Qualitative and Quantitative Analysis of Cathinones in Human Urine by SPE-GC-MS.

OBJECTIVES: To propose an alternative solid phase extraction-gas chromatography-mass spectrometry （SPE-GC-MS） method for the sensitive determination of cathinones in human urine samples, plus methodological verification. METHODS: Human urine samples were concentrated by solid phase extraction （SPE） sorbent and converted into the corresponding heptafluorobutyric acid anhydride derivatives. Methcathinone, 4-methyl methcathinone and 3,4-methylenedioxy-N-methylcathinone were detected by gas chromatography-mass spectrometry （GC-MS）. With quantitative analysis by internal standard method, methodological verification was carried out from the aspects of specificity, precision and reco-very rate. RESULTS: Methcathinone, 4-methyl methcathinone and 3,4-methylenedioxy-N-methylcathinone showed good linearly in the range of 25-200 ng/mL of urine （r>0.99）, with the limits of detection 2.0 ng/mL, limit of quantitation 25.0 ng/mL, both intra- and inter-day coefficients of variation lower than 6.0%, and recovery rates of 98.4%-105.7%. CONCLUSIONS: he proposed SPE-GC-MS procedure has good accuracy and specificity, can meet the need of qualitative and quantitative analysis of cathinones in the urine of drug abusers, and therefore provide technical support for the detection of cathinone abuse.

Is there any difference in patterns of use and psychiatric symptom status between injectors and non-injectors of mephedrone?

OBJECTIVE: In recent years, increasing intravenous mephedrone use was reported in several countries. The aim of this study was to describe the characteristics of such a form of mephedrone use, while identifying the differences between injectors and non-injectors in patterns of mephedrone use and psychiatric symptom status. METHODS: One hundred and forty-five mephedrone users were surveyed on patterns of mephedrone use using a structured questionnaire as well as the Brief Symptom Inventory. RESULTS: Majority of users received mephedrone from acquaintances and used it in discos/parties settings regarding both first and current mephedrone use. Intranasal use was the most typical route of administration (84.4%). Injectors (11%) used the drug more frequently and in higher dosages. This group included a greater proportion of opiate users (37.5%) and showed more diffuse psychiatric symptoms. Regarding the predictors of being an injector, heroin use showed the highest odds ratio. CONCLUSIONS: Intravenous mephedrone use is associated with a higher risk of harmful drug use, elevated psychiatric symptom profile and increased possibility of mephedrone being considered as an addictive substance. These findings might be important in efficient treatment planning.

Manganese-enhanced magnetic resonance imaging reveals differential long-term neuroadaptation after methamphetamine and the substituted cathinone 4-methylmethcathinone (mephedrone).

BACKGROUND: In recent years there has been a large increase in the use of substituted cathinones such as mephedrone (4-methylmethcathinone, 4-MMC), a psychostimulant drug that shows a strong resemblance to methamphetamine (METH). Unlike METH, which can produce clear long-term effects, the effects of 4-MMC have so far remained elusive. We employ manganese-enhanced magnetic resonance imaging (MEMRI), a highly sensitive method for detecting changes in neuronal activation, to investigate the effects of METH and 4-MMC on the brain. METHODS: In Wistar rats we performed a MEMRI scan two weeks after binge treatments (twice daily for 4 consecutive days) of METH (5 mg/kg) or 4-MMC (30 mg/kg). Furthermore, locomotor activity measurements and novel object recognition tests were performed. RESULTS: METH produced a widespread pattern of decreased bilateral activity in several regions, including the nucleus accumbens, caudate putamen, globus pallidus, thalamus, and hippocampus, as well as several other cortical and subcortical areas. Conversely, 4-MMC produced increased bilateral activity, anatomically limited to the hypothalamus and hippocampus. Drug treatments did not affect the development of locomotor sensitization or novel object recognition performance. CONCLUSIONS: The pattern of decreased brain activity seen after METH corresponds closely to regions known to be affected by this drug and confirms the validity of MEMRI for detecting neuroadaptation two weeks after amphetamine binge treatment. 4-MMC, unlike METH, produced increased activity in a limited number of different brain regions. This highlights an important difference in the long-term effects of these drugs on neural function and shows precisely the anatomical localization of 4-MMC-induced neuroadaptation.

Mephedrone concentrations in clinical intoxications and fatal cases: a systematic review.

BACKGROUND/PURPOSE: Mephedrone, a ring-substituted synthetic cathinone derivative, gained popularity as a recreational drug in the late 2000s. Reports of fatalities related to mephedrone use have emerged with varying concentrations of blood mephedrone upon forensic investigations. This study aims to evaluate the existing literature on mephedrone concentrations in instances of clinical intoxication and fatal cases. METHODS: We comprehensively searched electronic databases, including Web of Science, PubMed, Embase, and the Cochrane Library, from inception to July 26, 2023. We selected case reports or case series of mephedrone intoxication presented with individual blood mephedrone concentration. Patient demographics, clinical characteristics, blood mephedrone concentrations, and outcomes were extracted for analysis. RESULTS: 77 cases from 14 case reports and 6 case series were identified for review. There were 34 deaths and 43 non-fatal intoxication cases. The median patient's age was 24 years (IQR: 10), and 91.4% were male. Forty-five of the 63 cases (71.4%) were reported with alcohol or other illicit drugs detected. The median blood mephedrone concentration was 0.37 mg/L (IQR: 1.09 mg/L). Death cases were older than non-fatal cases (median = 30 vs. 22 years, p = 0.029). The median blood mephedrone concentration was higher in death cases (1.30 mg/L vs. 0.12 mg/L, p < 0.0001). CONCLUSIONS: Blood mephedrone concentration in dead patients is approximately 11 times higher than in non-fatal cases. This finding could serve as a stepping stone to the diagnosis of concentrations in clinical poisoning cases and deaths, especially in the treatment of poisoning patients. In more extensive prospective studies, further research is necessary to establish a standardized, real-time available methodology and validate the predictive value of mephedrone concentrations in the prognostic value of mephedrone concentrations.

Substitutional potential of mephedrone: an analysis of the subjective effects.

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

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.

Computational study of IR, Raman, and NMR spectra of 4-methylmethcathinone drug.

Molecular electronic structure, IR, UV, and NMR spectra of the most popular cathinone, known as mephedrone or 4-methylmethcathinone (4-MMC), is studied thoroughly by quantum chemical calculation in terms of the density functional theory (DFT). Geometry optimization of 4-MMC and its hydrochloride complex is performed with the B3LYP functional, and all vibrational frequencies are analyzed in all details. On this background, the IR and Raman spectra are interpreted. The importance of low-frequency terahertz and Raman spectra is stressed for distinguishing of various MMC isomers. The UV spectrum is calculated by time-dependent DFT method which allows complete interpretation of intense absorption bands at 270 and 210 nm as combinations of various ππ*, nπ*, and charge transfer excitations in amino-phenyl moieties. Very informative analysis of UV absorption and NMR spectra provides useful details on the structure-activity relationship for mephedrone molecule.

Acute Pharmacological Effects of Oral and Intranasal Mephedrone: An Observational Study in Humans.

Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of mephedrone, orally (n = 5, 100-200 mg; mean 150 mg) or intranasally (n = 5, 50-100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of mephedrone in oral fluid and also the total amount of mephedrone and metabolites in urine showed that concentrations of mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results.

Mephedrone and Alcohol Interactions in Humans.

Mephedrone (4-MMC, mephedrone) is a synthetic cathinone derivative included in the class of new psychoactive substances. It is commonly used simultaneously with alcohol (ethanol). The aim of the present study was to evaluate the interactions on subjective, cardiovascular and hormone effects and pharmacokinetics between mephedrone and alcohol in humans. Eleven male volunteers participated as outpatients in four experimental sessions in a double-blind, randomized, cross-over, and placebo-controlled clinical trial. Participants received a single oral dose of 200 mg of mephedrone plus 0.8 g/kg of alcohol (combination condition); 200 mg of mephedrone plus placebo alcohol (mephedrone condition); placebo mephedrone plus 0.8 g/kg of ethanol (alcohol condition); and placebo mephedrone plus placebo alcohol (placebo condition). Outcome variables included physiological (blood pressure, heart rate, temperature, and pupil diameter), psychomotor (Maddox wing), subjective (visual analogue scales, Addiction Research Center Inventory 49 item short form, and Valoración de los Efectos Subjetivos de Sustancias con Potencial de Abuso questionnaire), and pharmacokinetic parameters (mephedrone and ethanol concentrations). The study was registered in ClinicalTrials.gov, number NCT02294266. The mephedrone and alcohol combination produced an increase in the cardiovascular effects of mephedrone and induced a more intense feeling of euphoria and well-being in comparison to the two drugs alone. Mephedrone reduced the sedative effects produced by alcohol. These results are similar to those obtained when other psychostimulants such as amphetamines and 3,4-methylenedioxymethamphetamine are combined simultaneously with alcohol. The abuse liability of mephedrone combined with alcohol is greater than that induced by mephedrone alone.

Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4-methylmethcathinone.

RATIONALE: Although the synthetic cathinone 4-methylmethcathinone (4-MMC, mephedrone) has been a subject of intensive research investigation, the pharmacological mechanisms involved in its interoceptive stimulus effects have yet to be fully characterized. OBJECTIVE: The present study employed drug discrimination methods in rats to compare the interoceptive stimulus properties of two different training doses of 4-MMC to other substances with similar pharmacological actions. METHODS: Sixteen male Sprague-Dawley rats were trained to discriminate either 1.0 mg/kg (N = 8) or 3.0 mg/kg (N = 8) 4-MMC from saline. Substitution tests were conducted with drugs that increase extracellular monoamine levels (d-amphetamine, (+)-methamphetamine, 4-MMC, MDMA, MDPV, and (-)-cocaine), a serotonin releaser (+)-fenfluramine, and a serotonergic (5-HT2A) hallucinogen (+)-LSD. RESULTS: Stimulus control was established in fewer sessions in the subjects trained with 3.0 mg/kg compared to those trained with 1.0 mg/kg 4-MMC. Cocaine, MDMA, and d-amphetamine produced full substitution in the 1.0 mg/kg 4-MMC-trained rats at doses that did not decrease response rate. However, doses of test drugs that engendered > 80% 4-MMC-lever selection concurrently produced rate-decreasing effects in rats trained to discriminate 3.0 mg/kg 4-MMC. CONCLUSIONS: These findings further characterize the interoceptive stimulus effects of 4-MMC and indicate that these effects vary little with training dose; however, qualitative differences in substitutability of test drugs were observed between training groups. This study expands existing knowledge regarding the psychopharmacology of 4-MMC and the potential neurochemical substrates contributing to its subjective effects.