3-fluoromethcathinone and cathinone

Synthetic stimulants commonly sold as "bath salts" are an emerging abuse problem in the U.S. Users have shown paranoia, delusions, and self-injury. Previously published in vivo research has been limited to only two components of bath salts (mephedrone and methylone). The purpose of the present study was to evaluate in vivo effects of several synthetic cathinones found in bath salts and to compare them to those of cocaine (COC) and methamphetamine (METH). Acute effects of methylenedioxyphyrovalerone (MDPV), mephedrone, methylone, methedrone, 3-fluoromethcathinone (3-FMC), 4-fluoromethcathinone (4-FMC), COC, and METH were examined in male ICR mice on locomotor activity, rotorod, and a functional observational battery (FOB). All drugs increased locomotor activity, with different compounds showing different potencies and time courses in locomotor activity. 3-FMC and methylone decreased performance on the rotorod. The FOB showed that in addition to typical stimulant induced effects, some synthetic cathinones produced ataxia, convulsions, and increased exploration. These results suggest that individual synthetic cathinones differ in their profile of effects, and differ from known stimulants of abuse. Effects of 3-FMC, 4-FMC, and methedrone indicate these synthetic cathinones share major pharmacological properties with the ones that have been banned (mephedrone, MDPV, methylone), suggesting that they may be just as harmful.

Topics: Alkaloids; Analysis of Variance; Animals; Central Nervous System Stimulants; Cocaine; Dose-Response Relationship, Drug; Exploratory Behavior; Hypoglycins; Male; Methamphetamine; Mice; Mice, Inbred ICR; Motor Activity; Observation; Propiophenones; Psychomotor Performance; Rotarod Performance Test; Time Factors

The synthetic cathinones are powerful psychostimulants that have been associated with impairment, intoxication and fatal overdose. Forensic laboratories must be able to identify these new drugs as part of antemortem and postmortem toxicology investigations. Preliminary reports have indicated that some of the synthetic cathinones are unstable in biological matrices. It is important to understand drug stability in biological evidence so that analytical findings can be interpreted appropriately. The objective of this study was to systematically evaluate the concentration, temperature and analyte-dependent stability of synthetic cathinones in preserved blood using liquid-chromatography/quadrupole-time of flight-mass spectrometry (LC/Q-TOF-MS). Cathinone stability was investigated at frozen, refrigerated, ambient and elevated temperature (-20°C, 4°C, 20°C and 32°C). Although no concentration dependent differences in stability were observed, cathinone stability was highly temperature and analyte-dependent. Substituents on the aromatic ring and nitrogen profoundly influenced stability. Tertiary amines (pyrrolidinyl analogs) were significantly more stable than their N-alkylated (secondary amine) counterparts. Furthermore, the methylenedioxy (MD) group also exerted a significant stabilizing effect, for both secondary and tertiary amines. The unsubstituted and ring-substituted secondary amines were the least stable, most notably 3-fluoromethcathinone (3-FMC). Under some conditions, significant losses were observed within hours of storage. Half-lives ranged from a little as 8 h (3-FMC) to 21 days (3,4-methylenedioxy-α-pyrrolidinobutiophenone, MDPBP) at elevated temperature (32°C). In contrast, half-lives ranged from 0.4 to >10 months when refrigerated and demonstrated even greater stability when frozen. Biological evidence may be subjected to a variety of environmental conditions prior to, and during transport to the laboratory. These findings highlight the need to consider the potential for both temperature and analyte-dependent differences. Due to the inherent instability of certain drugs within the class, quantitative drug findings in toxicological investigations must be interpreted with caution, and within the context of specimen storage and integrity.

Topics: Alkaloids; Chromatography, Liquid; Forensic Toxicology; Humans; Mass Spectrometry; Propiophenones; Psychotropic Drugs; Substance Abuse Detection

3-Bromomethcathinone (3-BMC) and 3-Fluoromethcathinone (3-FMC) are two new designer drugs, which were seized in Israel during 2009 and had also appeared on the illicit drug market in Germany. These two compounds were sold via the Internet as so-called "bath salts" or "plant feeders." The aim of the present study was to identify for the first time the 3-BMC and 3-FMC Phase I and II metabolites in rat urine and human liver microsomes using GC-MS and LC-high-resolution MS (HR-MS) and to test for their detectability by established urine screening approaches using GC-MS or LC-MS. Furthermore, the human cytochrome-P450 (CYP) isoenzymes responsible for the main metabolic steps were studied to highlight possible risks of consumption due to drug-drug interaction or genetic variations. For the first aim, rat urine samples were extracted after and without enzymatic cleavage of conjugates. The metabolites were separated and identified by GC-MS and by LC-HR-MS. The main metabolic steps were N-demethylation, reduction of the keto group to the corresponding alcohol, hydroxylation of the aromatic system and combinations of these steps. The elemental composition of the metabolites identified by GC-MS could be confirmed by LC-HR-MS. Furthermore, corresponding Phase II metabolites were identified using the LC-HR-MS approach. For both compounds, detection in rat urine was possible within the authors' systematic toxicological analysis using both GC-MS and LC-MS(n) after a suspected recreational users dose. Following CYP enzyme kinetic studies, CYP2B6 was the most relevant enzyme for both the N-demethylation of 3-BMC and 3-FMC after in vitro-in vivo extrapolation.

Topics: Alkaloids; Animals; Aryl Hydrocarbon Hydroxylases; Chromatography, Liquid; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Designer Drugs; Gas Chromatography-Mass Spectrometry; Humans; Kinetics; Male; Microsomes, Liver; Oxidoreductases, N-Demethylating; Propiophenones; Rats