Metabolic profile of N-ethylhexedrone, N-ethylpentedrone, and 4-chloromethcathinone in urine samples by UHPLC-QTOF-HRMS.

Forensic laboratories are constantly required to identify new drugs and their metabolites. N-ethylhexedrone (NEH, HEXEN), N-Ethylpentedrone (NEP), and 4-Chloromethcathinone (4-CMC, clephedrone) are synthetic substances structurally related to natural cathinone, alkaloid present in the leaves of the Catha edulis (Khat) plant. These synthetic cathinones (SC) are members of the heterogenous family of new psychoactive substances (NPS) that raised major concerns in scientific and forensic communities over the past years due to their widespread consumption. In this context, we investigated their metabolic profile using of UHPLC-QTOF-HRMS to elucidate the distribution of the parent drug and its metabolites in urine samples over time. Initially, both male and female volunteers were divided into three groups and eight subjects of each group were administered intranasally or orally with one SC (20-40 mg of NEH or NEP intranasal, 100-150 mg of 4-CMC oral). Urine samples were collected at 0-2 and 2-4 or 2-5 h. Urine (50 µL) was diluted 1:2 with acetonitrile/methanol (95:5) and injected into the UHPLC-QTOF-HRMS. Phase-I and phase-II metabolites were identified on the basis of fragmentation patterns and exact masses. Several phase-I and glucuronide-phase-II metabolites were identified in urine samples. Keto group reduction, hydroxylation and dealkylation were the common metabolic pathways identified for all cathinones and the presence of NEH-glucuronide, NEP-glucuronide and 4-CMC-glucuronide was also relevant. Significant is the slower metabolite formation for 4-CMC, which was detected at high concentrations in its original form even 5 h after administration, due to its long half-life and low intrinsic clearance compared to the other SCs. UHPLC-QTOF-HRMS demonstrated a considerable capability to semi-quantify the three synthetic cathinones and identify the target metabolites with high reliability. The introduction of new target compounds improves the efficiency of toxicological screening analysis on real samples and extends the window of detection of the SCs in biological matrices.

GC-MS/MS Determination of Synthetic Cathinones: 4-chloromethcathinone, N-ethyl Pentedrone, and N-ethyl Hexedrone in Oral Fluid and Sweat of Consumers under Controlled Administration: Pilot Study.

This study presents a validated GC-MS/MS method for the detection and quantification of 4-chloromethcathinone or clephedrone (4-CMC), N-ethyl Pentedrone (NEP), and N-ethyl Hexedrone (NEH, also named HEXEN) in oral fluid and sweat and verifies its feasibility in determining human oral fluid concentrations and pharmacokinetics following the administration of 100 mg of 4-CMC orally and 30 mg of NEP and NEH intranasally. A total of 48 oral fluid and 12 sweat samples were collected from six consumers. After the addition of 5 µL of methylone-d3 and 200 µL of 0.5 M ammonium hydrogen carbonate, an L/L extraction was carried out using ethyl acetate. The samples, dried under a nitrogen flow, were then derivatized with pentafluoropropionic anhydride and dried again. One microliter of the sample reconstituted in 50 µL of ethyl acetate was injected into GC-MS/MS. The method was fully validated according to international guidelines. Our results showed how, in oral fluid, the two cathinones taken intranasally were absorbed very rapidly, within the first hour, when compared with the 4-CMC which reached its maximum concentration peak in the first three hours. We observed that these cathinones were excreted in sweat in an amount equivalent to approximately 0.3% of the administered dose for 4-CMC and NEP. The total NEH excreted in sweat 4 h after administration was approximately 0.2% of the administered dose. Our results provide, for the first time, preliminary information about the disposition of these synthetic cathinones in the consumers' oral fluid and sweat after controlled administration.

Pharmacological effects of methylone and MDMA in humans.

Methylone is one of the most common synthetic cathinones popularized as a substitute for 3,4-methylenedioxymethamphetamine (MDMA, midomafetamine) owing to its similar effects among users. Both psychostimulants exhibit similar chemistry (i.e., methylone is a ß-keto analog of MDMA) and mechanisms of action. Currently, the pharmacology of methylone remains scarcely explored in humans. Herein, we aimed to evaluate the acute pharmacological effects of methylone and its abuse potential in humans when compared with that of MDMA following oral administration under controlled conditions. Seventeen participants of both sexes (14 males, 3 females) with a previous history of psychostimulant use completed a randomized, double-blind, placebo-controlled, crossover clinical trial. Participants received a single oral dose of 200 mg of methylone, 100 mg of MDMA, and a placebo. The variables included physiological effects (blood pressure, heart rate, oral temperature, pupil diameter), subjective effects using visual analog scales (VAS), the short form of the Addiction Research Center Inventory (ARCI), the Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SSE), and the Sensitivity to Drug Reinforcement Questionnaire (SDRQ), and psychomotor performance (Maddox wing, psychomotor vigilance task). We observed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects, such as stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone exhibited an effect profile similar to MDMA, with a faster overall onset and earlier disappearance of subjective effects. These results suggest that abuse potential of methylone is comparable to that of MDMA in humans. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05488171; Identifier: NCT05488171.

Abuse Potential of Cathinones in Humans: A Systematic Review.

Introduction and objective: Assessing the abuse potential of new substances with central nervous system activity is essential for preventing possible risks of misuse and addiction. The same methodology is recommended for the evaluation of the abuse potential of recreational drugs. This systematic review aims to assess the pharmacological effects related to the abuse potential and pharmacokinetics of cathinones, which are evaluated in both experimental and prospective observational studies in humans. Materials and Methods: A systematic search of the published literature was conducted to retrieve studies that had administered cathinone, mephedrone, methylone, and diethylpropion to evaluate their acute pharmacological effects related to abuse potential. Results: The search yielded 583 results, 18 of which were included to assess the abuse potential of cathinone (n = 5), mephedrone (n = 7), methylone (n = 1), and diethylpropion (n = 5). All four substances induce stimulant and euphorigenic effects that resemble those of amphetamines and MDMA, and their different intensities may be associated with varying levels of abuse potential. Conclusions: Cathinone, mephedrone, methylone, and diethylpropion induce a range of desirable and reinforcing effects that may, to some extent, result in abuse potential. Further investigation is needed to minimize and prevent their impact on society and public health.

Interaction of Energy Drinks with Prescription Medication and Drugs of Abuse.

In recent years, the consumption of energy drinks (EDs) has become increasingly popular, especially among adolescents. Caffeine, a psychostimulant, is the main compound of EDs which also contain other substances with pharmacological effects. This review aims to compile current evidence concerning the potential interactions between EDs, medicines, and drugs of abuse as they are frequently consumed in combination. The substances involved are mainly substrates, inductors or inhibitors of CYP1A2, psychostimulants, alcohol and other depressant drugs. Furthermore, intoxications reported with EDs and other substances have also been screened to describe acute toxicity. The results of our review show that the consumption of both EDs alone and in combination is not as safe as previously thought. Health professionals and consumers need to be aware of the potential interactions of these drinks as well as the absence of long-term safety data.

Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review.

BACKGROUND AND OBJECTIVE: Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. METHODS: A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. RESULTS: The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. CONCLUSIONS: Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.

MDMA interactions with pharmaceuticals and drugs of abuse.

Introduction: MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, has become one of the most widely used recreational psychostimulant drugs in the world. Among recreational ecstasy/MDMA users, polydrug use is a phenomenon whose common purpose is to experience the synergistic effect of the combined drugs, moderate MDMA effects, prevent potential toxicity, enhance a high or come down from a high from other drugs, or simply to treat existing medical conditions. Thus, MDMA-drug interactions (MDMA-DIs) lead to a higher risk of acute and life-threatening MDMA toxicity.Areas covered: This article provides an overview of the MDMA-DIs with pharmaceuticals and drugs of abuse. In addition, available evidence is summarized along with clinical recommendations. Finally, the increasing importance of MDMA-DIs is highlighted.Expert opinion: There is a reduced number of published MDMA-DIs studies and scarce clinically significant MDMA-DIs documented in the literature. Experimental evidence points out the relevance of MDMA-DI's when MDMA is co-administered with pharmaceuticals that are metabolized by the CYP2D6 due to MDMA inhibitory action and in the case of repeated MDMA administration (MDMA-MDMAIs).

Cannabinoids: from pot to lab.

Cannabis is becoming increasingly present in our society. In recent years, the line between the natural (cannabis) and the synthetic (synthetic cannabinoids), the recreational (cannabis) and the medical (pharmaceutical cannabinoids and medical cannabis) has been crossed. In this paper we review some of the novel aspects of cannabis and cannabinoids in relation to their legal situation, changes in their composition and forms of cannabis use, the concept of medical cannabis, and synthetic cannabinoids as new psychoactive substances (NPS). We have also analyzed serious adverse reactions and intoxications associated with the use of synthetic cannabinoids, as well as the latest developments in the research of pharmaceutical cannabinoids.

Results from screening immigrants of low-income countries: data from a public primary health care.

BACKGROUND: A total of 3,132 immigrants from low- and middle-income countries were involved in a cross-sectional observational study to screen for infectious diseases among immigrants attending public primary health care (PHC) centers. The study was conducted to clarify the degree of demographic differences and risk predictors of these diseases. METHODS: Demographic and clinical variables, screening for infectious diseases [hepatitis B and C, human immunodeficiency virus infection, syphilis, and tuberculosis (TB)], and analytical data (anemia, hematuria, and liver function) were recorded from immigrants attending a public PHC unit in Barcelona. RESULTS: Global hepatitis B, including chronic and previous, reached 18.1%; Morocco as the country of origin [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.07-4.14] and gastrointestinal symptoms (OR 1.9, CI 1.18-3.02) were risk factors. Hepatitis C prevalence was 3.3% with elevated hepatic transaminase levels as a risk factor (OR 26.1, CI 8.68-78.37). Positive syphilis was 3.1%; latent and active TB rates were 28.1 and 5.8%, respectively. Concerning TB, we found remarkable differences both among WHO regions of origin (the Eastern Mediterranean region showed the highest rate of active TB, 8%) and the three categories of years of residence in Spain (6.5% for <1 year, 12.8% for 1-5 years, and 10% for >5 years). CONCLUSIONS: The data allowed recommendation of a minimal screening of TB in immigrants from low-income countries regardless of the years of residence in Spain, hepatitis C in patients with altered transaminase levels, and hepatitis B in patients with gastrointestinal symptoms and/or from Morocco.