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Official websites use. Share sensitive information only on official, secure websites. Specialty section: This article was submitted to Addictive Disorders, a section of the journal Frontiers in Psychiatry. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor 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. A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. After the emergence of a novel psychoactive substance NPS and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. This review shows not only emerging harm potentials but also some potential medical applications. It appears to be a human trait to constantly seek for new psychoactive substances and to explore potential use of them. As long as human record keeping dates back, humans consume psychoactive plant preparations. Despite the risk of being toxic upon single or chronic consumption, there are constantly new drugs that find their way into drug-taking communities 3. Novel stimuli and novel information about the external world have an incentive salience and maintain seeking behavior in animals and in humans 4 , 5. Human brains generate distinct working modes that are subjectively perceived as mental states. This is at the neurobiological side believed to be organized by the summatory tonic activity of modulatory transmitter systems. Mental states can determine how an organism perceives, processes, and stores external and internal information. It also affects how efficiently behavior is generated 6 — 8. Mental states change spontaneously or as a consequence of environmental influences, thereby some mental states are perceived as more pleasurable and useful for goal-directed behavior than others. The rewarding value of novelty may, thus, be expanded to novel mental states, which have never been incurred by natural means. Psychoactive substances can induce and maintain a desired mental state. Some of them may also provoke novel mental states. Most psychoactive substances, however, induce mental states that are primarily useful for other purposes. In that, they exert complex reinforcing effects during drug instrumentalization 6 — Thus, the mental state that is induced by a psychoactive drug and for which humans develop a memory 11 may facilitate other behaviors with positive or negative reinforcing outcome, such as the facilitation of social interaction, mating behavior, coping with stress, and cognitive enhancement 9 , 12 — When a new drug is discovered and experimentally used, the new user may not only judge the novelty and emotional impact of the newly experienced mental state but subsequently decide for what purposes this new mental state may serve 17 , Once a new drug is made available, an experimental consumption starts that determines individual subjective effects as well as context and possibility of instrumentalization. This may not only work in humans but also for a newly experienced psychoactive drug in animals A major factor that fuels continuous search for new psychoactive drugs is the need to replace existing ones in routine use. Once a long known drug has been criminalized and banned, availability of the drug becomes limited. Legal control imposes punishment on drug possession, trade, and use, which limits its instrumentalization for frequently performed behavior, such as coping with stress If the drug was useful for this behavior, e. The way of a NPS in society, from its introduction, experimental use, instrumentalization, habitual abuse, up to its legal control, depends essentially on the relationship of adverse side effects and potential medical use. The adverse side effects are those effects of the drug that threaten the physiological integrity and behavioral repertoire of the whole organism, beyond the desired psychoactive action. Many known psychoactive drugs are strong toxins and harm the user. This can occur after acute consumption or after chronic intake 3. Humans establish cultural rules for the consumption and the control of side effects of psychoactive drugs This keeps even highly dangerous drugs, such as alcohol, legal and limits their harm potential when incorporated in cultural activities Drugs can be labeled as addictive drugs and made illicit. However, many new substances are at the same time tested for a potential beneficial application, e. There is occasionally also a reversal of the discourse decision in that addictive drugs may receive an additional medical application, e. Newly introduced psychoactive substances do not usually arise from controlled pharmacodevelopment. However, the drug discourse requires evidence, ideally scientific, arising from controlled experimentation. This evidence should go well beyond the accumulation of single cases. Quite naturally, during the information collecting period, the NPS is used, and thus, not brand new anymore. What is new afterward is the certainty with which sufficiently reliable statements about the drug can be made It has to be admitted that the legal status discourse is in practice way more complicated and also culturally selective, which shall not be the focus of this review that rather focuses on the neurobiological evidence that feeds into this discourse. In this article, we review the state of knowledge on a number of NPS for which now a considerable penetration of society has developed in distinct cultural or geographical regions and for which sufficient evidence has been gathered to allow for evidence-based statements. This should provide a comprehensive overview on some of the currently most relevant NPS, thereby the choice of substances discussed was driven by the perceived progress in the understanding of their neuropharmacological action by the authors. In that, the review does not provide a complete coverage of all currently available NPS. Mitragyna speciosa Korth. In Malaysia, M. Previous studies mainly described the traditional uses of Kratom among rural folk, peasants, and laborers in Southeast Asia 33 , 35 , More recently, studies on Kratom use are emerging from Europe and the US 37 — They suggest that Kratom is now also used outside its traditional context. Kratom leaves are also used as an opium substitute to treat morphine addiction in Malaysia and Thailand 31 , Because of its unique healing properties, rural inhabitants use Kratom leaves to treat various medical conditions such as cough, fever, pain, diarrhea, diabetes, and hypertension 32 , 44 , However, Kratom is potentially addictive and chronic users find it difficult to refrain from prolonged Kratom use 33 , 36 , The common side effects of long-term use include constipation, weight loss, hyperpigmentation, dehydration, fatigue, insomnia, and increased urination 33 , 36 , The majority of Kratom users believe its use is not as harmful as those of other illicit substances, such as methamphetamine and heroin, and that Kratom dependence carries little or no health risks 45 — So far, there have been no deleterious incidents directly related to Kratom use in Southeast Asia. Only one study from Thailand has reported Kratom poisoning cases, with palpitation, seizure, and nausea. However, these effects may have been arisen from coadministration of other illicit substances Regular users are more likely to increase the quantity and frequency of Kratom use over time. In Thailand, traditional users often chew fresh or powdered Kratom leaves 33 , In the US and in Europe, Kratom is primarily used as a natural alternative to self-medicate for chronic pain and as an opioid withdrawal treatment 37 , 50 , As a consequence of the rise in Kratom mortality and toxicity cases in the West, regulatory agencies have begun to view Kratom negatively 39 , 53 , However, it appears that most, if not all of the Kratom-induced medical complications in the West were triggered by the use of adulterated Kratom products 53 , About 40 alkaloids have been identified in M. The alkaloid content in the leaves varies, depending on geographical location and season of harvest Mitragynine and 7-hydroxymitragynine are the principal psychoactive constituents of M. The synthesis of the mitragynine was reported by Takayama et al. Thus, direct isolation of mitragynine from the leaves is much more efficient and cost-effective. A comprehensive pharmacokinetic description of mitragynine in rats was provided by Parthasarathy et al. The blood concentration peaked at 1. The volume of distribution was rather small with 0. Mitragynine is a lipophilic alkaloid with poor water solubility Mitragynine has a biphasic metabolism. The first phase produces seven identified metabolites, thereby mitragynine is processed through hydrolysis of methyl ester in position 16 and O-demethylation of the 9-methoxy- and of the methoxy groups The second phase involves further oxidation to carboxylic acids or reduction to alcohols and the combinations of some steps via the intermediate aldehydes. Four metabolites were additionally conjugated to glucuronides and to sulfates in rats and humans Abuse of mitragynine and related compounds can be detected through gas chromatography or liquid chromatography with mass spectrometry, respectively 65 — It was also found to inhibit forskolin-stimulated cyclic adenosine monophosphate cAMP formation in vitro in an opiate receptor-dependent way 73 , A study by Fakurazi et al. Mitragynine was extensively investigated for its antinociceptive effects. A study by Reanmongkol et al. Another study showed prolonged antinociceptive effect in both tests Intraperitoneal administration also yielded positive antinociceptive results in the hot plate, formalin-, and acetic-acid tests In animal models, mitragynine induces anxiolytic effects after acute treatment in several test paradigms Withdrawal from chronic mitragynine induces anxiety-related behavior in rats There have been conflicting reports of mitragynine affecting cognitive function. Apryani et al. Another study, however, showed no impairment of short-term memory in the Y-maze task. The mice, however, were given M. In rats, a study showed an increase in learning ability when given M. However, mitragynine alone did not have significant effects on long-term memory consolidation in both tasks In parallel, mitragynine-treated rats showed a disrupted low frequency rhythm delta and theta in the electroencephalogram EEG , which may account for the learning and memory impairments Thus, mitragynine likely possess both opioid and psychostimulant effects. These effects are opiate receptor dependent and can be blocked by the opiate receptor antagonist naloxone Altogether, Kratom and its main psychoactive ingredient mitragynine are drugs that are widely used in Southeast Asia with an increasing appearance in Western countries. Experimental studies in animals have now shown that mitragynine has an addictive potential, however, only at higher doses. Human users in countries of frequent use with a traditional context report a rather low daily consumption with only mild side effects. Kratom and mitragynine can be instrumentalized to enhance physical work power and endurance. A major reason for Kratom consumption is its reported efficacy to replace opiates in chronic users. This makes the Kratom plant preparation and also the isolated compound mitragynine interesting options to treat opiate addiction. The abuse of herbal preparations spiked with synthetic cannabinoids is still increasing. Synthetic cannabinoid preparations are frequently mislabeled as research chemicals, herbal incenses, or as legal highs, including the explicit warning that it is not for human consumption 92 — The first evidence of synthetic cannabinoid use as a recreational drug appeared in However, a wide spread use of synthetic cannabinoids did not emerge until Research in the active ingredients of synthetic cannabinoids such as Spice and their neuropharmacological action has revealed several hundred compounds that are artificially added to a carrier medium of herbal origin The synthetic compounds usually display a high affinity for cannabinoid receptors CB-R , which reaches far beyond that of natural cannabinoids , Synthetic cannabinoid preparations also lack the naturally occurring cannabidiol, which is present in cannabis preparations and which is supposed to antagonize some of the psychotogenic effects of THC , However, the variability in substance composition and amount between one package and another is high and largely unpredictable. Additional ingredients have been found and may include, e. The latter is usually added to blur chemical detection — Occasionally, some investigated herbal preparations did not contain any pharmacologically active synthetic cannabinoids, but only psychoactive compounds from plant-derived carrier material, such as mitragynine — Users report that synthetic cannabinoids can cause psychotropic effects that are qualitatively similar, but much more intense, than those of cannabis. Additional diffuse effects, which are different from cannabis, include palpitations, tachycardia, and unspecific effects in the electrocardiogram , , Harmful somatic effects comprise gastrointestinal and renal defects 91 , — Neuropsychiatric symptoms were reported, such as psychosis, panic and anxiety attacks, agitation, and aggressive behavior , , , A psychosis induced by synthetic cannabinoids manifests by delusions, acoustic and visual hallucinations, and paranoia. Neurological symptoms may include seizures, dystonia, and tremors. Other frequently reported side effects are nausea, vomiting, diaphoresis, and respiratory depression — Use of synthetic cannabinoids may have fatal consequences. Reported single cases mention coronary ischemic events and suicide caused by an extreme anxiety attack , Synthetic cannabinoids were originally developed for research purposes in the s with the goal of better understanding the endogenous cannabinoid pathways and to develop pharmacotherapies for conditions such as cancer-associated pain Synthetic cannabinoids may contain aminoalkyl-indoles of the JWH series, which was first synthesized by the chemist J. These compounds are lipid-soluble, non-polar, and typically contain 20—26 carbon atoms. However, there are at least chemically related compounds currently known , — While some of them have been legally controlled on individual level, recent legislation in Germany now considers the lead structures and attempts to control whole drug classes. It is expected that this will make it more difficult to simply replace single banned compounds by their substituted analogs in the synthetic cannabinoid preparations , — At the current stage, one may conclude that synthetic cannabinoids constitute dangerous psychoactive drug preparations with a rather chimeric nature It is not a single compound, but draws from a plethora of already available synthetic cannabinoids that are unsystematically mixed and brought on a plant carrier material, that may even by itself have psychoactive effects. The natural claim is now clearly rejected by the understanding that most psychoactive effects are brought about by purely synthetic compounds added to a natural carrier. Given the strong cannabinoid-like effects of synthetic cannabinoids, which are now increasingly understood, single substances have been legally banned. But this has done little damage to the unique drug design of synthetic cannabinoid preparations in that single disallowed compounds were almost immediately replaced by substituted analogs that had not been banned yet. The now emerging control of whole substance classes will most likely put an end to this strategy and help to reduce harm that is clearly associated with synthetic cannabinoid consumption. N - N -dimethyltryptamine DMT is an indole alkaloid found in plants and animals. It has been proposed that the endogenous DMT may act as a neurotransmitter. DMT is a natural psychedelic substance and has similar effects as other serotonergic hallucinogens such as lysergic acid diethylamide LSD , psilocybin, and mescaline. When DMT is ingested at high concentrations, the user experiences episodic visual hallucinations , The recreational use of DMT has been rising for its acclaimed self-perceived benefits. Capsules, known as pharmahuasca, became available containing DMT as a free base together with some monoamine oxidase inhibitors MAOIs , such as synthetic harmaline, or plant-based MAOIs such as Harmala alkaloids , The MAOIs inhibit the otherwise rapid metabolization of DMT and, thus, allow for the hallucinogenic effects when the drug is taken orally. Endogenous DMT can be found in the human brain and other tissues of the body such as blood, urine, cerebral spinal fluid , , , and the pineal gland , Synthesis of endogenous DMT begins with the decarboxylation of tryptophan to tryptamine. N -methyltryptamine NMT and DMT are the products of methyl group additions to tryptamine by the enzyme indolethylamine- N -methyltransferase DMT levels were found to increase under stress in the rodent brain and adrenal gland It was suggested that endogenous DMT has a role in cellular protective mechanisms The routes of DMT administration are via smoking or snorting. For the hallucinogenic or psychedelic effects to occur, an oral formulation must contain MAOIs to prolong the half-life of DMT in the body. MAOIs block the enzyme in the stomach after which DMT is able to be absorbed through the stomach lining into the blood stream. An oral dosing of DMT, e. DMT also interacts with various ionotropic and metabotropic receptors in the glutamate, DA, and acetylcholine systems. DMT does not affect DA receptors but may alter DA levels in the brain with subsequent neurochemical and behavioral effects. Chronic DMT induces tolerance for some behavioral and subjective effects. However, it failed to elicit tolerance to the disruption of responding maintained on a fixed-ratio schedule of food reinforcement , Beside its sought-after acute effects, DMT can cause considerable side effects. The ingestion of DMT may induce intense fear, paranoia, anxiety, grief, and depression, which may result in physical harm to the user or others There have been no serious adverse events reported on long-term use of DMT apart from the acute cardiovascular effects. Single and repeated administrations of DMT produce marked changes in the cardiovascular system In fact, DMT has been reported to act as neuroprotective agent, working via Sigma-1 receptor Sig-1R activation — Sig-1Rs activate the antioxidant response elements Hence, DMT may function as an indirect antioxidant. Frecska et al. At the same time, it may serve mechanisms such as neuroprotection and neuroregeneration. Interestingly, ayahuasca and DMT mixtures have been proposed as a treatment for psychiatric disorders. Symptoms of schizophrenia, such as delusions and hallucinations, have been assumed to involve activation of 5-HT 2A -Rs along with changes in the DA system , Endogenous DMT has been reported to be increased in schizophrenic patients during psychotic episodes indicating that the endogenous DMT signaling pathway might be a treatment target for schizophrenia. Based on animal models and on clinical studies in humans, DMT has potential antidepressant and anxiolytic effects , possibly mediated by a 5-HT 1A -R agonistic action Further therapeutic applications include the treatment of cancer and inflammations. DMT has been shown to increase immune system activity , Sig-1R activation can reduce pro-inflammatory cytokines and enhance the production of the anti-inflammatory cytokine IL In conclusion, DMT is a naturally occurring psychoactive compound found in various plants. It is now understood that its main psychoactive effects are mediated by 5-HT 2A -R activation. Endogenous DMT may play a role in the immunoregulation in peripheral and brain tissues. Preliminary evidence now suggests a possible therapeutic use of DMT. Since thousands of years, indigene cultures in North and South America have used plants and mushrooms containing serotonergic hallucinogens for shamanic rituals and religious ceremonies Classical serotonergic hallucinogens usually have either a tryptamine or phenylethylamine basic structure Typical tryptamines, such as psilocybin and its psychoactive metabolite psilocin, 5-methoxy- N , N -dimethyltryptamine 5-MeO-DMT , and bufotenine, resemble in their structure the neurotransmitter 5-HT, while the phenylethylamine mescaline has a similar basic structure as the neurotransmitter DA and as amphetamines. However, all 5-HT hallucinogens have in common that they induce altered states of consciousness , According to Hollister , the psychoactive effects of classical serotonergic hallucinogens usually include 1 somatic symptoms: dizziness, weakness, tremors, nausea, drowsiness, paresthesia, and blurred vision; 2 perceptual symptoms: altered shapes and colors, difficulty in focusing on objects, sharpened sense of hearing, and rarely synesthesia; and 3 psychic symptoms: alterations in mood happy, sad, or irritable at varying times , tension, distorted time sense, difficulty in expressing thoughts, depersonalization, dream-like feelings, and visual hallucinations. All tryptamine- and phenylethylamine-based hallucinogens share the agonistic mechanism of action at postsynaptic 5-HT 2A -Rs and 5-HT 2C -Rs, where they act as partial, mixed-partial, or full agonists , In animals and humans, 5-HT 2A -R antagonists such as ketanserin are able to block most of the behavioral and psychotropic effects of psilocybin, mescaline, DOI, and LSD, indicating that the 5-HT 2A -R agonism is necessary for the induction of psychedelic effects — These additional mechanisms are likely to contribute to the specific psychotropic effects of each compound , , A decade ago, it has been proposed that only 5-HT 2A -Rs coupled to metabotropic mGluR2 mediate the psychotogenic effects of 5-HT hallucinogens —a position that has been questioned recently In addition, they increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic 5-HT 2A -Rs located on large glutamatergic pyramidal cells in deep cortical layers V and VI. Historically, LSD was probably one of the first NPS of the hallucinogen class as it was a semi-synthetic compound whose psychedelic effects have only accidentally been discovered by its inventor Albert Hofmann in Shulgin, who synthesized hundreds of novel hallucinogenic tryptamines and phenylethylamines in his home laboratory. He created several dimethoxy-substituted phenylethylamines, such as DOM, 2,5-dimethoxybromoamphetamine DOB , 2,5-dimethoxyiodoamphetamine DOI , and 2,5-dimethoxyethylamphetamine DOET , which all display strong hallucinogenic properties. Because their structure can be easily changed without losing their psychoactive properties, 2C drugs have, thus, often been referred as a typical class of designer drugs However, their human toxicology and their consequences are still unknown as they are neither used frequently nor purely enough in order to systematically investigate their chronic effects in recreational users. In the last decade, a substantial amount of new serotonergic hallucinogens appeared on the drug markets. As their number grows each day, it is simply not possible to list them exhaustively here. Thus, only some prototypical exponents of each class will be discussed. Again the main classes are either tryptamines and related ergolines or substituted phenethylamines but also some new classes such as benzodifurans and aminoindanes occurred — They combine hallucinogenic effects with stimulant and empathogenic features , They are slightly more potent as LSD and have a comparable duration of action. They are also mostly marketed as blotters , Anecdotal user reports consider them as very strong hallucinogens , , At least 5-IAI was recently demonstrated to show a strong affinity for 5-HT 1A -Rs and 5-HT 2A -Rs, thus, indicating that aminoindanes can not only be empathogens, but they can also display hallucinogenic properties At the moment, systematic investigations on the prevalence of novel serotonergic hallucinogens are rare. In the global drug survey of , Moreover, 2. For comparison, It should be noted that DMT was the only hallucinogenic NPS that was systematically asked for but that participants were given the opportunity to type in the names of NPS they used, indicating that these numbers are likely underestimated Overall frequencies for the development of acute psychosis following experimentally administered LSD range between 0. However, if 5-HT hallucinogens can also induce long-lasting psychotic disorders is still controversially discussed Moreover, also nausea and vomiting, serotonin syndrome including hyperthermia, liver and kidney failures, and cardiovascular complications have been reported for serotonergic hallucinogens. The acute toxicity of high potency dimethoxyphenylethylamines, NBOMEs, and 2C drugs seems to be considerably increased compared to classical hallucinogens. It is highly likely that potent novel serotonergic hallucinogens bear a strong risk to induce HPPD too. In general, 5-HT-Rs show considerable plasticity after exposure to serotonergic drugs. Accordingly, due to post-transcriptional mechanisms, 5-HT 2A -Rs show a rapid and long-lasting downregulation in response to 5-HT agonists — This might explain the strong tolerance effect of 5-HT hallucinogens Recently, it was shown that 5-HT hallucinogens can also reduce either 5-HT 2A -R binding sites or glutamate-binding sites and that tolerance effects were correlated with changes in both binding sites High potency 5-HT hallucinogens—specifically if they have a long duration of action—are probably neurotoxic due to their sustained activation of 5-HT 2A -Rs that can induce apoptosis in neurons Thus, it is likely that all long-acting dimethoxyphenylethylamines, 2C drugs, NBOMes, tryptamines, and ergolines with strong agonistic actions at 5-HT 2A -Rs have a neurotoxic potential. In conclusion, beyond LSD, mescaline, and psilocybin, a vast amount of new serotonergic hallucinogens appeared on the drug market during the last decades. Their distribution has strongly increased and will likely further increase in the future due to their easy availability on the Internet. Alarmingly, little is known about the acute and chronic effects of novel 5-HT hallucinogenic drugs in human users. The neuropsychiatric long-term consequences of regular intake of such compounds are completely unclear. However, it is becoming increasingly apparent that high potency drugs with very strong affinities to 5-HT 2A -Rs and long durations of action bear a considerable risk for negative health effects and fatalities. However, an exhaustive discussion of all of them is not possible here due to space restrictions Thus, in this section, the two generic compounds, mephedrone and methylone, are discussed as important examples. Mephedrone 4-methylmethcathinone is a substituted cathinone homolog of ephedrine first described in , Mephedrone has a ring-substituted cathinone structure which is related to the phenethylamine family, to which also drugs such as amphetamine, MDMA, and methamphetamine belong to As a hydrochloride salt, mephedrone is a water soluble white, yellow, beige, or brown powder. Mephedrone is available on the Internet, or from street dealers. On Internet sources, mephedrone is often marketed as bath salt, plant fertilizer, or research chemical , Mephedrone was first identified as an abused drug by European authorities in , By , mephedrone use spread, and the drug was found in many European countries Mephedrone is frequently used together with other synthetic cathinones, such as methylone, butylone, or ethylcathinone The predominant user populations are teenagers and young adults , thereby use of new psychoactive cathinones is highly correlated with binge-drinking habits in young adults Mephedrone can be consumed by different routes. In an oral preparation, mephedrone powder is rolled up in cigarette paper bombing. Furthermore, intranasal, intramuscular, intravenous slamming , and rectal routes of administration have been reported Mephedrone is also mixed with other drugs, such as heroin, alcohol, cocaine, MDMA, or cannabis , Consumption usually takes place in a social context at home, at rave parties, clubs, or music festivals. Intranasal mephedrone elicits rapid effects within minutes. The sought-after psychoactive effects of mephedrone comprise an elevated mood, the feeling of an intense euphoria, a sense of well-being, increased self-esteem, motor excitation, reduced tiredness, increased alertness and concentration, talkativeness, empathy, disinhibition, and a mild sexual stimulation , , Those include cardiovascular, gastrointestinal, and neurological side effects , Well-described effects are also jaw clenching, reduced appetite, increased body temperature, increased sweating, abnormal vision, dilated pupils, headaches, tachycardia, palpitations, hypertension, arrhythmias, chest pain, nausea, bruxism, teeth grinding bruxism , rhabdomyolysis, and renal failure An important dangerous side effect is the significant hyponatremia. This is similar to that shown after acute MDMA consumption. It is supposed to be induced by a combination of sweating, electrolyte loss, and antidiuretic hormone secretion The intranasal application of mephedrone is associated with a significant nasal irritation. Mephedrone addiction is often associated with intravenous drug use that is also found to be linked to an increased risk of using other addictive drugs Intravenous mephedrone injections often result in vein blockages, leading to localized infections, blisters, abscesses, scabs, lumps, gangrenous tissue, blood clots, and large necroses at the injection site Major adverse psychiatric effects associated with mephedrone use include agitation, anxiety, dysphoria, depression, insomnia, hallucinations, paranoia, delusions, aggressive behavior, as well as suicidal ideation and suicidal action. Cognitive impairments affect short-term memory and attention span Psychotic effects predominantly occur after a high mephedrone dose, after binge consumption in one session, and in users with an individual vulnerability for psychiatric disorders — Fatalities resulting from mephedrone use have been reported worldwide now They are related to hyponatremia and brain edema — However, the lethal dose LD 50 is not known yet Accumulating evidence suggests that mephedrone has a clear addiction potential , , The abuse potential for intranasally consumed mephedrone was suggested to be comparable with that of cocaine or methamphetamine Mephedrone withdrawal effects include tiredness, insomnia, impaired concentration, irritability, tremor, temperature dysregulation, palpitations, headaches, depression, anxiety, and paranoia , , Virtually all synthetic cathinones are considered to inhibit the monoamine uptake in the brain, thereby mephedrone acts as a substrate for the transporter proteins and evokes a reverse neurotransmitter transport and, thus, neurotransmitters release , , Synthetic cathinones including mephedrone are now classified as illicit substances in many countries However, since the legal ban of single substances came in place, various second-generation analogs have appeared, including 4-methyl- N -ethylcathinone 4-MEC. The consumption may in the long term only effectively be limited when whole substance classes, i. Methylone 3,4-methylenedioxymethcathinone is a substituted cathinone methylated on the amine group of the keto-phenethylamine backbone. It has a chemical structure similar to that of MDMA by a methylenedioxy ring attached to the aromatic ring Methylone was first synthesized in as a potential antidepressant and anti-Parkinson agent , which, however, never made it into pharmacotherapy. Methylone was marketed initially in a liquid solution as a vanilla-scented room odorizer. Following its introduction in , methylone could be purchased in the Internet and in headshops , where it was sold in powder form and as tablets Methylone use has been reported to be high in the club scene and in addicts on substitution therapy Similar to other cathinones, methylone can be administered by different routes, such as orally, intranasally, intravenously, sublingually, or rectally. The most popular route is the oral administration. They have been described as an amphetamine-like stimulation with calm euphoria, happiness, thought acceleration, alertness, restlessness, reduced fatigue, and increased locomotor activity. They might also involve MDMA-like entactogenic effects with a strong sense of emotional openness, enhanced empathy, and reduced fear A methylone high can be from moderate to extreme euphoria with tingling sensation , The adverse effects of methylone include anxiety and psychosis with derealization, depersonalization, hallucinations, and suicidal ideation. Cognitive impairments affect the short-term memory Furthermore, methylone may induce seizures and hyponatremia, similar to that induced by MDMA. Methylone may also induce a hyperthermia This is believed to be a major cause for the fatal consequences of a methylone overdose Other factors in fatal overdose can be cardiac events, metabolic acidosis, rhabdomyolysis, acute renal failure, intravascular coagulation, and a serotonin syndrome — Accumulating evidence suggests a considerable addictive potential of methylone , Much like mephedrone, methylone acts as a monoamine reuptake blocker that leads to a profound hyperactivity of DA, 5-HT, and NA in the brain and periphery In particular, dopaminergic and serotonergic adaptations in the brain may drive the addiction potential of psychostimulant drugs , The use and abuse of the substance emerged with considerable side effects around the world The legal ban of methylone started in with now an increasing number of countries controlling it It has been widely used in clinical settings as an anesthetic agent and in veterinary medicine. However, ketamine is also recreationally consumed in entertainment settings for its hallucinogenic, mood enhancing, and reinforcing properties by young club goers 28 , — Ketamine is a derivative of phencyclidine PCP , which was discovered as anesthetic in and became a popular street drug during s Ketamine is regulated in many countries due to its abuse potential as a psychotropic substance A significant number of studies have demonstrated that ketamine has a short-acting antidepressant effect and is increasingly used to treat therapy-refractory major depression and pain 29 , — Although ketamine is viewed as a safe substance in medical settings, its recreational use is reported to impose adverse effects on users by producing neurological and peripheral toxicity , Ketamine can be administered through intravenous, intramuscular, smoking, and snorting routes Apparently, snorting or intranasal use is the main route of ketamine consumption among recreational users Ketamine produces dose-dependent effects. Lower doses are associated with a feeling of relaxation. Chronic ketamine use is reported to induce schizophrenia-like positive and negative symptoms, including hallucinations, detachment, delusion, auditory, and verbal hallucinations A major concern of ketamine use is that people drive under the influence of the drug Ketamine can impair cognitive functioning, such as executive and memory function, as well as attentional control , Ketamine users are also more vulnerable to HIV infections. The use of the drug is reported to enhance sexual experience and predispose users to engage in unprotected sex , Some of the most common complaints of ketamine use include chest pain, palpitations, and tachycardia However, these symptoms are often transient Abdominal pain and urinary tract symptoms, such as suprapubic pain, dysuria, and hematuria, are common symptoms of chronic regular ketamine use — Findings from clinical case studies have shown that ketamine use can decrease bladder volume, bladder wall thickening, mucosal enhancement, dilation of ureter, and cause perivesical inflammation , The renal toxicity of ketamine is due to the direct toxic action of ketamine and its metabolites Fatigue, poor appetite, drowsiness, craving, anxiety, sleeping problems, and dysphoria are common physical and psychological side effects of ketamine use , Currently, there is no specific treatment for ketamine users presenting with peripheral toxicity. However, it was reported that cessation from ketamine abuse may lead to a recovery from organ damage Despite its abuse potential and reported side effects, ketamine has promising medicinal properties. Currently, it is used to treat therapy-refractory depression , although the antidepressant effect of a single infusion only last for some days. Despite that development, which moved the drug increasingly out of the drug abuse focus, proper prevention strategies for young club goers engaged in recreational ketamine use are still warranted. Moreover, addiction experts warned recently that psychiatrist should not underestimate the addictive potential of ketamine when treating depressive patients with the drug It more generally denotes hallucinogenic drugs inducing dissociative states, including sensory alterations and hallucinations as well as dream-like states or trance More than 14 known derivatives of PCP have been marketed for non-medical but also illicit use already between the late s and the s. Starting with the first dissociative, 4-MeO-PCP in , thenceforth at least 12 novel dissociative drugs appeared on the drug marked, which were unknown in the scientific literature prior to their introduction to the drug market PCP, ketamine, and its novel derivatives belong to the chemical class of arylcyclohexylamines, which have in common that they act as non-competitive antagonists at the PCP-binding site of the NMDA receptor Beyond their high affinity for NMDA receptors, some of the arylcyclohexylamines have shown agonistic actions at DA receptors e. It is plausible that the specific receptor profile of each compound mediates its characteristic psychotropic effects Beyond the desired dissociative acute effects, these drugs exert a number of severe and sometimes fatal side effects. Following MXE ingestion, users were confused, agitated, hallucinating, and unresponsive. The somatic and neurological adverse effects included tachycardia, hypertension, ataxia, mydriasis, nystagmus, seizures, leukocytosis, massive rhabdomyolysis, hepatic failure, onset of acute renal failure, sinus bradycardia, elevated creatinine kinase, and hyponatremia However, animal studies have shown that MXE and likely all arylcyclohexylamines are in fact equally toxic for the bladder and the kidneys as ketamine when applied chronically Further chronic side effects of novel arylcyclohexylamines have not been investigated yet, but it is likely that the total class might have an addictive potential similar to that of ketamine and PCP , This seems to be specifically high in adolescents and young adults Moreover, like PCP and ketamine, all arylcyclohexylamines with a strong action at the NMDA receptor may impair memory function and induce psychotic symptoms after acute and chronic consumption , These drugs are used clinically for the treatment of neuropsychiatric disorders such as narcolepsy, alcohol withdrawal, and fibromyalgia but also instrumentalized illicitly for hedonic purposes The psychoactive effects of the drug result from this conversion , GHB is an endogenous short-chain fatty acid. While physiological concentrations of GHB seem to be insufficient to stimulate GABA-B receptors, the subjective and behavioral effects of the exogenously applied drug, and thus GBL and 1,4-BD, result from direct stimulation of these receptors All compounds are metabolized to water and carbon dioxide through the citric acid cycle A seemingly paradoxical pattern of concomitant sedation and stimulation was described in several reports , GHB, GBL, and 1,4-BD strongly influence behaviors related to core autonomic functions, such as the control of food intake, sexual behavior, and sleep—wake regulation GHB was reported to normalize dysfunctional food intake behavior and body weight in preclinical and in clinical studies — It was effective in the treatment of binge-eating disorder Confirming subjective reports from illicit GHB users — , the drug was experimentally shown to have prosocial , and prosexual effects in healthy male subjects Moreover, GHB and its precursors have a unique effect on sleep—wake regulation Since GHB improves sleep and daytime vigilance, it is used as standard treatment for disorders of the sleep—wake cycle, such as narcolepsy and fibromyalgia — Resting state EEG studies showed a paradoxical EEG-behavioral dissociation with the occurrence of increased delta and theta oscillations, during wake states, which usually occur during sleep , Moreover, increased nocturnal slow wave sleep under the influence of GHB was demonstrated Moreover, the drug increased the susceptibility of the mesolimbic reward system, resulting in an increased sexual arousal after the presentation of erotic but also neutral pictures of persons. This effect correlated with an increased activity in the nucleus accumbens and the ACC Reliable prevalence data are difficult to obtain After GHB was used in a deadly case of drug-facilitated sexual assault in the USA in the year , the drug was internationally banned However, a recent meta-analysis showed that GHB is very infrequently used as a date rape drug Both addiction and withdrawal can be severe and in extreme cases lead to psychosis, delirium, and death Interestingly, the development of addiction after medical use of GHB is at a very low rate with an estimated risk of about 0. Internationally, GHB is approved for the treatment of narcolepsy with cataplexy. In a recent meta-analysis, it was confirmed to be effective in treating major, clinically relevant narcolepsy symptoms and sleep architecture impairments in patients Another clinical indication is the treatment of alcohol withdrawal, for which GHB is used since two decades in Italy and Austria Moreover, several randomized controlled trials showed a therapeutic effect of GHB on clinical course and life quality in patients suffering from fibromyalgia , — Because disrupted homeostatic processes including food intake, sexual behavior, and the sleep—wake cycle frequently occur in major depressive disorder, GHB was proposed as an experimental therapeutic in this condition , However, therapeutic use of the drug is limited by side effects, such as nausea, vomiting, altered consciousness, and nocturnal O 2 desaturations , — These, however, seem to be outweighed by a unique spectrum of clinically relevant psychopharmacological effects, which warrant further studies in neuropsychiatric conditions such as major depressive disorder following a personalized treatment paradigm The amount of evidence on the psychoactive drugs discussed shows that many of them are not really novel anymore. For most of them a classification in terms of their use and harm potential has been made. In fact, most of them are already legally controlled or banned in certain countries. An important feature of this process is that it appears socio-geographically biased. Even in a globalized world, new psychoactive drugs emerge and spread in a regionally bound way. This brings about that evidence on their use, instrumentalization, and abuse accumulates often only regionally. Also, the drug may for a long time not spread beyond the socio-geographic boundaries. It also means to delineate future research needs for those drugs that are brand new as a psychoactive drug. This review shows that despite accumulating evidence, for many of those NPSs, a final classification is still in progress and gathering of more evidence is pivotal. CM and ZH planned the review article and contributed to several chapters. CM prepared the final version of the 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. As a library, NLM provides access to scientific literature. Front Psychiatry. Find articles by Zurina Hassan. Find articles by Oliver G Bosch. Find articles by Darshan Singh. Find articles by Suresh Narayanan. Find articles by B Vicknasingam Kasinather. Find articles by Erich Seifritz. Find articles by Johannes Kornhuber. Find articles by Boris B Quednow. Received Jun 1; Accepted Aug 2; Collection date 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.

Shrimps, drugs and rocks ‘n’ blow: Cocaine found in UK river wildlife

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Traces of cocaine, pesticides, and other illicit drugs were found in freshwater shrimps in Suffolk, UK. Traces of cocaine and other illicit drugs have been found in freshwater shrimps in the UK, a study released on Thursday has revealed. Scientists from King's College London and the University of Suffolk tested freshwater shrimps from 15 different sites across Suffolk, a largely rural area north-east of the UK capital. Cocaine was found in all samples tested. Other illicit drugs such as ketamine, pesticides and pharmaceuticals were also widespread. We might expect to see these in urban areas such as London, but not in smaller and more rural catchments,' Leon Barron from King's College London, said. Thomas Miller, the lead author of the study — published in the Environment International journal — said, however, that 'the potential for any effect is likely to be low'. Traces of cocaine and other drugs including amphetamine, methamphetamine and MDMA ecstasy were found in wastewater from approximately 46 million people across Europe earlier this year. The European Monitoring Centre for Drugs and Drug Addiction tested wastewater from 73 cities across the continent and detected higher levels of four illicit drugs than in Cocaine residues were highest in western and southern European cities, particularly in cities in Belgium, the Netherlands, Spain and the UK. By Alice Tidey. Share this article Comments. Share this article. You might also like Scientists race against time to tackle the expanding designer drug market. I will run for Russian president, pledges Alexei Navalny's widow Yulia. Environment Drugs wild life pesticides Water.

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