Mephedrone effects on the brain

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Try out PMC Labs and tell us what you think. Learn More. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases Medline, Scopus, etc. Of the sources initially found, only 36 papers were suitable for the review.

Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no ificant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function.

Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported.

In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the de of the experiments, including temperature and animal model used, the are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public Mephedrone effects on the brain.

Due to those effects, mephedrone is becoming increasingly popular as a recreational drug of abuse, not only among youngsters, but also in other age groups, including but not limited to young and older adults [ 3 - 5 ]. Mephedrone was first synthesized in as a ring-substituted cathinone 4-methyl aromatic analogue of methcathinone and its structure, such that of other synthetic cathinones e. It can be obtained in fine crystals or as white or yellowish powder and less frequently in tablet or capsule form [ 8 - 11 ].

The remarkable increase of its use in recent years has made it a ificant public health threat both in the US and in Europe [ 91213 ]. Furthermore, in Octoberthe US Drug Enforcement Administration DEA issued a temporarily Schedule I for the more frequently encountered substances of the cathinones class, including mephedrone among others, in response to this increasing epidemic of its abuse [ 15 ].

In many other European and non-European countries, this drug has also been banned to limit its availability. Specifically, vasoconstriction and bruxism observed in acute intoxication with mephedrone [ 1 ] and case of a year-old male who displayed diaphoresis, clonus, hypertonia, hyper-reflexia and was tachycardic after mephedrone ingestion supported the idea that substance toxicity may be linked to the serotonin syndrome [ 31 ].

Not only severe intoxications have been attributed to mephedrone consumption, but also a of fatal cases Mephedrone effects on the brain the drug either alone or in combination to other substances, such as: MDMA, GHB and heroin was identified in biological matrices from deceased [ 3233 ].

Notwithstanding these evidences on mephedrone hazard, limited and controversial information is currently available on the way mephedrone acts on the central nervous system CNS and on its neurotoxicity potential. Mephedrone shares a of effects with MDMA and methamphetamine on the CNS, interacting with monoamine plasma membrane transporters for serotonin 5-hydro-xytryptamine, 5-HT dopamine DA and likely norepinephrine NE [ 192334 - 39 ], blocking their reuptake [ 1934353739 ] while stimulating their release [ 2634384041 ].

It was originally hypothesized that mephedrone could cause methamphetamine-like neurotoxicity due to the fact that it simultaneously stimulates both DA release and inhibition of its uptake, cause hyperthermia and increase the locomotor activity Mephedrone effects on the brain 42 - 45 ]. Moreover, mechanistic and structural similarities with MDMA and methamphetamine led to the hypothesis that mephedrone could also cause toxic effects to DA nerve terminals.

However, this hypothesis was ruled out after a of studies [ 12384046 - 48 ]. In addition, its effects are evident not only on dopaminergic and -serotoninergic systems, but also on other pathways.

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As an example, German et al. To clarify all the above-reported issues, this review examined the emerging scientific literature on the possible mephedrone-induced neurotoxicity and the neuro-pharmacological profile of this substance yet not well defined due to the limited of experimental studies mainly carried out in animal models [ 2634374950 ]. The articles initially found were screened to exclude duplicate sources and papers not suitable for the purpose of the review. Only 36 papers 26 experimental studies, 6 review articles, 3 patents and 1 case report were included in the present review [ 912192326343537 - 4049 ].

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All sources have been screened independently by three of the authors, and selected by at least two of them. A of studies reported that mephedrone acts as an uptake inhibitor of monoamine neurotransmitters in the CNS, suggesting this drug could be a transporter blocker [ 193435373951 ]. Hadlock et al. No damages in the dopaminergic system were noticed while a persistent serotonergic deficit 5-HT depletion and reduction in SERT activity was observed seven days after exposure. This occurrence was also evidenced with MDMA, but not with methamphetamine.

The authors concluded that mephedrone displayed both neurotoxicity and abuse potential, and its toxicity, predominantly exerted on 5-HT terminals, mimicked that of MDMA with which it Mephedrone effects on the brain the same subjective sensations on abusers, although mephedrone is more potent on DA release in in vitro experiments. Although data suggest that mephedrone blocks the uptake of [3H] DA, [3H] 5-HT and [3H] NE into rat brains synaptosomes [ 52 ], traditional uptake-inhibition assays cannot distinguish between drugs acting as transporter substrates and those operating as blockers, taking into that both types prevent the accumulation of [3H] neurotransmitters in tissue.

Consequently, in vitro release assays have been developed to discriminate between these two types [ 235354 ]. According to other authors [ 55 ], mephedrone, s. Because of its similarity to methamphetamine and methcathinone, known to determine damages to striatum DA nerve endings, mephedrone harm potential has been Mephedrone effects on the brain in an animal study involving female mice treated with a binge like scheme of the substance [ 12 ].

This regimen consisted in four intra-peritoneal i. Although locomotor excitement and hyperthermia were observed, two or seven days after administration, striatum examination showed no neurotoxicity involving DA nerve terminals, as no persistent decrease in DAT activity was observed. This suggested that mephedrone mechanism of action consists in raising DA synaptic amount without causing neurotoxicity. For this purpose, the authors treated mice with mephedrone 30 minutes before the administration of neurotoxic doses of methamphetamines, amphetamines or MDMA.

Toxicity was observed, ranging from moderate to severe, and essentially increased with the co-administration of mephedrone and each of the other substances. Although mephedrone had ly been described as a substance with poor toxic effects on DA nerve terminals, in this study the drug was characterized by unsafe interaction with methamphetamines, amphetamines and MDMA, commonly co-abused with this synthetic cathinone [ 957 ].

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Mephedrone did not seem to damage DA nerve terminals although it increased the neurotoxicity of other amphetamine like substances. No increase of typical hyperthermia was observed, therefore the raise of neurotoxic effects should be considered independent from the added raising of body temperature of amphetamines.

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In the author opinion, its neurotoxicity enhancement could be indicative of an atypical interaction with DAT. However drug effects on 5-HT nerve endings are controversial and not fully established as some authors report damage and others do not. They concluded that when mephedrone was administered alone, it caused a non-persistent decrease in 5-HT, SERT, whereas when it was administered together with MDMA or methamphetamine there were no changes on the status of 5-HT nerve endings other than the effects produced by MDMA and methamphetamine alone.

It was found that the administration of methamphetamine 30 minutes after that of mephedrone Mephedrone effects on the brain a ificant decrease in 5-HT metabolite 5-hydroxyindoleacetic acid 5HIAA concentration when compared to controls and this effect was not observed when mephedrone was administered together with MDMA.

However, a limitation of this study could have been that the authors used mice in their experiments and these animals are not so susceptible to the 5-HT damaging of MDMA as rats. To observe the neurotoxic effects of different doses of mephedrone in relation with the exposure time, an animal study involving mice was deed as detailed [ 58 ].

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Three s. Loss in weight gain, hyperthermia, as well as aggressive behavior, were observed with all three dosages. The first administration program caused seven days lasting neurotoxicity on both serotoninergic and dopaminergic systems. The second administration program resulted in temporary damage on the dopaminergic system, whereas the third one, seven days after exposure, in DAT loss in striatum and frontal cortex and SERT in the hippocampus loss. After the third administration program, there was a predominant damage in the frontal cortex nerve terminals dopaminergic and hippocampus serotoninergic.

It was observed that mephedrone caused a decrease of D2 receptor concentration in the striatum and of 5-HT2 a receptors in the frontal cortex; moreover, there was also a depression-like behavior and this result suggested a greater vulnerability to addictive drugs. Pifl et al. Moreover, mephedrone and MDMA had a different interaction with the human brain vesicular monoamine uptake; with mephedrone displaying a 10 times lower transport inhibitory potency compared to MDMA. In vitro experiments on striatal suspension of rats, showed that mephedrone [ 34 ] was able to determine a DA release, similar to that of methamphetamine, displaying more adverse effects than those of MDMA.

Moreover, rodents which self-administered mephedrone, showed a trend towards an increase of the intake, therefore suggesting a certain abuse liability. In vivo microdialysis studies showed that intravenous injection of Mephedrone effects on the brain 0.

Some other studies reported a rise of dialysate 5-HT and DA in rat nucleus accumbens after s. The rise in 5-HT was similar to that following MDMA intake, but higher than that caused by amphetamine, whereas DA elevation was comparable after mephedrone and amphetamine injection and more marked than after MDMA administration [ 2651 ].

It is interesting to note that the elevation in extracellular 5-HT was of greater ificance in comparison to DA increase after mephedrone or methylone another abused synthetic cathinone treatment, suggesting therefore that neuro-chemical effects of the latter substances relate more to those of MDMA and less to those of methamphetamine [ 2638 ].

However, after Mephedrone effects on the brain s. In the study of Lopez-Arnau et al. In another study, the same authors [ 40 ] evaluated tryptophan hydroxylase 2 TPH2 levels after i. Den Hollander et al. It was also proved that these substances are selective and effective reductants of electron acceptors, even at physiological pH. However, at pH from 7. Both mephedrone and methamphetamine caused a decrease in mitochondrial respiration, but displayed different effects on the electron transport chain.

Mephedrone effects on the brain was concluded that this synthetic cathinone was actually able to determine cytotoxicity in vitro. Changes in memory and spatial learning were also investigated. Glutathione peroxidase values were found to be elevated in the frontal cortex, striatum and hippocampus and a rise in lipid peroxidation was observed in the frontal cortex. These findings suggested an mephedrone-related oxidative stress. Damage of the reference memory was displayed seven days after the end of drug administration, whereas spatial learning was not affected.

Other authors [ 58 ] performed in vitro experiments on cerebral cortex neuronal cultures, observing a dose-dependent cytotoxic effect of mephedrone on these cells, superior to that of MDMA. Another study [ 40 ], measuring the GFAP levels on mice did not reveal cellular activation in the hippocampus, microglia or astrocytes.

Martinez-Clemente et al. Only in the hippocampus an apparent increase in GFAP was noted. Conditioned place preference and motor activity tests were carried out on rats to investigate behavioral effects of mephedrone. An increased ambulatory activity after acute drug i. The injection of low doses of the synthetic cathinone 0. These findings suggest an abuse liability of the drug [ 50 ]. Behavioral effects on memory, depression and anxiety were investigated two weeks after the administration of binge-like dose mephedrone or methylone to mice [ 48 ]. Depression and anxiety-associated behavior did not appear to be affected by mephedrone.

The drug seemed to produce long-term effects on biochemical or behavioral pathways in rodents. Marusich et al. Regarding locomotor activity, mephedrone showed ificant effects related to time, dose and interaction with other substances. ificant increases in beam breaks were produced by all drug doses. of the functional observational battery illustrated that mephedrone ificantly increased hyperactivity, stereotyped head weaving and circling and stimulation.

Mephedrone effects on the brain

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Neurotoxicity Induced by Mephedrone: An up-to-date Review