Alterations in the fecal microbiota of methamphetamine users with bad sleep quality during abstinence.

BACKGROUND: Methamphetamine (MA) abuse has resulted in a plethora of social issues. Sleep disturbance is a prominent issue about MA addiction, which serve as a risk factor for relapse, and the gut microbiota could play an important role in the pathophysiological mechanisms of sleep disturbances. Therefore, improving sleep quality can be beneficial for treating methamphetamine addiction, and interventions addressing the gut microbiota may represent a promising approach. METHOD: We recruited 70 MA users to investigate the associations between sleep quality and fecal microbiota by the Pittsburgh Sleep Quality Index (PSQI), which was divided into MA-GS (PSQI score < 7, MA users with good sleep quality, n = 49) and MA-BS group (PSQI score ≥ 7, MA users with bad sleep quality, n = 21). In addition, we compared the gut microbiota between the MA-GS and healthy control (HC, n = 38) groups. 16S rRNA sequencing was applied to identify the gut bacteria. RESULT: The study revealed that the relative abundances of the Thermoanaerobacterales at the order level differed between the MA-GS and MA-BS groups. Additionally, a positive correlation was found between the relative abundance of the genus Sutterella and daytime dysfunction. Furthermore, comparisons between MA users and HCs revealed differences in beta diversity and relative abundances of various bacterial taxa. CONCLUSION: In conclusion, the study investigated alterations in the gut microbiota among MA users. Furthermore, we demonstrated that the genus Sutterella changes may be associated with daytime dysfunction, suggesting that the genus Sutterella may be a biomarker for bad sleep quality in MA users.

"Everything is kind of the same except my mind is with me": exploring cannabis substitution in a sample of adults in early recovery from an opioid or stimulant addiction.

BACKGROUND: Recovery from addiction is frequently equated with abstinence. However, some individuals who resolve an addiction continue to use substances, including via substitution (i.e., increased use of one substance after eliminating/ reducing another). Substitution may play a distinct role during early recovery (≤ 1 year), as this period is marked by dramatic change and adjustment. Cannabis is one of the most used substances and is legal for medical and recreational use in an increasing number of states. Consequently, cannabis an increasingly accessible substitute for substances, like fentanyl, heroin, cocaine and methamphetamine, with higher risk profiles (e.g., associated with risk for withdrawal, overdose, and incarceration). METHODS: Fourteen participants reported that they had resolved a primary opioid or stimulant addiction and subsequently increased their cannabis use within the previous 12 months. Using grounded theory, the interviewer explored their experiences of cannabis use during early recovery. Data were analyzed in three stages: line by line coding for all text related to cannabis use and recovery, focused coding, and axial coding to generate a theory about recovery with cannabis substitution. The motivational model of substance use provided sensitizing concepts. RESULTS & DISCUSSION: The final sample included eight men and six women ranging in age from 20 to 50 years old. Three participants resolved an addiction to methamphetamine and the remaining 11, an addiction to opioids. Participants explained that cannabis was appealing because of its less harmful profile (e.g., no overdose risk, safe supply, few side effects). Participants' primary motives for cannabis use included mitigation of psychiatric symptoms, withdrawal/ cravings, and boredom. While cannabis was effective toward these ends, participants also reported some negative side effects (e.g., decreased productivity, social anxiety). All participants described typical benefits of recovery (e.g., improved self-concept, better relationships) while continuing to use cannabis. Their experiences with and beliefs about substitution suggest it can be an effective strategy for some individuals during early recovery. CONCLUSIONS: Cannabis use may benefit some adults who are reducing their opioid or stimulant use, especially during early recovery. The addiction field's focus on abstinence has limited our knowledge about non-abstinent recovery. Longitudinal studies are needed to understand the nature of substitution and its impact on recovery over time.

Motivation and context of concurrent stimulant and opioid use among persons who use drugs in the rural United States: a multi-site qualitative inquiry.

BACKGROUND: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings. METHODS: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use. RESULTS: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment. CONCLUSION: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes.

Effects of Aerobic Exercise Combined With Attentional Bias Modification in the Care of Male Patients With a Methamphetamine Use Disorder.

OBJECTIVE: It remains unclear which individual or combined strategies are most beneficial for methamphetamine use disorders (MUDs). We compared the effects of aerobic exercise, attentional bias modification, and combined intervention on male patients with MUD. METHOD: One hundred male patients with MUD were randomly assigned to combined intervention, aerobic exercise, attentional bias modification, or control groups (25 patients per group). The 8-week intervention protocol included three 60-minute sessions of aerobic exercises per week. Primary outcomes included high- and low-frequency heart rate variability, executive function, and cardiorespiratory fitness measured by customized software, computerized tests, and the Harvard step test, respectively. Secondary outcomes included psychiatric symptoms, drug craving, training acceptability, and persistence. RESULTS: Participant characteristics were matched between groups at baseline. Executive function, heart rate variability, cardiorespiratory fitness, drug craving, and most psychiatric symptoms had significant time-group interactions at posttest (p < .05, η2 = .08-.28). Compared with the attentional bias modification and control groups, the combined intervention and aerobic exercise groups improved significantly in executive function, heart rate variability, cardiorespiratory fitness, and most secondary outcomes. In addition, high-frequency heart rate variability and cardiorespiratory fitness in the aerobic exercise group were significantly higher than those in the combined intervention group. CONCLUSIONS: Combination strategies showed comparable efficacy to aerobic exercise alone in improving executive function, psychiatric symptoms, and drug craving and significantly exceeded other conditions. For heart rate variability and cardiorespiratory fitness, aerobic exercise alone was the most effective. For acceptability and persistence, combination strategies were preferred over single-domain training and health education intervention.

High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats.

Drug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.

An electrochemical aptasensor for methylamphetamine rapid detection by single-on mode based on competition with complementary DNA.

A simple and rapid electrochemical sensing method with high sensitivity and specificity of aptamers was developed for the detection of methylamphetamine (MAMP). A short anti-MAMP thiolated aptamer (Apt) with a methylene blue (MB) probe at 3'-end was immobilized on the surface of a gold electrode (MB-Apt-S/GE). The electrochemical signal appeared when MAMP presenting in the sample solution competed with cDNA for binding with MB-Apt-S. Under optimized conditions, the liner range of this signal-on electrochemical aptasensor for the detection of MAMP achieved from 1.0 to 10.0 nmol/L and 10.0-400 nmol/L. LOD 0.88 nmol/L were obtained. Satisfactory spiked recoveries of saliva and urine were also obtained. In this method, only 5 min were needed to incubate before the square wave voltammetry (SWV) analysis, which was much more rapid than other electrochemical sensors, leading to a bright and broad prospect for the detection of MAMP in biological sample. This method can be used for on-site rapid detection on special occasions, such as drug driving scenes, entertainment venues suspected of drug use, etc.

Drogas de abuso asociadas a las intoxicaciones agudas: descripción global y análisis de las diferencias en mujeres atendidas en el servicio de urgencias / Street drugs associated with acute poisoning: description and analysis of differences in women attended in a hospital emergency department

Objetivos. La prevalencia del uso de drogas de abuso es difícil de establecer en mujeres, debido a los estigmas asociados a ello. El objetivo principal fue analizar las posibles diferencias de las intoxicaciones agudas (IA) según el sexo en una muestra de pacientes atendidos en dos servicios de urgencias hospitalarios (SUH). El objetivo secundario fue identificar las variables asociadas a las intoxicaciones graves, definidas de forma arbitraria como las que requerían una atención intensiva médica de más de 12 horas y posterior ingreso hospitalario. Métodos. Estudio retrospectivo en dos SUH que incluyeron pacientes mayores de 18 años atendidos por IA por drogas de abuso, en el periodo comprendido entre el 1 de julio 2020 y el 31 de julio 2023. Se recogieron variables epidemiológicas, clínicas y de laboratorio. Resultados. Se incluyeron 1.032 pacientes, un 18,5% (191) mujeres. La edad media fue de 35 (DE 10) años, con elevada prevalencia de enfermedad mental aguda (32,2%) e infección por VIH (35,7%). El principal motivo de consumo fue lúdico (90,9%). Las principales drogas de abuso fueron cocaína, alcohol y metanfetaminas. El análisis multivariado mostró que únicamente la edad (OR: 1,03, IC 95%: 1,01-1,05, p = 0,003), el VIH (OR: 2,10, IC 95%: 1,29-3,41, p = 0,003), el consumo de benzodiacepinas (OR: 3,48, IC 95%: 2,14-5,66, p < 0,0001), y la ideación autolítica (OR: 1,82, IC 95%: 1,25-3,79, p = 0,004), se asociaron a gravedad de la intoxicación. Conclusiones. Las IA por drogas de abuso en mujeres presentan algunas diferencias en relación a las de los hombres, ya que son más jóvenes y asocian consumo de alcohol con mayor frecuencia. Las campañas de prevención y políticas sanitarias sobre el uso de sustancias deberían tener en cuenta las diferencias en el consumo según el sexo para adaptarlas a la población a las que vayan dirigidas. (AU)

Background. The prevalence of street drug abuse is difficult to establish in women because of stigma associated withthe practice. The main objective of this study was to analyze possible differences between men and women in a sample of patients attended for emergencies due to acute poisonings. The secondary aim was to identify variables associated with severe poisonings defined arbitrarily as requiring intensive care for more than 12 hours after hospital admission. Methods. Retrospective study in 2 hospital EDs. We included patients over the age of 18 years attended for street drug poisonings between July 1, 2020, and July 31, 2023. Epidemiologic, clinical, and laboratory variables were analyzed. Results. A total of 1032 patients were studied; 191 (18.5%) were women. The mean (SD) age was 35 years, and the prevalences of acute mental illness and HIV infection were high at 32.2% and 35.7%, respectively. Drug use was recreational in most cases (90.9%). Cocaine, alcohol, and methamphetamines were the substances most often used. Multivariate analysis showed that the factors associated with the seriousness of poisoning were age, with an odds ratio (OR) of 1.03 (95% CI, 1.01-1.05; P = .003); HIV (OR, 2.10; 95% CI, 1.29-3.41; P = .003); use of benzodiazepines (OR, 3.48; 95% CI, 2.14-5.66; P < .0001); and suicidal ideations (OR, 1.82; 95% CI, 1.25-3.79; P = .004). Conclusions. Differences in poisoning characteristics in women were found, probably related to the younger ages of men in the sample and their higher frequency of alcohol consumption. Public health policies and campaigns to prevent drug abuse should take gender differences into consideration in order to adapt messages to the target populations. (AU)

Moderate Salinity Stress Affects Rice Quality by Influencing Expression of Amylose- and Protein-Content-Associated Genes.

Salinity is an environmental stress that severely impacts rice grain yield and quality. However, limited information is available on the molecular mechanism by which salinity reduces grain quality. In this study, we investigated the milling, appearance, eating and cooking, and nutritional quality among three japonica rice cultivars grown either under moderate salinity with an electrical conductivity of 4 dS/m or under non-saline conditions in a paddy field in Dongying, Shandong, China. Moderate salinity affected rice appearance quality predominantly by increasing chalkiness rate and chalkiness degree and affected rice eating and cooking and nutritional quality predominantly by decreasing amylose content and increasing protein content. We compared the expression levels of genes determining grain chalkiness, amylose content, and protein content in developing seeds (0, 5, 10, 15, and 20 days after flowering) of plants grown under saline or non-saline conditions. The chalkiness-related gene Chalk5 was up-regulated and WHITE-CORE RATE 1 was repressed. The genes Nuclear factor Y and Wx, which determine amylose content, were downregulated, while protein-content-associated genes OsAAP6 and OsGluA2 were upregulated by salinity in the developing seeds. These findings suggest some target genes that may be utilized to improve the grain quality under salinity stress conditions via gene-pyramiding breeding approaches.

Modeling methamphetamine use disorder in mammals: Sex differences in behavioral, biochemical, and transcriptional consequences.

Methamphetamine (METH) is the most commonly misused amphetamine-type stimulant throughout the globe. METH is very rewarding, and its misuse can lead to a diagnosis of METH use disorder (MUD). Although METH use is observed in both sexes, there are, however, reported differences in the clinical manifestations of METH use and its consequences. These observations indicate the need for more research on the long-term sex-dependent consequences of METH taking in both preclinical and clinical settings. In effect, sex is a biological variable that can impact conclusions drawn from various basic and clinical studies. Thus, the present chapter provides a succinct review of the current state of the research on METH and its sex-associated consequences. In addition to behavioral and cognitive aspects of METH use, we discuss METH-induced changes in neurotransmitter systems and structures in the brain. Thus, the book chapter serves to highlight the significance of sex as a critical element that needs to be considered during discussions of novel therapeutic approaches to MUD.

The role of sex and drug use during adolescence in determining the risk for adverse consequences of amphetamines.

Use of amphetamines during adolescence, a critical period of brain development and reorganization, may lead to particularly adverse outcomes that are long-lasting. Similarly, female users may be uniquely vulnerable to certain aspects of drug use. A recognition of the role of use during adolescence and sex on outcomes of amphetamine and methamphetamine exposure are of critical importance in understanding and treating substance use disorders. This chapter highlights what human research, which has been largely epidemiological, suggests about sex and age differences in drug use patterns and outcomes. We also discuss work in laboratory animals that has typically utilized rats or mice exposed to drugs in a non-contingent manner (i.e., involuntarily) or through volitional self-administration. Lastly, we draw attention to the fact that advancing our understanding of the effects of amphetamine and methamphetamine use, the development of problematic drug taking, and the mechanisms that contribute to relapse will require an emphasis on inclusion of age and sex as moderating factors in future studies.

The pharmacology and neurotoxicology of synthetic cathinones.

The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter include mephedrone, MDPV, methcathinone and methylone. These drugs are colloquially known as "bath salts". This misnomer suggests that these drugs are used for health improvement or that they have legitimate medical uses. The synthetic cathinones are dangerous drugs with powerful pharmacological effects that include high abuse potential, hyperthermia and hyperlocomotion. These drugs also share many of the pharmacological effects of the amphetamine class of drugs including methamphetamine, amphetamine and MDMA and therefore have high potential to cause damage to the central nervous system. The synthetic cathinones are frequently taken in combination with other psychoactive drugs such as alcohol, marijuana and the amphetamine-like stimulants, creating a situation where heightened pharmacological and neurotoxicological effects are likely to occur. Despite the structural features shared by the synthetic cathinones and amphetamine-like stimulants, including their actions at monoamine transporters and receptors, the effects of the synthetic cathinones do not always match those of the amphetamines. In particular, the synthetic cathinones are far less neurotoxic than their amphetamine counterparts, they produce a weaker hyperthermia, and they cause less glial activation. This chapter will briefly review the pharmacology and neurotoxicology of selected synthetic cathinones with the aim of delineating key areas of agreement and disagreement in the literature particularly as it relates to neurotoxicological outcomes.

Determination of Methamphetamine by High-Performance Liquid Chromatography in Odor-Adsorbent Material Used for Training Drug-Detection Animals.

The objective of the present report was to develop and validate a simple, sensitive, and selective analytical method for the determination of methamphetamine in an odor-adsorbent material (gauze) which was used to improve and standardize the training method used for drug-detection animals. High-performance liquid chromatography (HPLC) was performed using a Spherisorb ODS2 C18 column (200 mm × 4.6 mm, 5 µm), with a mobile phase consisting of a 0.25% methanol/triethylamine aqueous solution (V:V = 20:80), the pH of which was adjusted to 3.1 using glacial acetic acid, at a flow rate of 1.0 mL/min. The column temperature was 25 °C, and the detection of the analytes was performed at a wavelength of 260 nm. Methamphetamine showed good linearity (R2 = 0.9999) in the range of 4.2~83.2 mg/mL. The stability of the test material was good over 24 h. The precision of the method was good, with an average spiked recovery of 86.2% and an RSD of 2.9%. The methamphetamine content in the gauze sample was determined to be 7.8 ± 2.2 µg/sample. A high-performance liquid chromatography (HPLC) method was optimized and validated for the determination of methamphetamine in adsorbent materials (gauze). Validation data in terms of specificity, linearity, the limit of detection and the limit of quantification, reproducibility, precision, stability, and recovery indicated that the method is suitable for the routine analysis of methamphetamine in adsorbent materials (gauze) and provided a basis for training drug-detection animals.

Assessment of rTMS treatment effects for methamphetamine use disorder based on EEG microstates.

Microstates have been proposed as topographical maps representing large-scale resting-state networks and have recently been suggested as markers for methamphetamine use disorder (MUD). However, it is unknown whether and how they change after repetitive transcranial magnetic stimulation (rTMS) intervention. This study included a comprehensive subject population to investigate the effect of rTMS on MUD microstates. 34 patients with MUD underwent a 4-week randomized, double-blind rTMS intervention (active=17, sham=17). Two resting-state EEG recordings and VAS evaluations were conducted before and after the intervention period. Additionally, 17 healthy individuals were included as baseline controls. The modified k-means clustering method was used to calculate four microstates (MS-A∼MS-D) of EEG, and the FC network was also analyzed. The differences in microstate indicators between groups and within groups were compared. The durations of MS-A and MS-B microstates in patients with MUD were significantly lower than that in HC but showed significant improvements after rTMS intervention. Changes in microstate indicators were found to be significantly correlated with changes in craving level. Furthermore, selective modulation of the resting-state network by rTMS was observed in the FC network. The findings indicate that changes in microstates in patients with MUD are associated with craving level improvement following rTMS, suggesting they may serve as valuable evaluation markers.

Influences of hair dyeing on the distribution shapes of zolpidem and methoxyphenamine in hair.

In order to investigate the influences of hair dyeing on the distribution shapes of drugs in hair, different hair dyeing processes ("semi-permanent coloring without bleaching" and "permanent coloring with bleaching") were performed in vitro on black hair specimens collected from two subjects (Asians) who took a single dose of zolpidem (ZP, 10 mg of ZP tartrate) or methoxyphenamine (MOP, 50 mg of MOP hydrochloride). Under the following three different dyeing conditions, (1) semi-permanent coloring, (2) permanent coloring (once), (3) permanent coloring (twice), drug distributions in single hair specimens were investigated using a 2-mm segmental analysis by liquid chromatography-tandem mass spectrometry. Distribution shapes of drugs changed significantly only under the permanent coloring (twice) condition, resulting in reduced peak concentration and extended distribution width. There was, however, no significant difference in the amounts of drugs in hair between non-treated and dyed specimens, suggesting the drugs hardly leaked out of hair or were only slightly degraded during dyeing. In addition, while assuming contact with aqueous environment such as daily hair washing after dyeing, dyed hair specimens were individually immersed in ultrapure water for 20 hours, then the outflow of drugs in ultrapure water as well as the distribution shapes of drugs remaining in hair were determined. The drug outflow after permanent coloring (once and twice) was significantly larger than those after semi-permanent coloring, and the outflow ratios, [outflow]/([outflow] + [amount remaining in hair]), ranged over 9.8-24% (n = 3) for ZP and 68-71% (n = 3) for MOP after permanent coloring (once), and 54-72% (n = 3) for ZP and 86-91% (n = 3) for MOP after permanent coloring (twice). The distribution shapes of drugs after 20 h of immersion tended to flatten as outflow ratios increased, resulting in no change in the shapes after semi-permanent coloring, and complete collapse of their shapes after permanent coloring (twice). Thus, the present results indicated that hair dyeing involving bleaching and subsequent contact with aqueous environment after dyeing could significantly influence distribution shapes of drugs in hair.

Effects of the designer drug 4-methylamphetamine on core temperature and serotonin levels in the striatum and hippocampus of rats.

New psychoactive substances (NPS) are typically synthesized in clandestine laboratories in an attempt to chemically modify already federally regulated drugs in an effort to circumvent the law. Drugs derived from a phenethylamine pharmacophore, such as 4-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), reliably induce thermogenesis and serotonergic deficits in the striatum and hippocampus of rodents. 4-methylamphetamine (4-MA), a relative newcomer to the NPS scene, was originally investigated in the mid-1900 s as a potential anorexigenic agent. With its phenethylamine pharmacophore, 4-MA was hypothesized to produce similar toxicological alterations as its chemical analogs. In the present study, three doses (1.0, 2.5, and 5.0 mg/kg, ip.) of 4-MA were administered to rats twice daily for two days. Core temperature data were calculated and analyzed as temperature area under the curve (TAUC). On the second day of dosing, a hypothermic response to 4-MA (2.5 and 5.0 mg/kg) was noted between 0.5 and 2.0 h post-treatment. Only the highest dose of 4-MA decreased body weight on the second day of treatment and maintained this reduction in weight for seven days after treatment ceased. None of the doses of 4-MA evaluated significantly altered serotonin levels in the hippocampus or striatum seven days after final treatment. The present findings demonstrate that the 4-methyl substitution to amphetamine generates a pharmacological and toxicological profile that differs from other similar phenethylamine analogs.

Optimization of enantioselective high-performance liquid chromatography-tandem mass spectrometry method for the quantitative determination of 3,4-methylenedioxy-methamphetamine (MDMA) and its phase-1 metabolites in human biological fluids.

Recently we published in this journal an enantioselective high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of 3,4-methylenedioxymethamphetamine (MDMA) and its major phase-1 metabolites, 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA) and 3,4-methylenedioxyamphetamine (MDA) in human plasma, sweat, oral fluid and urine. Since we did not achieve simultaneous enantioseparation of all 4 compounds with a single chiral column, two amylose-based chiral columns were used alternatively. Further optimization of the mobile phase in the present study enabled baseline separation of all four pairs of enantiomers on a single Lux AMP column. In addition, by optimization of the column dimension and applied flow-rate it became possible to complete the separation within 6 minutes. These new methods were applied to the analysis of human plasma, oral fluid and urine. While results on the concentration of MDMA and its metabolites in various biological fluids were reported in our recent publication, in the present study an attempt was made to hydrolyze glucuronides in urine samples by using alternatively, hydrochloric acid or glucuronidase and to evaluate the effect of hydrolysis on the concentration and enantiomeric distribution of hydroxy metabolites of MDMA such as HMA and HMMA.

Metaphedrone (3-Methylmethcathinone): Pharmacological, Clinical, and Toxicological Profile.

Introduction: Synthetic cathinones are a group of novel psychoactive substances used as an alternative to classical recreational drugs. As a result of legal prohibitions on older generations of these compounds, new formulations appeared on the drug market. One of them is metaphedrone (3-methylmethcathinone, 3-MMC), a structural isomer of 4-methylmethcathinone and a psychostimulant drug. Metaphedrone became popular in a large number of countries in a short period of time. The aim: The collection, analysis, and review of relevant research on the subject of metaphedrone in order to present information about the pharmacological, clinical, and toxicological profile of this compound. An assessment of the significance and role of metaphedrone in consumption patterns of novel psychoactive substances among recreational drug users. Methodology: By using search engines like Google Scholar and PubMed, the relevant literature on metaphedrone was looked for and analyzed. The search was not limited to a specific period of time. All information regarding the compound of interest was analyzed and presented. Key results and discussion: All novel psychoactive substances are abused due to their pronounced stimulatory, hallucinogenic, dissociative, and euphoric and/or relaxing characteristics. Users of 3-methylmethcathinone usually opt for this substance for recreational purposes and/or sexual stimulation. Metaphedrone has the potential to cause a psychological dependence to the users. It was determined in relevant studies that most users are from 17 to 50 years of age. Older users usually administer metaphedrone intravenously, while younger ones usually choose snorting and oral ingestion of the drug. In Serbia, metaphedrone is a legally controlled substance. The pharmacodynamic properties make metaphedrone similar to classical recreational drugs. The method of administration, mainly repeated administration in a single session, could be explained using the pharmacokinetic profile of the drug. The most reported symptoms of intoxication were those of a sympathomimetic nature, such as tachycardia, chest pain, hypertension, diaphoresis, and agitation. Most intoxications and fatal outcomes occurred to users who combined several psychoactive substances. The correlation between measured blood concentrations of the drug and outcomes of intoxication was not found. The mechanisms of metaphedrone's toxicity are not fully understood. Conclusions: There is an increasing trend of abuse of metaphedrone among recreational drugs users. Future studies should focus on pharmacological and toxicological effects of metaphedrone on animals and humans.

Adulterants present in the San Diego county fentanyl supply: a laboratory analysis of seized law enforcement samples.

BACKGROUND: The opioid overdose crisis is one of the worst public health crises ever to face the US and emerging evidence suggests its effects are compounded by the presence of drug adulterants. Here we report our efforts to characterize the adulterants present within the local fentanyl supply of San Diego County, obtained from undifferentiated drug samples seized by local law enforcement over the calendar year 2021. METHODS: Thirty-two participating local law enforcement agencies across San Diego submitted 4838 unknown individual illicit drug samples (total of 312 kg) to the San Diego County Sheriff's Department Regional Crime Laboratory for identification. RESULTS: Qualitative analysis of these samples via FTIR and GC-MS identified methamphetamine (38.7%), fentanyl (20.8%), diacetylmorphine (heroin) (10.2%), codeine (5.8%) and alprazolam (4.3%) as the most common illicit substances and the presence of 52 unique adulterants. The most common adulterants included 4-methylaminoantipyrine (4-MAAP) (10.9%), mannitol (9%), acetaminophen (8.5%), methamphetamine (4.2%), diacetylmorphine (heroin) (3.6%), tramadol (1.9%), and xylazine (1.7%). Several additional pharmacologically active adulterants and contaminants of interest were also identified. CONCLUSION: This analysis is vital for public health use and harm reduction efforts at the level of the individual consumer. Continued direct surveillance of the drug supply is necessary for the detection of potentially harmful adulterants that may pose serious threats to the public.

Determination of fentanyl contamination on United States paper currency by LC-QQQ-MS.

Previous research has evaluated the extent to which cocaine and other drugs were detectable on currency in the USA. The literature was in agreement that the majority of bills exhibited some degree of contamination. With the increase of fentanyl in the illicit drug supply, this study was designed to evaluate the extent that fentanyl, cocaine, methamphetamine and other substances were present on circulating currency in 2022. A quantitative assay using liquid chromatography-triple quadrupole mass spectrometry was developed and validated to detect six analytes: fentanyl, 4-anilino-N-phenethylpiperidine, acetylfentanyl, benzylfentanyl, cocaine and methamphetamine. One-dollar bills were collected from 13 cities across the country. Sample preparation consisted of soaking the bills in methanol followed by liquid-liquid extraction. Chromatographic separation was achieved using a C18 analytical column and gradient elution with ammonium formate in water (5 mM, pH 3) and 0.1% formic acid in acetonitrile. The quantitative working range for this assay was 0.1 µg to 1.0 µg per bill (equivalent to 1 ng/mL to 100 ng/mL of extract). Fentanyl was detected on the majority (63%) of samples, with 61% of samples having ≥0.1 µg of fentanyl and 4% of samples having ≥1.0 µg. Cocaine and methamphetamine were detected on 100% and 98% of bills, respectively, typically in amounts >1.0 µg. The remaining fentanyl-related substances were detected in 15% of samples in amounts no >0.69 µg per bill and exclusively in the presence of fentanyl. Unsurprisingly, areas of the country with higher incidence of fentanyl use yielded higher frequency of contaminated bills and higher concentrations. Human exposure to drugs on currency is unlikely to have any significant impacts toxicologically or pharmacologically; however, our research findings suggest that paper currency could serve as a useful substrate for surveillance of drug trends regionally, nationally and/or internationally.

Dysfunctional feedback processing in male methamphetamine abusers: Evidence from neurophysiological and computational approaches.

Methamphetamine use disorder (MUD) as a major public health risk is associated with dysfunctional neural feedback processing. Although dysfunctional feedback processing in people who are substance dependent has been explored in several behavioral, computational, and electrocortical studies, this mechanism in MUDs requires to be well understood. Furthermore, the current understanding of latent components of their behavior such as learning speed and exploration-exploitation dilemma is still limited. In addition, the association between the latent cognitive components and the related neural mechanisms also needs to be explored. Therefore, in this study, the underlying neurocognitive mechanisms of feedback processing of such impairment, and age/gender-matched healthy controls are evaluated within a probabilistic learning task with rewards and punishments. Mathematical modeling results based on the Q-learning paradigm suggested that MUDs show less sensitivity in distinguishing optimal options. Additionally, it may be worth noting that MUDs exhibited a slight decrease in their ability to learn from negative feedback compared to healthy controls. Also through the lens of underlying neural mechanisms, MUDs showed lower theta power at the medial-frontal areas while responding to negative feedback. However, other EEG measures of reinforcement learning including feedback-related negativity, parietal-P300, and activity flow from the medial frontal to lateral prefrontal regions, remained intact in MUDs. On the other hand, the elimination of the linkage between value sensitivity and medial-frontal theta activity in MUDs was observed. The observed dysfunction could be due to the adverse effects of methamphetamine on the cortico-striatal dopamine circuit, which is reflected in the anterior cingulate cortex activity as the most likely region responsible for efficient behavior adjustment. These findings could help us to pave the way toward tailored therapeutic approaches.