The Neuropsychiatric Complications of Stimulant Abuse

Katrin Sikk , Pille Taba , in International Review of Neurobiology, 2015

Abstract

Methcathinone abuse is a significant crusade of parkinsonism among immature patients in the Eastern European countries. The drug is synthesized from over-the-counter cold remedies containing ephedrine or pseudoephedrine. The final mixture contains a high concentration of manganese if potassium permanganate is used every bit the oxidant agent. Though manganese is an essential trace chemical element and its homeostasis is well maintained, exposure to a high level of manganese is neurotoxic. The utilise of manganese-contaminated methcathinone may crusade permanent neurological damage and severe disability. Drug users develop a distinctive extrapyramidal syndrome that resembles classic manganese intoxication. Methcathinone could accept additive neurotoxic effect to the progression of parkinsonism. The most prevalent symptoms are symmetrical bradykinesia, dystonias, and early postural, gait, and spoken communication damage. Later abeyance of exposure, the syndrome is generally irreversible and can even progress.

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Challenges in Laboratory Detection of Unusual Substance Corruption

A. Dasgupta , in Advances in Clinical Chemistry, 2017

iv.2 Constructed Cathinone Derivatives: Bath Salts

Methcathinone is an illicit drug also known on the street as "true cat" or "ephedrine." This illicit drug is a methyl derivative of cathinone. Methcathinone can exist easily manufactured by oxidation of pseudoephedrine in underground laboratories. Methcathinone can produce neuropsychiatric symptoms including agitation, insomnia, and tremors. Belhadj-Tahar and Sadeg reported the case of a 29-year-old woman who was admitted to the hospital in coma due to drug toxicity. The family indicated that she was taking an amphetamine-like drug. Her blood booze level was 167  mg/dL and assay of urine showed the presence of benzodiazepines and loftier levels of methcathinone, 17.24   mg/L; ephedrine, 11.threescore   mg/L; and methyl ephedrine, eleven.10   mg/L. The assay of serum also showed the presence of methcathinone (0.50   mg/Fifty), methyl ephedrine (0.19   mg/Fifty), and bromazepam (8.89   mg/50). The authors concluded that ingestion of alcohol and bromazepam altered the typical symptoms of methcathinone-induced intoxication, namely, hypertension and convulsion. The authors farther stated that the identification of methyl ephedrine, which is an impurity in the synthesis of methcathinone, tin serve equally a tag, indicating fraudulent constructed origin of methcathinone [53].

According to the American Association of Poison Control Centre, exposure to constructed cathinone increased from 306 in 2010 to 6137 in 2011. The drug abuse alert network reported that out of 2.5 million emergency department visits due to misuse of drugs, 22,094 visits were related to exposure of bath salts in 2011. The preferred route of administration of bathroom salts is snorting and ingestion. Like cathinone, bath salts are classified as Schedule I drugs with no known medical use but high corruption potential [54]. Common bathroom salts are mephedrone (4-methylmethylcathinone), methylone (3,four-methylenedioxy methylcathinone), iv-FMC (four-fluoromethcathinone), methedrone (4-methoxymethcathinone), and MDPV. Expiry from abuse of bath salts has been reported. Kesha et al. reported fatal intoxication in a human consuming bath salt (3,iv-methylenedioxypyrovalerone: MDPV). The patient was agitated during admission to the emergency department and developed ventricular tachycardia, hyperthermia, and then died. His eye blood showed 0.7   mg/L of MDPV and peripheral blood showed 1.0   mg/L of MDPV, and the authors concluded that his death was related to bath common salt abuse [55]. Detail discussion on bathroom salt is beyond the telescopic of this review. Banks et al. reviewed bathroom salts in item [56].

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The Neuropathology of Move Disorders in ane-Methyl-iv-Phenyl-ane,two,3,6-Tetrahydropyridine (MPTP) and Methcathinone (Ephedrone) Addictions

Ainars Stepens , Pille Taba , in Neuropathology of Drug Addictions and Substance Misuse, 2016

Introduction

Methcathinone (ephedrone, 2-methylamino-one-phenylpropan-1-one) is a psychostimulant drug with amphetamine- and methamphetamine-like acute behavioral effects like euphoria, agitation, anxiety, and hallucinations, which are caused by the increasing release of catecholamines acting every bit a preferential dopamine and noradrenalin uptake inhibitor in the encephalon. It is chemically an N-methyl structural analog of cathinone that naturally is present in the leaves of the khat bush (Catha edulis), which has been used for its stimulating properties in social traditions in African countries for several centuries (Emerson & Cisek, 1993; Simmler et al., 2013).

Synthesis of methcathinone by reduction from ephedrine or pseudoephedrine was described get-go by Roger Adams and his researchers in 1928 (Hyde, Browning, & Adams, 1928). Using chromium trioxide every bit the oxidant, Parke Davis patented methcathinone equally an analeptic agent in 1957 (50'italien & Rebstock, 1957). This mode of chemic training was observed in clandestine laboratories in the United States at the beginning of the 1990s, and the inhalation or sniffing of the obtained pulverisation induced acute toxicity similar to amphetamine-like drugs, but no long-term neurologic consequences were reported (Emerson & Cisek, 1993).

Methcathinone became more popular in the USSR where it had been "rediscovered" in 1982 using potassium permanganate as the different oxidant in the drug-synthesizing process (Zhingel, Dovensky, Crossman, & Allen, 1991). Methcathinone has become a substantial drug of abuse under its street names "Jeff," "Cat," "Mulka," and "Russian cocktail" in Eastern Europe, but cases have also been described in Western and Southern Europe and Canada. Components and guides for the preparation of the drug are hands available on the cyberspace in several languages (Sikk, Haldre, Aquilonius, & Taba, 2011).

In the region of the sometime USSR methcathinone has been synthesized by drug addicts in the dwelling house environs from over-the-counter cold remedies containing ephedrine, pseudoephedrine, or phenylpropanolamine (Levin, 2005; Stepens et al., 2008). Potassium permanganate and acetic acrid (vinegar) are added for inducing oxidation. The solution made with boiling h2o is cooled, filtered through a cotton pad, and injected intravenously. If ephedrone is made from pharmaceuticals containing pseudoephedrine hydrochloride, about one-half of the pseudoephedrine is converted to methcathinone (Sikk et al., 2007). Moreover, since the solution is not purified appropriately, intravenous injection exposes users to an extremely high Mn load: it is estimated that the daily load of Mn reaches upwardly to 60–180   mg, which is about 200 times more than the daily average dose of 0.two–0.55   mg available in standard formulations for intensive intendance patients receiving full parenteral nutrition (Sikk et al., 2007; Singer et al., 2009).

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The Neuropsychiatric Complications of Stimulant Abuse

Atbin Djamshidian , in International Review of Neurobiology, 2015

2.three Methcathinone

Methcathinone also sometimes called ephedrone is a constructed derivate that stems from the leaves of the khat bush which contains cathinone. Similar to amphetamines and cocaine it also inhibits the uptake of catecholamines in the brain and causes euphoria, agitation, anxiety, and hallucinations ( Sikk, Haldre, Aquilonius, & Taba, 2011; Zhingel, Dovensky, Crossman, & Allen, 1991). Typically, information technology is used in a binge blueprint, injecting several times a day, followed by ane–2 days of forbearance. The ingestion of potassium permanganate during the procedure of oxidation of pseudoephedrine (Emerson & Cisek, 1993) causes pallidal bespeak abnormalities leading to devastating neurological side effects including generalized dystonia, postural instability, dopaminergic unresponsive bradykinesia, and a typical "cock gait" (Sanotsky et al., 2007). These side effects are most likely a event of chronic manganese toxicity (Colosimo & Guidi, 2009; de Bie, Gladstone, Strafella, Ko, & Lang, 2007; Sikk et al., 2011).

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Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse

Richard A. Glennon , in Advances in Pharmacology, 2014

vi.ane Transporter studies

Cathinone and MCAT were shown quite some time ago to cause release of DA (Glennon et al., 1987). Afterwards, S(−)MCAT was found to human activity at Internet, DAT, and SERT (serotonin transporter) and displayed potencies similar to S(+)METH (i.due east., Cyberspace   ≈   DAT   >   SERT) (Rothman et al., 2003). Notable is that reduction of the keto grouping of S(−)MCAT, to afford (−)ephedrine and (+)pseudoephedrine, resulted in decreased say-so at Net and DAT and loss of activeness at SERT. Others take since establish that MCAT is most equipotent as a DA-releasing agent and reuptake inhibitor, whereas cathinone was severalfold more stiff as a releasing agent (Simmler et al., 2012). Both agents were more stiff at releasing NE than DA, and neither agent had a pregnant consequence at SERT. MCAT and methylone were substantially less strong as inhibitors of the vesicular monoamine transporter (bovine VMAT2) than at inhibiting transmembrane reuptake by serotonin (human platelets), DAT, and Internet (expressed in human glial cells) (Cozzi, Sievert, Shulgin, Jacob, & Ruoho, 1999).

Among the newer synthetic cathinones, 2 of the outset to be examined were mephedrone and MDPV. Using a frog oocyte training transfected with hDAT, mephedrone produced DA-like depolarization, whereas MDPV produced cocaine-like hyperpolarization (Cameron, Kolanos, Solis, Glennon, & De Felice, 2013; Cameron, Kolanos, Vekariya, De Felice, & Glennon, 2013; Kolanos, Cameron, Vekariya, De Felice, & Glennon, 2011). These are signatures of a releasing agent and a reuptake inhibitor, respectively. Simmler et al. (2012) found mephedrone to be well-nigh equipotent as an inhibitor and releaser of DA and 5-HT; it was substantially more strong as an inhibitor of NET. In contrast, MDPV was a potent inhibitor of DAT and NET, a very weak inhibitor of SERT, but neither released DA or 5-HT (Simmler et al., 2012). Others (Eshleman et al., 2013) reported comparable results. A study of butylone, methylone, ethylone, flephedrone pyrovalerone, MDPV, and several other agents concluded that all of the cathinone analogs were inhibitors of the three monoamine transporters but with varying selectivities; most of the compounds (with the exception of methylone, pyrovalerone, and MDPV) were substrate releasers (Simmler et al., 2012). These aforementioned agents displayed low affinity for 5-HT1A, 5-HT2A, 5-HT2C, D1, Dii, D3, and Hi histamine receptors and α1A- and α2A-adrenoceptors (Simmler et al., 2012). Pyrovalerone and several related agents had been constitute before to act equally DAT/Internet inhibitors, to take little effect at SERT, and to lack affinity for 5-HT1A, five-HT1B, v-HT2C, D1, D2, or D3 receptors (Meltzer et al., 2006). Mephedrone displayed low micromolar affinity for v-HTtwo receptors and even lower analogousness for DA receptors (Martínez-Clemente, Escubedo, Pubill, & Camarasa, 2012). An examination of a series of cathinone analogs revealed that 4-FMC, mephedrone, and methylone, simply not butylone or MDPV, by and large induced release of neurotransmitter from DAT, NET, and SERT; these agents were likewise shown demark with low (i.due east., μM) affinity at 5-HT1A, 5-HT2A, and five-HT2C receptors, with little to no affinity for DA receptors (Eshleman et al., 2013). Iversen et al. (2013) examined the bounden of several synthetic cathinones (including mephedrone, 4-MEC, and four others not discussed here) at 49 receptors and transporters. Except for the transporters, and a modest affinity (pYard i  =   6.one) for mephedrone at 5-HT2B receptors, the agents typically displayed, at all-time, micromolar affinity. Synthetic cathinones currently being abused seem to produce their actions primarily at the DA, norepinephrine (NE), and/or serotonin (v-HT) transporter; that is, they either release and/or block the reuptake of i or more than of these neurotransmitters. Simmler et al. (2012) suggested a nomenclature of various cathinone analogs, based on their transporter profiles, equally (i) cocaine–MDMA mixed cathinones, (ii) methamphetamine-like cathinones, and (iii) pyrovalerone cathinones. Additional agents will need to be examined, and conscientious SAR studies need to be performed, but transporter profiles volition certainly be a cardinal to unraveling the behavioral (and other) deportment of these agents. In a contempo written report, for example, it was demonstrated that both the extended chain and the pyrrolidine moiety of pyrovalerone- or MDPV-type agents demand not be nowadays for the agents to function as hyperpolarizing agents at DAT expressed in frog oocytes; for example, dimethylone, 3,4-methylenedioxy-α-PPP, and Northward-methyl-iii,4-methylenedioxypentylone all produced MDPV-like hyperpolarization (i.eastward., cocaine-like DAT inhibition) (Kolanos, Solis, Sakloth, De Felice, & Glennon, 2013).

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Mephedrone

Mariana Angoa-Pérez , Donald M. Kuhn , in Neuropathology of Drug Addictions and Substance Misuse, 2016

Introduction

Mephedrone (4-methyl-methcathinone) is a synthetic psychoactive substance of corruption that has gained worldwide notoriety as one of the components of "bath salts." Other related "bath salts" substituents include methylone, butylone, and three,four-methylenedioxypyrovalerone (MDPV). These cathinone derivatives are dangerous drugs that have loftier abuse potential in humans and their misuse is associated with clinically significant toxicity ( Dargan, Sedefov, Gallegos, & Forest, 2011; Kelly, 2011; Prosser & Nelson, 2012; Winstock, Mitcheson, Ramsey, et al., 2011). These agents also bear remarkable structural similarity to the amphetamines and their possession of a β-keto moiety is the simply feature that differentiates them from their respective amphetamine congeners (e.chiliad., 3,iv-methylenedioxymethamphetamine (MDMA) is the deketo form of methylone). The pharmacological actions of these drugs are thought to derive largely from their interactions with monoamine transporters. It is now known that mephedrone and methylone are substrates (i.eastward., transported in) for the transporters for DA, 5HT, and norepinephrine (NE) and they also cause release of these neurotransmitters via carrier-mediated exchange (Baumann et al., 2012; Cameron, Kolanos, Solis, Glennon, & De Felice, 2013; Cameron, Kolanos, Vekariya, De Felice, & Glennon, 2013; Eshleman et al., 2013; Kolanos, Solis, Sakloth, De Felice, & Glennon, 2013; Simmler, Buser, et al., 2013; Simmler, Wandeler, & Liechti, 2013). On the other hand, MDPV is a pure transport inhibitor (i.e., it is not transported) and is more than potent in inhibiting the DA transporter (DAT) than cocaine (Baumann, Partilla, Lehner, Thorndike, et al., 2013; Cameron, Kolanos, Solis, et al., 2013; Cameron, Kolanos, Vekariya, et al., 2013; Kolanos et al. 2013). These drugs cause many of the same behavioral effects equally the amphetamine psychostimulants to include increased locomotor activity, altered learning and memory, disruptions in thermoregulation, and the ability to serve as discriminative drug stimuli (Baumann, Partilla, Lehner, Thorndike, et al., 2013; Glennon, 2014; Gregg & Rawls, 2014; Marusich et al., 2014). The abuse potential of these drugs is affirmed by the ability to support the germination of a conditioned place preference, sustain self-administration, and enhance intracranial self-stimulation (Aarde et al., 2013; Bonano, Glennon, De Felice, Banks, & Negus, 2014; Hadlock et al., 2011; Karlsson, Andersson, Kronstrand, & Kugelberg, 2014; Lisek et al., 2012; Robinson, Agoglia, Fish, Krouse, & Malanga, 2012; Watterson et al., 2012). The preclinical pharmacology of mephedrone and related designer psychostimulants has been discussed in a number of excellent review articles (Baumann, Partilla, & Lehner, 2013; De Felice, Glennon, & Negus, 2014; Glennon, 2014; Green, King, Shortall, & Fone, 2014; Gregg & Rawls, 2014; Iversen, White, & Treble, 2014; Zawilska & Wojcieszak, 2013).

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Chemistry/Trace/Drugs of Abuse

S. Fu , North. Stojanovska , in Encyclopedia of Forensic Sciences (Second Edition), 2013

β-Keto Amphetamine Designer Drugs

Some mutual β-keto designer drugs include cathinone, ephedrone (methcathinone), mephedrone (ii-methylamino-one- p-tolylpropane-1-one, 4-methylmethcathinone, bk-methylmethamphetamine, bk-MMA), butylone (2-methyl-amino-i-(iii,iv-methylenedioxyphenyl)butan-1-i, bk-MBDB), ethylone (3,iv-methylenedioxyethylcathinone, bk-methylenedioxyethylamphetamine, bk-MDEA), and methylone (3,four-methylenedioxymethcathinone, bk-MDMA).

Cathinone can be extracted from Catha edulis or synthesized from α-bromopropiophenone, a compound that can be fabricated from propiophenone. Methcathinone can exist prepared from oxidation of ephedrine. Fifty-fifty the chiral synthesis of these materials has been reported, using amino acids as precursors, with ease. The ease of preparation of these materials has contributed to the emergence of an increasing number of cathinone analogs in the illicit market.

Despite being relatively new as drugs of abuse, these β-keto designer drugs have been around since the 1930s. Ephedrone, originally used every bit an antidepressant in the 1930s, went on to be used recreationally in the Netherlands and in the United States during the 1970s–90s. Similarly, mephedrone was beginning synthesized in the belatedly 1920s merely did not become widely known until early 2000s. Intelligence from Australia Customs and Border Protection Service has identified Communist china and the United kingdom of great britain and northern ireland equally being the principal sources of mephedrone. The compound three-fluoromethcathinone has been identified in capsules marketed as institute feeders available from Internet suppliers in the Great britain. Other materials were also identified in the tablet and include caffeine and methylamine salt. Methylone was found in street drugs in the Netherlands in 2004 and is the main ingredient of a new liquid designer drug that appeared on the Dutch drug market, chosen 'Explosion.'

When administered to experimental animals, methcathinone and cathinone were found to crusade hyperactivity, with methcathinone beingness ~ten times more potent than cathinone. The subjective effects of methylone exhibit subtle differences with those of MDMA. A vast majority of the drugs in this course, especially those recently introduced, exercise not have any pharmacological and toxicological information recorded thus far.

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Metal Related Neurodegenerative Disease

Karin Tuschl , ... Peter T. Clayton , in International Review of Neurobiology, 2013

4.2.ane.iv Mn in methcathinone formulation

In recent years, several cases of Mn poisoning have occurred in intravenous methcathinone users ( Levin, 2005; Sanotsky et al., 2007; Sikk et al., 2007; Stepens et al., 2008). In Eastern Europe and Russian federation, methcathinone, a psychostimulant otherwise known as ephedrone, is prepared from ephedrine and pseudoephedrine by adding the oxidant potassium permanganate in the presence of acetic acrid. Regular use leads to Mn intoxication with typical neurological symptoms. Onset of symptoms occurs at an average of 5.8 years after the start of methcathinone use with some individuals becoming symptomatic within the first year of apply (Stepens et al., 2008). Characteristic MRI brain appearances are accompanied by the typical cock-walk gait, particularly difficulties with backward move, and speech impairment (Levin, 2005; Sikk et al., 2007; Stepens et al., 2008). Cognitive function appears preserved; however, some drug users show balmy executive dysfunction (Selikhova et al., 2008). Following cessation of methcathinone utilise, claret Mn levels decrease and MRI brain appearances normalize. Even so, the neurological symptoms persist in the majority of cases, leaving many handicapped with an irreversible parkinsonian syndrome (Sikk et al., 2013; Stepens et al., 2008). Response to both l-dopa and chelation therapy with disodium calcium edetate is poor. Information technology is probable that the oxidizing potential of permanganate together with the amphetamine-like effect of methcathinone enhances Mn neurotoxicity, causing irreversible neuronal harm. Neuroimaging studies again suggest intact presynaptic nigrostriatal neurons as observed in other cases of Mn toxicity (Sikk et al., 2010).

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Detection of New Psychoactive Substances

Alberto Salomone , in Pilus Analysis in Clinical and Forensic Toxicology, 2015

eleven.four.ane GC-MS Methods

In a preliminary written report in 2007 [45] , the incorporation into hair of methylone and other new designer drugs, namely methcathinone and North-methyl-1-(iii,4-methylenedioxyphenyl)butan-2-amine (MBDB), was performed on an beast model. The authors concluded that new designer drugs such as methylone and MBDB (simply not methcathinone) are highly incorporated into the keratin matrix.

Martin et al. [46] developed a specific and accurate method for mephedrone assay and practical to 67 hair specimens. Xiii of them were found positive. The mean of the results was two.9   ng/mg, excluding i outlier sample which resulted at very high concentration (313.2   ng/mg) These levels are comparable to those of amphetamines, namely in the range of nanograms per milligrams, at least in case of repeated corruption.

13 psychotropic phenylalkylamine derivatives, including cathinone and methcathinone, were determined in human pilus by Kim et al. [47]. A total of 141 samples were collected from possible drug abusers. Several samples tested positive for amphetamine and methamphetamine, two for phentermine and two for MDMA, but ane for MDA and i for norketamine. Cathinone and methcathinone were not detected in any sample.

In one fatal case in which the concomitant intake of mephedrone, cocaine, and ethanol likely accounted for the death [48], mephedrone was determined in several biological specimens including pilus. The analytical finding at 0.25   ng/mg revealed past exposure to mephedrone. Withal, in this case, the level of mephedrone appears relatively depression if compared with existing data [46], leading to the conclusion that the deceased was unlikely a heavy consumer of mephedrone [48].

One of the first examples of detection of three phenylpiperazine in hair was presented by Barroso et al. [43]. The process was applied to authentic samples obtained either from autopsies or living subjects. Interestingly, samples belonging to persons undergoing treatment with trazodone were as well analyzed, for the detection of mCPP, which in turn can be detected in biological fluids equally a metabolite of trazodone.

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Emerging Designer Drugs

David E. Nichols , William East. Fantegrossi , in The Effects of Drug Corruption on the Human Nervous System, 2014

2.2.three Substituted Cathinone Derivatives

A variety of band- and sidechain-substituted cathinones (β-ketophenethylamines) accept appeared over the years. Initially, but cathinone and methcathinone were seen on the illicit market. More recently, mephedrone has been widely used, and its effects have been compared to those of MDMA. Mixtures of mephedrone and pyrovalerone have been marketed as "bath salts," although that is nothing merely a marketing ploy, because they have no value in bathing or cleaning. One frequent constituent of these products is 3,4-methylenedioxypyrovalerone (MDPV), which is structurally like to both MDMA and methamphetamine. MDPV surprisingly acts as a cocaine-like reuptake inhibitor at dopamine transporters ( Baumann et al., 2013), although it has MDMA- and methamphetamine-similar actions in mice (Fantegrossi et al., 2013). Past inspection of the structures in Figure viii it tin can be surmised that a variety of side chain lengths and amines can be used to create new compounds that probable will have similar pharmacology. And, as was noted for some phenethylamines, the presence of one or more than chiral carbon atoms allows for stereoisomerism amid the cathinones. Of all the designer drugs to take appeared recently, these may have some of the nearly serious reported adverse effects, primarily affecting the heart and cardiovascular system (run into e.g. Warrick et al. (2012)). The reader should consult the chapter in this book by Richard Glennon for a more detailed discussion of substituted cathinone derivatives.

Figure 8. Examples of substituted cathinone derivatives.

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