Cathinone neurotoxicity ("The "3Ms").

Synthetic cathinones are designer drugs of the phenethylamine class, structurally and pharmacologically similar to amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), cathinone and other related substances. New analogues, legal at least, until formally banned (a time consuming process), are introduced almost daily The United Nations estimates nearly 250 new drug analogues are produced per year. Various combinations of these drugs are sold under the name of "bath salts". They can be ingested by any route and some appear capable of causing great harm, mostly behavioral. One drug in particular, MDVP, appears to frequently cause symptoms indistinguishable from the classic findings in Excited Delirium Syndrome (ExDS). Little is known about the pathology or clinical toxicology of these drugs but their molecular mechanism of action seems to be identical with that of cocaine. This mini-review examines what little is known on the subject and explains the suspected mechanisms of excited delirium syndrome.

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs.

Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure-activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.

Comparative pharmacological evaluation of the cathinone derivatives, mephedrone and methedrone, in mice.

Mephedrone and methedrone are cathinone-related compounds, which act as non-selective substrates for monoamine transporters, facilitating a neurotransmitter release. We compared the acute pharmacological effects of mephedrone and methedrone, attempting to further evaluate the action mechanisms of methedrone by responsibly and ethically using mice under approved procedures. The effects of both compounds were examined from 10 to 60 min, in a series of behavioral paradigms, namely open-field, plus-maze, hot-plate and tail suspension tests, whereas neurotransmitter brain tissue levels were determined ex vivo by HPLC. Separate groups were pre-treated with the dopamine (DA) antagonist haloperidol, or the serotonin (5-HT) synthesis inhibitor ρCPA, to further assess the mechanisms underlying methedrone effects. The compounds caused marked hyperlocomotion, displaying dissimilar stereotyped behavior, in an open-field arena. Mephedrone caused anxiolytic-like effects, while methedrone induced anxiogenic-like actions in the elevated plus-maze. Both compounds displayed thermal antinociception, with a reduced immobility time in the tail suspension model. Mephedrone triggered a 2- and 3-fold increment of dopamine and serotonin tissue levels, respectively, in the nucleus accumbens, with a 1.5-fold elevation of tissue dopamine in the frontal cortex. Methedrone caused a 2-fold increment of tissue dopamine in the nucleus accumbens and in the striatum, and a 1.5-fold increment of serotonin tissue levels in the hippocampus and striatum. In vivo methedrone effects were partially inhibited by a pre-treatment with haloperidol or ρCPA. Despite similar actions on locomotion, analgesia, and depression-like behavior, the acute administration of mephedrone and methedrone elicited divergent effects on anxiety-like behavior and stereotyped movements in mice, which might be related to the distinct modulation of brain tissue neurotransmitter levels.

Analytical profiles of "legal highs" containing cathinones available in the area of Lisbon, Portugal.

Thirteen "legal highs" were purchased in different "smart shops" in the area of Lisbon, Portugal, during the month of February 2013. The samples were analyzed by a battery of analytical methods including Fourier transform infra-red (FTIR), gas chromatography coupled with mass spectrometry (GC-MS), proton nuclear magnetic resonance ((1)H NMR) and wavelength dispersive X-ray fluorescence (WD-XRF). Active ingredients were found either as single component or in mixtures in the different products. The cathinone derivative methedrone was present in three products; it is suspected to have a particular high toxicity and narrow therapeutic window linked with the methoxy group. A total of seven compounds were identified: 4-fluoromethcathinone, ethcathinone, buphedrone, methedrone, pentedrone, 3,4-dimethylmethcathinone and 4-methylethcathinone. Analytical profiles of all the samples were obtained and compared. Elemental composition of the products was obtained by XRF analysis. The inorganic profiles obtained contain useful information and can be used to distinguish and classify samples according to their origin.