Drosophila learning and memory centers and the actions of drugs of abuse.

Drug addiction and the circuitry for learning and memory are intimately intertwined. Drugs of abuse create strong, inappropriate, and lasting memories that contribute to many of their destructive properties, such as continued use despite negative consequences and exceptionally high rates of relapse. Studies in Drosophila melanogaster are helping us understand how drugs of abuse, especially alcohol, create memories at the level of individual neurons and in the circuits where they function. Drosophila is a premier organism for identifying the mechanisms of learning and memory. Drosophila also respond to drugs of abuse in ways that remarkably parallel humans and rodent models. An emerging consensus is that, for alcohol, the mushroom bodies participate in the circuits that control acute drug sensitivity, not explicitly associative forms of plasticity such as tolerance, and classical associative memories of their rewarding and aversive properties. Moreover, it is becoming clear that drugs of abuse use the mushroom body circuitry differently from other behaviors, potentially providing a basis for their addictive properties.

Molecular insights into GPCR mechanisms for drugs of abuse.

Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity.

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

Genotoxicological Characterization of (±)cis-4,4'-DMAR and (±)trans-4,4'-DMAR and Their Association.

The novel psychoactive substance (NPS) 4-Methyl-5-(4-methylphenyl)-4,5-dihydroxazol-2-amine (4,4'-DMAR) shows psychostimulant activity. Data on the acute toxicity of 4,4'-DMAR are becoming increasingly available, yet the long-term effects are still almost unknown. In particular, no data on genotoxicity are available. Therefore, the aim of the present study was to evaluate its genotoxic potential using the "In Vitro Mammalian Cell Micronucleus Test" (MNvit) on (±)cis-4,4'-DMAR and (±)trans-4,4'-DMAR and their associations. The analyses were conducted in vitro on human TK6 cells. To select suitable concentrations for MNvit, we preliminarily evaluated cytotoxicity and apoptosis. All endpoints were analysed by flow cytometry. The results reveal the two racemates' opposite behaviours: (±)cis-4,4'-DMAR shows a statistically significant increase in micronuclei (MNi) frequency that (±)trans-4,4'-DMAR is completely incapable of. This contrast confirms the well-known possibility of observing opposite biological effects of the cis- and trans- isomers of a compound, and it highlights the importance of testing single NPSs that show even small differences in structure or conformation. The genotoxic capacity demonstrated stresses an additional alarming toxicological concern related to this NPS. Moreover, the co-treatments indicate that consuming both racemates will magnify the genotoxic effect, an aspect to consider given the unpredictability of illicit drug composition.

Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia.

Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.

New/emerging psychoactive substances and associated psychopathological consequences.

BACKGROUND: The present paper provides an updated review of both the large number of new/novel/emerging psychoactive substances (NPS) and their associated psychopathological consequences. Focus was here given on identification of those NPS being commented in specialised online sources and the related short-/long-term psychopathological and medical ill-health effects. METHODS: NPS have been identified through an innovative crawling/navigating software, called the 'NPS.Finder®', created in order to facilitate the process of early recognition of NPS online. A range of information regarding NPS, including chemical and street names; chemical formula; three-dimensional image and anecdotally reported clinical/psychoactive effects, were here made available. RESULTS: Using the 'NPS.Finder®' approach, a few thousand NPS were here preliminarily identified, a number which is about 4-fold higher than those figures suggested by European and international drug agencies. NPS most commonly associated with the onset of psychopathological consequences included here synthetic cannabinoids/cannabimimetics; new synthetic opioids; ketamine-like dissociatives; novel stimulants; novel psychedelics and several prescription and over-the-counter medicines. CONCLUSIONS: The ever-increasing changes in terms of recreational psychotropics' availability represent a relatively new challenge for psychiatry, as the pharmacodynamics and pharmacokinetics of many NPS have not been thoroughly understood. Health/mental health professionals should be informed about the range of NPS; their intake modalities; their psychoactive sought-after effects; the idiosyncratic psychotropics' combinations and finally, their medical and psychopathological risks.

An updated review on synthetic cathinones.

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a ß-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.

Naphyrone (naphthylpyrovalerone): Pharmacokinetics, behavioural effects and thermoregulation in Wistar rats.

Naphthylpyrovalerone (naphyrone) is a pyrovalerone cathinone that potently inhibits monoamine transporters and provides stimulatory-entactogenic effects. Little is known about the safety of naphyrone or its effects in vivo, and more research is needed to acquire knowledge about its fundamental effects on physiology and behaviour. Our objective was to investigate naphyrone's pharmacokinetics, acute toxicity, hyperthermic potential and stimulatory and psychotomimetic properties in vivo in male Wistar rats. Pharmacokinetics after 1 mg/kg subcutaneous (sc.) naphyrone were measured over 6 h in serum, the brain, liver and lungs. Rectal temperature (degree Celsius) was measured over 10 h in group-versus individually housed rats after 20 mg/kg sc. In the behavioural experiments, 5, 10 or 20 mg/kg of naphyrone was administered 15 or 60 min prior to testing. Stimulation was assessed in the open field, and sensorimotor processing in a prepulse inhibition (PPI) task. Peak concentrations of naphyrone in serum and tissue were reached at 30 min, with a long-lasting elevation in the brain/serum ratio, consistent with observations of lasting hyperlocomotion in the open field and modest increases in body temperature. Administration of 20 mg/kg transiently enhanced PPI. Naphyrone crosses the blood-brain barrier rapidly and is eliminated slowly, and its long-lasting effects correspond to its pharmacokinetics. No specific signs of acute toxicity were observed; therefore, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.

Can emergency department clinicians diagnose gamma-hydroxybutyrate (GHB) intoxication based on clinical observations alone?

OBJECTIVES: Gamma-hydroxybutyrate (GHB) is a drug of abuse with central depressing effects, which may cause coma with a GCS score as low as 3. A rapid diagnosis 'GHB intoxication' may prevent unnecessary diagnostic work-up and may lead to guided, less invasive, treatment. The aim of this study was to evaluate if ED physicians' clinical evaluation were sufficient for diagnosis in patients with suspected GHB-intoxication. METHODS: Patients presenting at the ED with a GCS<15 and a potential intoxication with drugs of abuse for whom urine toxicology screen was performed were included consecutively. After a first assessment, the ED physician registered the most likely initial diagnosis in the hospital information system. Urine of these patients was tested with a validated gas chromatography analytical method for GHB (confirmation test). The initial diagnoses were compared for agreement with the results of the confirmation test. RESULTS: A total of 506 patients were included, 100 patients tested positive for GHB and 406 patients tested negative for GHB. Sensitivity and specificity of the ED physicians compared with the confirmation test to diagnose GHB intoxications were 63% (95% CI 52 to 73) and 93% (95% CI 90 to 95), respectively. The positive predictive value was 67% (95% CI 60 to 77) and the negative predictive value was 92% (95% CI 88 to 94). CONCLUSION: Physicians underestimate the presence of GHB intoxication and can fail to diagnose GHB intoxication based on clinical observations alone. In the future, a rapid reliable initial analytical GHB test in addition to clinical judgement could be valuable to reduce false negative diagnosis.

Metabolic effects of repeated ketamine administration in the rat brain.

Ketamine is a popular recreational drug used in club and dance music settings. Evidence suggests that chronic or repeated ketamine use could induce neurological and psychological harm, while the mechanisms underlying ketamine's effects on the nervous system are still unclear. The aim of this study was to explore the metabolic changes that occur in the prefrontal cortex (PFC), hippocampus (Hip) and striatum of rats with repeated ketamine exposure and withdrawal intervention and to identify the potential metabolic pathways influenced by ketamine. An untargeted ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS)-based metabolomics method coupled with multivariate and univariate statistical analysis was applied to analyze the metabolic profiles of the PFC, Hip, and striatum and to identify metabolite alterations. The pathway analysis tool in MetaboAnalyst was subsequently applied for pathway predictions. A total of 79, 54 and 58 changed metabolites were identified in the PFC, Hip and striatum, respectively, after repeated ketamine exposure. Pathway analysis indicated that purine metabolism and glycerophospholipid metabolism were the main pathways disturbed by ketamine in all three brain regions. After one week of withdrawal intervention, most changed metabolites in the Hip and striatum had been restored to control levels, while the metabolite alterations in the PFC were persistent. These results revealed that repeated ketamine exposure significantly changed purine metabolism and glycerophospholipid metabolism in the PFC, Hip and striatum, which might be involved in the neurotoxic effects of ketamine. Additionally, this study also identified that the PFC, rather than the Hip or striatum, was more likely to be the target region of the long-term effects of ketamine.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.

In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances.

The landscape of new psychoactive substances (NPS) is constantly evolving, with new compounds entering the illicit drug market at a continuous pace. Of these, opioid NPS form a threat given their high potency and prevalence. Whereas previously, the use of fentanyl and fentanyl derivatives was the main point of attention, legislations have reacted accordingly, which may have been a driving force towards the (ab)use of alternative µ-opioid receptor (MOR) agonists. In contrast to fentanyl (analogues), details on these novel non-fentanyl opioid NPS are scarce. We investigated the biological activity of a panel of 11 'alternative', newly emerging MOR agonists (2-methyl-AP-237, AP-237, bromadol, brorphine, butorphanol, isotonitazene, mitragynine, 7-OH-mitragynine, MT-45, piperidylthiambutene, and tianeptine) using two closely related in vitro MOR activation bio-assays, monitoring either G protein (mini-Gi), or ß-arrestin2 (ßarr2) recruitment. Activity profiles were obtained for all tested compounds, with values for potency (EC50) ranging from 1.89 nM (bromadol) to > 3 µM (AP-237 and tianeptine). Bromadol, brorphine, isotonitazene, piperidylthiambutene, and tianeptine had the highest efficacy (Emax) values, exceeding that of the reference compound hydromorphone ≥ 1.3-fold (ßarr2 assay) and > 2.6-fold (mini-Gi assay). Information on the recruitment of two distinct signaling molecules additionally enabled evaluation of biased agonism; none of the evaluated opioids being significantly biased. Taken together, this study is the first to systematically investigate the in vitro biological activity of a diverse panel of emerging non-fentanyl opioid NPS at MOR. Given the known danger of (fatal) intoxications with many opioid NPS, it is important to continuously monitor and characterize newly emerging compounds.

Synthetic cannabinoids and their impact on neurodevelopmental processes.

Cannabinoids comprise a broad group of psychoactive substances that activate endogenous cannabinoid (EC) receptors (ie, CB1 R and CB2 R), altering neurotransmitter release in the brain. The importance of their regulatory role in different biological processes has prompted the development of synthetic cannabinoids (SCs), substantially more potent than tetrahydrocannabinol (THC, the main psychoactive substance of cannabis). Although SCs were primarily designed given their therapeutic applications, their recreational use has become a major public health concern due to several reports of severe intoxications and deaths. SCs have favored increased popularity over recent years due to their intensified psychoactive effects, compared with THC, turning regular cannabis users into SCs. Among cannabinoid users (mainly young people), pregnant women and women of child-bearing potential (WoCBP) comprise particular risk groups, due to the potential onset of neurodevelopment disorders in the offspring (eg, schizophrenia and autism spectrum disorders). Understanding the role played by cannabinoids, and the potential action of emerging SCs in the regulation of the neuronal function, especially during neuronal development, thus assumes critical relevance. Here, we review the mechanistic regulation of neuronal processes, namely during neuronal development, by the endocannabinoid system. Most important, we further develop on the potential of SCs to modulate such mechanisms and subsequently disrupt proper neurodevelopment.

Determining the Roles that Club Drugs, Marijuana, and Heavy Drinking Play in PrEP Medication Adherence Among Gay and Bisexual Men: Implications for Treatment and Research.

Researchers have established that substance use interferes with anti-retroviral medication adherence among gay and bisexual men (GBM) living with HIV. There is limited parallel examination of pre-exposure prophylaxis (PrEP) adherence among HIV-negative GBM. We conducted retrospective 30-day timeline follow-back interviews and prospective semi-weekly diary data for 10 weeks with 104 PrEP-using GBM, half of whom engaged in club drug use (ketamine, ecstasy, GHB, cocaine, or methamphetamine)-generating 9532 days of data. Participants reported their day-by-day PrEP, club drug, marijuana, and heavy alcohol use (5 + drinks in one sitting). On average, club drug users were no more likely to miss a dose of PrEP than non-club drug users (M = 1.6 doses, SD = 3.0, past 30 days). However, we found that club drug use (at the event level) increased the odds of missing a dose on the same day by 55% and the next day (e.g., a "carryover effect") by 60%. Further, missing a dose on one day increased the odds of missing a dose the following day by eightfold. We did not identify an event-level effect of marijuana use or heavy drinking on PrEP adherence. Our data suggest club drug users could have greater protective effects from daily oral or long-acting injectable PrEP compared to a time-driven PrEP regimen because of the concurrence of club drug use and PrEP non-adherence.

Accurate and sensitive determination of sildenafil, tadalafil, vardenafil, and avanafil in illicit erectile dysfunction medications and human urine by LC with quadrupole-TOF-MS/MS and their behaviors in simulated gastric conditions.

The widespread use of phosphodiesterase-5 inhibitors has attracted broad attention of counterfeiters to develop illicit erectile products with inaccurate amounts, unknown toxicity, and purity of active ingredients. Correspondingly, intake of these products endangers consumer health and needs to be screened for precautionary actions to reduce this risk. Therefore, in this study, a sensitive and rapid analytical method has been developed for simultaneous determination of selected phosphodiesterase-5 inhibitors present in illicit erectile medications and human urine. Quantification of the analytes was performed by liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry system. The chromatographic separation was successfully achieved with a run period of 8 min. Low detection limits were obtained in the range of 1.63-9.81 ng/g with relative standard deviations below 7.72% obtained using the replicate measurements of lowest concentration in calibration plots. The analytical performance of the proposed method proved good linearity, low detection limits, good accuracy and precision with high percent recoveries for human urine samples. Developed method was successfully applied to real samples including four different brands of illicit erectile medications. The results obtained revealed the presence of high levels of sildenafil in analyzed samples. The behaviors of selected phosphodiesterase-5 inhibitors were also studied in simulated gastric conditions.

Chasing the rainbow: pleasure, sex-based sociality and consumerism in navigating and exiting the Irish Chemsex scene.

Club drug use among gay, bisexual and other men who have sex with men is increasingly normalised within sexual contexts and is associated with increased sexual risk behaviours. The term Chemsex is used to describe sexualised drug use lasting several hours or days with multiple sexual partners. A small pilot study, underpinned by interpretative phenomenological analysis (IPA), was conducted in Dublin, Ireland. Interviews were conducted with 10 men who were experiencing physical and emotional health problems as a consequence of their participation in sexualised drug use and wished to exit the Chemsex scene. Interviews explored experiences of sexualised drug use, motives to partake, the organisation of Chemsex parties and group connectivity, drugs used, harm reduction, pleasure and consequences of participation over time. Four basic themes emerged from the analysis: social and cyber arrangements within the Dublin Chemsex scene; poly drug use and experiences of drug dependence; drug and sexual harm reduction within the Chemsex circle of novices and experts; and sexualised drug use, escapism and compulsive participation. Two higher-order themes were also apparent: first, the reinforcing aspects of drug and sexual pleasure; and second, the interplay between excess drug consumption and sex, and drug dependence.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Recreational Drug Use, Polydrug Use and Sexual Behaviors Among Men Who Have Sex With Men in Southwestern China: A Cross-Sectional Study.

Although recreational drug use is associated with risky sexual behaviors and HIV infection among men who have sex with men (MSM), it is unclear to what extent these behaviors and outcomes differ between single-drug users and polydrug users in China. This is a cross-sectional study conducted from July to September 2016 among MSM in three cities of Sichuan Province, China. Multinomial logistic regression was performed to examine factors correlated with single-drug and polydrug use. A total of 1,122 participants were included in the study. Overall, 28% of MSM have ever used recreational drugs, of whom 64.0% were single-drug users, and 36.0% were polydrug users. Factors associated with both single-drug and polydrug use included: receptive sexual role (single-drug use: AOR = 1.79, 95% CI: 1.05-3.07; polydrug use: AOR = 6.00, 95% CI: 2.54-14.17), engaging in group sex (AOR = 2.23, 95% CI: 1.28-3.87; AOR = 4.68, 95% CI: 2.41-9.08), frequent alcohol use (AOR = 3.11, 95% CI: 1.75-5.52; AOR = 6.41, 95% CI: 2.50-16.47), seeking partners mainly by Internet (AOR = 4.87, 95% CI: 3.31-7.17; AOR = 4.58, 95% CI: 2.58-8.14), history of STIs (AOR = 1.86, 95% CI: 1.08-3.21; AOR = 3.32, 95% CI: 1.77-6.26) and HIV infection (AOR = 1.76, 95% CI: 1.02-3.02; AOR = 3.19, 95% CI: 1.62-6.26). Our findings suggest the urgent need for HIV and STIs prevention programs among MSM in China to integrate strategies that mitigate recreational drug use.

Kratom: Implications for Health Care Providers.

Kratom is an herbal drug originating from the Mitragyna speciosa, a plant indigenous to Southeast Asia. Kratom has been widely used for its stimulant and opioid-like effects derived from its main psychoactive alkaloid properties mitragynine and 7-hydroxymitragynine. In the United States, kratom is gaining popularity as an herbal and natural dietary supplement, as well as a natural and legal alternative to narcotics. Kratom use is typically accompanied by increasing tolerance and dependence making it highly problematic. Kratom's potentially toxic and lethal properties have become an emerging public health threat. Due to deficiencies of governmental controls and its rising prevalence among individuals who ingest kratom, health care providers need to be familiar with the pharmacology, adverse effects, and problems associated with kratom ingestion when caring for individuals. [Journal of Psychosocial Nursing and Mental Health Services, 57(12), 15-20.].

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects.

New psychoactive substances (NPS), often referred as 'legal highs' or 'designer drugs', are derivatives and analogs of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. This work aims to review the state-of-the-art regarding chemical, molecular pharmacology, and in vitro and in vivo data on toxicokinetics of the potent synthetic cathinone α-pyrrolidinovalerophenone (α-PVP or flakka or zombie drug). Chemical, pharmacological, toxicological, and clinical effects of α-PVP were searched in PubMed (U.S. National Library of Medicine) and governmental websites without limitation of the period. α-PVP is a wide spread and easy to get special type of synthetic cathinone with seemingly powerful cocaine-like stimulant effects, high brain penetration, high liability for abuse and with increased risk of adverse effects such as tachycardia, agitation, hypertension, hallucinations, delirium, mydriasis, self-injury, aggressive behavior, and suicidal ideations. α-PVP undergoes extensive metabolism via different pathways and the α-PVP itself or its metabolites ß-hydroxy-α-PVP and α-PVP lactam represent the main targets for toxicological analysis in urine. There is a limited knowledge regarding the short- and long-term effects of α-PVP and metabolites, and pharmacogenetic influence, hence further clinical and forensic toxicological studies are required. Moreover, since α-PVP cannot be detected with classic routine analysis procedures, statements on the frequency of their consumption cannot be made.