bath salt users, particularly in the United States (US). This descriptive study aims to better characterize users and user behavior, including common motives for and consequences of use. Individuals with a lifetime history of bath salt use (BSU; n = 110) completed an Internet survey. Participants (50.9% male) were aged 18 to 58 (M = 31.21, SD = 10.25) years and were from 32 US states. Most participants reported past-year BSU, via intranasal use, obtained from a friend or acquaintance. Recreational motives (e.g., to get high, experimentation) were commonly reported, as was use due to drug availability. Participants reported experiencing an average of 5.50 consequences, with both physical (e.g., rapid heartbeat) and psychological (e.g., anxiety) negative outcomes commonly reported. This descriptive information on BSU from a small but diverse sample of users may inform efforts to reduce use and negative consequences, such as eliminating riskier routes of administration (e.g., injection) and targeting specific motives for use (e.g., providing alternative methods for mood expansion).

Acute and chronic neurobehavioral effects of the designer drug and bath salt constituent 3,4-methylenedioxypyrovalerone in the rat.

BACKGROUND: The substantial increase in use of 3,4-methylenedioxypyrovalerone (MDPV), a popular recreational synthetic cathinone, has raised legitimate questions about its behavioral consequences and abuse liability. AIMS: The aim of this study was to study MDPV-induced neurobehavioral effects in the rat, using different paradigms traditionally developed to study drug-attributed addictive properties. METHODS: Different patterns of intraperitoneal 3 mg/kg MDPV administration were investigated. Consequences on rat horizontal locomotion and behavior of acute, intermittent (once daily dosing over 10 days), and binge (three-time daily dosing for 3 days) MDPV administration as well as challenge after 10 day MDPV withdrawal were studied. The dopamine receptor-D1 antagonist, SCH23390, was bilaterally infused in the nucleus accumbens to determine the role of D1-receptors in MDPV-related effects on the associative memory recall using the conditioned place preference paradigm. In addition, in a separate experience using western blot, we investigated the effects of chronic MDPV administration (four injections during 24 h) on ΔFosB expression in the nucleus accumbens, caudate putamen, and prefrontal cortex. RESULTS: Acute MDPV administration increased stereotypies and open arm entries in the elevated plus maze while SCH23390 abolished MDPV-induced enhancing effects on memory consolidation. Intermittent MDPV administration resulted in sensitization of MDPV-induced locomotor effects and tolerance during the following challenge. With binge MDPV administration, locomotor activity was not altered despite tolerance onset after challenge. SCH23390 abolished MDPV-induced conditioned place preference. Chronic MDPV administration induced ΔFosB accumulation in the nucleus accumbens, caudate putamen, and prefrontal cortex. CONCLUSIONS: Our findings clearly show that MDPV produces profound behavioral alterations mediated by the activation of the dopaminergic system similarly to other amphetamines.