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These datasets underpin the analysis presented in the agency's work. Most data may be viewed interactively on screen and downloaded in Excel format. All countries. Topics A-Z. The content in this section is aimed at anyone involved in planning, implementing or making decisions about health and social responses. Best practice. We have developed a systemic approach that brings together the human networks, processes and scientific tools necessary for collecting, analysing and reporting on the many aspects of the European drugs phenomenon. Explore our wide range of publications, videos and infographics on the drugs problem and how Europe is responding to it. All publications. More events. More news. We are your source of drug-related expertise in Europe. We prepare and share independent, scientifically validated knowledge, alerts and recommendations. About the EUDA. Price and purity: mean national values — minimum, maximum and interquartile range. Countries vary by indicator. Show source tables. Back to list of tables. Homepage Quick links Quick links. GO Results hosted on duckduckgo. Main navigation Data Open related submenu Data. Latest data Prevalence of drug use Drug-induced deaths Infectious diseases Problem drug use Treatment demand Seizures of drugs Price, purity and potency. Drug use and prison Drug law offences Health and social responses Drug checking Hospital emergencies data Syringe residues data Wastewater analysis Data catalogue. Selected topics Alternatives to coercive sanctions Cannabis Cannabis policy Cocaine Darknet markets Drug checking Drug consumption facilities Drug markets Drug-related deaths Drug-related infectious diseases. Recently published Findings from a scoping literature…. Penalties at a glance. Frequently asked questions FAQ : drug…. FAQ: therapeutic use of psychedelic…. Viral hepatitis elimination barometer…. EU Drug Market: New psychoactive…. EU Drug Market: Drivers and facilitators. Statistical Bulletin home. Quick links Search news Subscribe newsletter for recent news Subscribe to news releases. Breadcrumb Home Media library Dashboard. Cocaine market in Europe, price, purity, seizures. A more recent version of this page exists: Dashboard. Cocaine market in Europe, price, purity, seizures updated June Publication date. List of tables Table 1. Cocaine metabolites benzoylecgonine in wastewater in selected European cities: most recent data Table 4. Percentages except where otherwise stated. Table 5. Trends in first-time cannabis treatment entrants Table 6. Markets seizures source data Table 7. Trends in the number of cocaine seizures x Table 8. Trends in the quantities of cocaine seizures and quantity of illicit drugs seized tonnes Table 9. Price, potency data Table Table 2. Prevalence of drug use in Europe, trends Country Country code Geographical scope Substance Recall period Age Austria AT National Table 3. Masaryk Water Resesrch institute, p. Table 4. Trends in first-time cannabis treatment entrants Country Germany Spain Italy France Other countries Table 6. Table 7. Table 8. Table 9. Table For the latest data and detailed methodological information please see the Statistical Bulletin Prevalence of drug use. Graphics showing the most recent data for a country are based on studies carried out between and Main subject. Target audience. Copyright status. Related assets in the Media library Previous slide. Next slide. Drug seizures in the European Union — number of reported drug seizures, breakdown by drug, percent updated June Forensic Toxicology Labs. Prevalence data presented here are based on general population surveys submitted to the EMCDDA by national focal points.
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Official websites use. Share sensitive information only on official, secure websites. Reviewed by: M. David Pubill , University of Barcelona, Spain. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Mephedrone 4-MMC , despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine METH. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH. During the last couple of decades, there has been an increasing supply of substituted cathinones in the illegal drug market Vardakou et al. Generally, these substances initially gain popularity as legal alternatives to existing amphetamine-type stimulants. As their popularity grows, they are subsequently banned by national governments and once banned, they become available on the illegal drug market next to already controlled substances. One of the better-known substituted cathinones is mephedrone 4-methylmethcathinone, 4-MMC , the usage of which has remained high even after its classification as illegal Deluca et al. However, long-term neurotoxic effects of mephedrone and METH appear to differ substantially. While METH is known to produce substantial and long-lasting reductions in monoamine levels and other markers of DA neurotoxicity, such findings are generally not replicated with 4-MMC. In fact, several studies have found little evidence of mephedrone neurotoxicity when administered under normal conditions Angoa-Perez et al. Nonetheless, 4-MMC neurotoxicity can be precipitated when the drug is administered under circumstances known to exacerbate stimulant neurotoxicity, such as high ambient temperatures Hadlock et al. This raises the question whether alcohol could also precipitate 4-MMC neurotoxicity. Currently, very little is known about this. One study reported evidence of neurotoxicity when 4-MMC was co-administered with EtOH, but this study also administered the drug at high ambient temperatures, making it difficult to conclusively attribute the effects to EtOH Ciudad-Roberts et al. Interestingly, the acute effects of 4-MMC alone or in combination with EtOH was investigated in a clinical study which demonstrated that EtOH increased the cardiovascular effects of the drug as well as self-reported euphoria. However, this study did not investigate long-term neurocognitive effects Papaseit et al. Further investigating this question is of importance considering that 4-MMC is often consumed together with EtOH and will help inform both drug users and healthcare providers of potential risks and help guide the development of an evidence-based harm reduction approach. We previously used manganese-enhanced magnetic resonance imaging MEMRI to assess the long-term effects of 4-MMC and METH in rats and showed that METH produced a pattern of widespread neuronal deactivation in monoamine-rich brain areas 2 weeks following a binge-dosing regimen; 4-MMC, conversely, produced an effect that was limited primarily to the parietal cortex, hypothalamus and hippocampus and was characterized by neuronal activation rather than deactivation den Hollander et al. Additionally, we used Golgi staining to evaluate potential changes in neuronal morphology in regions of interest identified based on MEMRI neuronal activity patterns. The rats were randomly allocated to six treatment groups, with eight rats per group. The rats were housed in one-animal, open-air cages containing woodchip bedding and environmental enrichment including hardwood blocks and plastic shelter tubes, with food pellets Teklad S, Envigo, Netherlands and tap water available ad libitum. The rats were maintained under a h light—dark cycle with lights on from 7. All treatments were given, and all tests were performed during daytime a. All effort was taken to minimize animal suffering and the number of animals used. Other products were acquired from Sigma-Aldrich unless specified otherwise. The 1. The aim of the dosing regimen was to mimic a pattern of heavy, recreational binge-abuse. As such, all treatments were administered twice daily morning and afternoon, approximately 8 h apart for four consecutive days. An overview of drug and EtOH treatments administered to the various experimental groups is shown in Figure 1. Experimental design shown as a flowchart. Core body temperatures were assessed 30 min after the first drug treatment on Day 1 using a thermometer equipped with a rectal probe Physiotemp BAT, Physiotemp Instruments Inc. One week after the final drug treatment, on Day 11, animals were administered manganese dichloride MnCl 2 as MEMRI contrast agent through the implantation of manganese-releasing osmotic minipumps. On day 18, following a week of manganese exposure and two weeks after the final drug treatments, animals were anesthetized and subjected to MEMRI brain imaging. Immediately following the completion of the scan, animals were sacrificed while still under isoflurane anesthesia , and brain tissues were collected and stored for Golgi staining. Manganese chloride was dissolved into Tris-buffered saline pH 7. The concentration of MnCl 2 in the pumps was adjusted according to the body weight of the animals. Animals were anesthetized with isoflurane Vetflurane, Virbac Animal Health, United Kingdom and the pumps were implanted subcutaneously on the dorsum, slightly caudal to the scapulae. MEMRI imaging was performed in a 9. Accurate positioning of the head was ascertained with the help of scout images. The total imaging time was approximately 1 h. In brief, T1-weighted and brain-extracted images were spatially normalized using a rat brain template co-registered to a rat brain atlas Schwarz et al. This template was co-registered to the digitized Paxinos and Watson atlas Paxinos and Watson, , which enabled atlas-based generation of region-of-interest ROI masks for further detailed anatomical analysis. Spatially normalized were smoothed with a 0. For creating statistical parametric maps of differential brain activation between experimental groups, the groups were compared by performing voxel-wise independent two-tailed t-tests using SPM8 version , www. Therefore, the mean global intensity was included as a covariate in the general linear model on a voxel-by-voxel basis Friston et al. Brain regions were selected based on the results from voxel-wise and ROI analyses. Particularly, regions with notable deactivation and distinguishable morphological dendritic spine profiles were chosen. The analyzed sections were 2. In short, the removed brains were immersed in an impregnation solution. Louis, MO, United States. During the imaging process, the correct brain regions were identified, and then z-stacks were taken from each brain region four z-stacks from both hemispheres , roughly from the same location within the area, keeping the order of the branch of the dendrite second to third constant. The imaging was performed blindly, so that the researcher did not know the treatment group of individual sections. For the Golgi-stained neurons, spine densities and morphologies were analyzed using previously published pipeline for efficient and unbiased classification of dendritic spines Risher et al. In short, the previously acquired images were converted to an analyzable file format using ImageJ version 1. The converted images were then imported to Reconstructs software 1. The data from the Reconstructs software were then exported to csv-files. Those files were imported to R-studio , version 1. The total number per spine type per brain region was divided by the total length of analyzed dendrites per brain region, which resulted in one datapoint per animal per brain region per spine type for the statistical analysis. Analyses were performed using SPSS version Post-hoc testing revealed a significant decrease in body temperature vs. Notably, concurrent treatment with EtOH had no modulatory effect on body temperatures in animals treated with the stimulants. Effect of treatment on body temperature ethanol EtOH decreased while all other treatments including the stimulants, increased core body temperatures as assessed 30 min after the first drug administration on Day 1 of the experiment. All treatments except 4-MMC induced long-term deactivation compared with saline vehicle in multiple cortical regions including the primary motor cortex and secondary somatosensory cortex Figure 3A. The deactivations were not limited to the cortex but were also present in the midbrain and striatum. Conversely, 4-MMC caused statistically significant activations in the primary and secondary somatosensory cortices and in some regions of the midbrain including the tectum. Effect of treatment on brain activity. A All treatments compared to the saline control. Signal intensities from 34 ROIs expressed as intensities relative to the saline-treated control group are shown in Table 1. Confirming previous results den Hollander et al. METH produced significant decreases in brain activity in DA terminal regions Table 1 as well a multitude of cortical and subcortical regions, including the cingulate and limbic cortex, ventral hippocampus, dorsal thalamus and raphe nucleus. In EtOH-treated animals, a decrease in brain activity was observed as compared with saline-treated group Table 1. This effect was most notable in DA terminal regions, such as the nucleus accumbens and caudate-putamen and throughout several cortical and subcortical regions, including the cingulate and prelimbic cortex and the bed nucleus of the stria terminalis. Brain regions which showed the most notable changes and had distinguishable dendritic spine morphology were chosen for analysis. With those criteria hippocampal CA1, nucleus accumbens and caudate-putamen were selected for analysis for representative examples, please see Figure 4. One representative dendrite section from the hippocampus, nucleus accumbens and caudate putamen shown as an example of the labeling process. Figure 5. Spine density per spine type shown in the hippocampus, nucleus accumbens and caudate putamen. Here we show that co-administration of EtOH with 4-MMC in a binge-abuse model produces a widespread pattern of neuronal deactivation in monoamine-rich brain areas when assessed with MEMRI two weeks after the last drug administration. This pattern of widespread deactivation is in contrast with the effect seen when 4-MMC was administered alone. However, when examining neuronal morphology in the hippocampus, nucleus accumbens and caudate-putamen, the three regions showing the strongest neuronal deactivation in animals treated with 4-MMC and EtOH, we found no morphological changes to dendrites suggestive of long-term neurotoxic effects. When administered alone, 4-MMC produces a subtle pattern of long-term neuronal activation in regions like the retrosplenial and primary somatosensory cortex, as well as the dorsal hippocampus, thalamic areas and the superior colliculus. These areas are not strongly innervated by DA, and the observed changes plausibly do not reflect DA neurotoxicity. A potential explanation for the increased neuronal activity is that during 4-MMC intoxication, it has been shown that plasma cortisol levels are elevated Papaseit et al. Elevation of cortisol levels in acute stress via the serotonergic effects on the hypothalamo-pituitary-adrenal axis has been shown to activate regions important for memory consolidation, like the hippocampus Herman and Cullinan, ; Kim et al. Interesting in this regard is that 4-MMC was shown to reduce memory performance 2 weeks after a similar binge-regimen as employed in this study without causing any reductions in monoamine levels that could be indicative of toxicity den Hollander et al. The pattern of widespread neuronal deactivation seen following treatment with 4-MMC in combination with EtOH as well as following METH, either alone or in combination with EtOH, is striking considering the anatomical correlation of the deactivation pattern with brain regions innervated by DA nerve ending and typically implicated in neurotoxicity of amphetamines Ares-Santos et al. Nonetheless, even the areas showing the strongest deactivation did not display signs of neurotoxicity as assessed by subsequent Golgi staining and dendritic spine analysis. This raises the question what the exact neurochemical correlates of the MEMRI deactivation pattern are. It is thus possible that the 4-MMC and EtOH-induced deactivation observed here reflects the long-term functional effects of increased oxidative stress-related adaptation in synaptic terminals. Considering that the EtOH dose employed in this study was moderate it is worth noting that neuronal deactivation as assessed by MEMRI should not be considered as conclusive evidence of neurotoxicity, although such a correlation has been observed previously Weng et al. The exact neurochemical correlates of altered activation patterns remain to be determined and until then the data must be interpreted with relative caution. Despite these caveats, our results appear in agreement with previous studies that have generally failed to observe neurotoxicity following administration of 4-MMC at normal ambient temperatures Angoa-Perez et al. Although there are some reports of neurotoxicity as assessed by levels of monoamines, their transporters and tyrosine hydroxylase Martinez-Clemente et al. This raises the question as to what pharmacological differences between 4-MMC and METH result in the latter much more readily inducing neurotoxicity in animal models. Anneken et al. However, their experiments showed that combining the drugs with l -DOPA, which increases the size of the release pool, did in fact not precipitate any 4-MMC neurotoxicity while enhancing the toxic effects of METH. In a subsequent experiment, the same group investigated whether differences in how the two drugs modulate core body temperatures may be responsible for differences in toxicity using tryptophan hydroxylase 2 knockout mice lacking brain serotonin. However, they reported that although the knockout mice did not experience the characteristics hypothermic response, no increase in toxicity was observed in the knockouts vs. Another possibility is that 4-MMC has a different effect of mitochondria than METH, which has been associated with mitochondrial-dependent mechanisms of toxicity Shin et al. However, 4-MMC in fact appears to also affect mitochondria. It has been shown to impair mitochondrial complexes II and IV, collapse mitochondrial membrane potential, induce mitochondrial swelling and lower mitochondrial respiration in vitro den Hollander et al. Nonetheless, in the case of 4-MMC, these in vitro results do not generally appear to translate into measurable neurotoxicity in vivo. In this study, core body temperatures vs. Since hyperthermia was seen in stimulant-treated groups and not affected by EtOH co-administration, any differences observed between groups were not due to a differing hyperthermic reaction in this study. Golgi staining followed by spine analysis has been suggested to be an effective and unbiased way to assess neuronal changes at the dendritic spine level Risher et al. This has also proven to be the case with stimulant-induced changes in dendritic spines Robinson and Kolb, ; Robinson and Kolb, However, in the present experiment, no statistically significant alterations were found in the spine analysis in three relevant brain regions. This lack of changes could be due to the limitations in Golgi staining, such as variability of staining intensity, variability in localizing the brain area within thick brain sections or the random nature at which neurons of different types are stained which is inherent to the Golgi method. Stimulant-induced increases in striatal spines have been found in studies in which prolonged psychomotor sensitization has been detected Li et al. Another aspect to be taken into account is the fact that changes in spine formation, deformation and maturation can be very fast and bidirectional Nagerl et al. To our knowledge there has been no previous research to assess the temporal stability of stimulant-induced alterations in spine morphology. It is possible that stimulant-induced alterations in spine morphology are not stable enough to persist following the 2-weeks recovery period after treatments. Lastly, it is conceivable that the isoflurane anesthesia employed during the MEMRI scanning could have produced alterations or reversals in morphology considering the fact that isoflurane has previously been associated with activation of neurotrophic signaling, but not with spine structure changes Antila et al. A limitation of this study is that only Golgi staining was employed to interpret the neuronal activation patterns observed in MEMRI experiment. The assessments of levels of monoamines or their transporters, as well as other assessments of inflammation and oxidative stress during and following the binge regimen could have provided further insights into potential causative factors. Also, other type of silver staining or terminal deoxynucleotidyl transferase dUTP nick end labeling could be used to assess cell-level neurotoxicity. Moreover, assessments of neurocognitive and neuropsychiatric function such as memory, mood and anxiety tests, could have provided further information about functional effects. These are aspects which will need to be addressed in future studies. When administered on its own, the effects of 4-MMC on neural activity are subtle, anatomically limited, and likely not reflective of long-term neurochemical perturbations. However, when administered in combination with EtOH, it produces a pattern of widespread neuronal deactivation in brain regions densely innervated by DA neurons similar to what is seen after METH. The deactivated regions nonetheless do not show clear morphological changes indicative of toxicity. This suggests the deactivation pattern is likely due to long-term neurochemical perturbations that are substantial but not so severe as to produce overt neurotoxicity. In conclusion, this study suggests that binge-treatment with 4-MMC on its own does not substantially alter brain activity, but in combination with EtOH may result in long-term reductions in brain activity. This is important from a harm-reduction perspective, although further studies are needed to outline the exact neurochemical changes responsible for the altered activity patterns. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. MG and BdH wrote the manuscript. All authors reviewed and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Front Pharmacol. Find articles by Milo Grotell. Find articles by Aaro Jalkanen. Find articles by Jouni Ihalainen. Find articles by Elena de Miguel. Find articles by Mateusz Dudek. Find articles by Mikko I Kettunen. Find articles by Markus M Forsberg. Find articles by Esko Kankuri. Find articles by Esa R Korpi. Korpi, esa. Received Mar 12; Accepted Apr 12; Collection date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Interstitial nucleus of the posterior limb of the anterior commissure.
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