Critical Review Report: p-Methoxy-butyrylfentanyl

Substance identification p-Methoxy-butyrylfentanyl (IUPAC name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4- yl]butanamide) is a synthetic analog of the opioid analgesic fentanyl. In Europe, it was first reported in 2015 followed by the Untied States of America later on. Samples obtained from seizures and collections suggest that p-methoxy-butyrylfentanyl occurs in powder, tablet, and nasal spray form. WHO Review History p-Methoxy-butyrylfentanyl has not been previously pre-reviewed or critically reviewed. Chemistry There is no specific information available about the routes of synthesis employed for the p- methoxy-butyrylfentanyl products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. Routes of synthesis also exist that might require the use of a controlled precursor. Ease of convertibility into controlled substances p-Methoxy-butyrylfentanyl could be converted into various other fentanils but retaining the 4- methoxyphenyl group would also render them uncontrolled at this time. Similarity to known substances / Effects on the central nervous system Data from human studies are not available but the information available so far suggests that the effects induced by p-methoxy-butyrylfentanyl are also shared by other synthetic opioids such as fentanyl and heroin. General pharmacology Pharmacological studies have shown that p-methoxy-butyrylfentanyl is qualitatively similar to fentanyl and heroin. p-Methoxy-butyrylfentanyl binds to μ-opioid receptors (MOR) with high selectivity over the κ- and δ-opioid receptors and has been shown to act as a partial agonist at MOR in a [35S]GTPγS binding assay. Similar to both fentanyl and morphine, p-methoxy- butyrylfentanyl was also shown to induce locomotor activity and antinociceptive effects in mice. Antinociceptive effects were attenuated by pre-treatment with naltrexone. Toxicology Data on the toxicology of p-methoxy-butyrylfentanyl could not be identified. Adverse reactions in humans p-Methoxy-butyrylfentanyl has been detected in biological samples obtained from acute intoxication cases. Reported clinical features included reduced level of consciousness, respiratory depression, miosis, tachycardia, renal insufficiency, suspected aspiration, and apea. Naloxone treatments were required in some cases to reverse drug-induced respiratory depression. Dependence potential No studies available. Experience with fentanyl and other synthetic opioids suggest that the dependence potential might extend to p-methoxy-butyrylfentanyl but further studies are warranted to explore this. Abuse potential Whilst no formal studies exist, the limited available information indicates that p-methoxy- butyrylfentanyl is used by experimental users (psychonauts) including people who have a history of abusing other synthetic opioids and opiates. It seems likely that p-methoxy-butyrylfentanyl might be associated with abuse liability. Therapeutic applications / usefulness p-Methoxy-butyrylfentanyl is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines p-Methoxy-butyrylfentanyl is not listed. Marketing authorizations p-Methoxy -butyrylfentanyl is not known to have any marketing authorizations. Industrial use p-Methoxy-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Non-medical use The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Similar to other fentanils, p-methoxy-butyrylfentanyl may be administered as a solution (e.g. using nasal sprays), orally as a powder (including in capsules or tablets), or by insufflation of a powder; it can also be administered sublingually or intranasally via a spray; administered by injection (intramuscular or intravenous) or inhaled by vaporizing. Nature and magnitude of public health problems Use of p-methoxy-butyrylfentanyl appears to be limited to recreational substance users rather than the general population. Marginalized and vulnerable opioid users including those who inject such substances also use fentanyl analogs. However, users may not be aware of using them and the high potency associated with fentanyl analogs might result in increased risks of life- threatening overdoses. At the same time, fentanyl and its analogs pose a serious risk of accidental exposure to products with the potential for subsequent poisoning of the public, law enforcement and emergency personnel, as well as medical/laboratory personnel. Licit production, consumption, and international trade p-Methoxy-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Illicit manufacture and traffic So far the total number of reports describing the identification of p-methoxy-butyrylfentanyl is very limited. p-Methoxy-butyrylfentanyl can be purchased from Internet retailers. Current international controls and their impact p-Methoxy-butyrylfentanyl is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls See Annex

XLR-11. Critical Review Report. Agenda Item 4.12.

Expert Committee on Drug Dependence. World Health Organization. Thirty-eighth Meeting. Geneva, 14-18 November 201

4‐Fluoromethcathinone (flephedrone; 4‐FMC). Critical Review Report. Agenda item 4.16. Expert Committee on Drug Dependence. Thirty‐sixth Meeting. Geneva, 16‐20 June 2014 (World Health Organization).

(R/S)-1-(4-Fluorophenyl)-2-(methylamino)propan-1-one, also known as flephedrone or 4- FMC, has emerged in recent years as a recreational psychostimulant. Its synthesis was first published in 1952 in order to explore the potential for antithyroidal, antibacterial and bacteriostatic properties. Publications about the detection of 4-FMC obtained from Internet sources and test purchases started to appear from 2009 onwards. The first official notification submitted to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) by a European member state was 2008. Since then, it has been detected across the globe as a reflection of modern forms of trade within a globalised world. As was the case with many other emerging substances with psychoactive properties, commonly used terms include "legal highs", "bath salts" or "new psychoactive substances" (NPS) in the attempt to highlight the fact that many, if not most, did not originally fall under any legislative control and that detailed data on both pre-clinical and clinical levels were normally less well explored. The amount of research data on 4-FMC is comparatively small in comparison with other cathinones such as 4-methyl-N-methylcathinone (mephedrone) or 3,4- methylenedioxypyrolvalerone (MDPV) but the currently available data suggest that the psychoactive and behavioural profile of 4-FMC, for example demonstrated by drug discrimination and in-vitro studies, show similarities to psychomotor stimulants such as cocaine, methcathinone and methamphetamine although it appears that it be less potent. It has been demonstrated that key targets of 4-FMC include monoamine transporters and that it functions as a catecholamine-selective substrate-type releaser of dopamine and norepinephrine. While 4-FMC was a low potency partial agonist at the 5-HT1A receptor, it was found to be an antagonist with very low potency at 5-HT2A and 5-HT2C receptors. 4-FMC was observed to act primarily as a substrate at the human dopamine (hDAT) and human norepinephrine transporter (hNET), with the latter being more pronounced than methamphetamine. In addition, it was observed to display appreciable affinity to the hα1A adrenoceptor and rat trace amine-associated receptor 1. The ability to induce DA release similar to methamphetamine-type substances known to act as hDAT substrates makes it likely that 4-FMC may show abuse potential. It seems conceivable that, especially at high dosage levels, extensive release of NE in combination with hα1A adrenoceptor activation might also contribute to enhanced cardiotoxic effects, in addition to dopamine-mediated stimulation

AB-PINACA. Critical Review Report

AB-PINACA (N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide), originally developed by Pfizer Inc. as a synthetic cannabinoid receptor agonist (SCRA), has been encountered outside medical settings as a synthetic constituent and found in herbal smoking mixtures that are sold under a variety of brand names. It is common for retailers to purchase bulk quantities of the synthetic substance and add the synthetic material to plant matter that is then distributed onto the market. However, AB-PINACA is also available in powdered form as a “research chemical”. The identification of AB-PINACA was reported first in 2012 by Japan and more forensic detections began to emerge in other countries in 2013. Data from law enforcement suggest that AB-PINACA was one of the most prevalent substances in the United States of America in 2014, which dropped again in the following years. A small number of in vitro and in vivo studies are currently available but the data indicate that AB-PINACA binds to and activates human CB1 and CB2 receptors at low nanomolar concentrations, and that it induces a number of biological responses also triggered by the naturally occurring phytocannabinoid Δ9-THC. In tetrad assays (locomotor suppression, antinociception, hypothermia, and catalepsy), for example, AB- PINACA was shown to be 2- to 14-fold more potent than Δ9-THC and the effects were rimonabant-reversible. In some in vitro assays, AB-PINACA acted as a full agonist with slight selectivity for the hCB2 receptor. AB-PINACA also fully substituted for Δ9-THC in the drug discrimination paradigm and was 1.5-fold more potent than the training drug, which suggests that AB-PINACA may have abuse liability similar to Δ9-THC and/or other internationally controlled synthetic cannabinoid receptor agonists. Reports indicate an increasing trend for SCRAs being implicated in mini epidemics that have been associated with severe adverse drug effects including deaths. Reported adverse drug reactions associated with a range of SCRAs frequently include gastrointestinal (e.g. nausea/hyperemesis), neurological (e.g. hallucination, agitation, anxiety, paranoia, confusion, delusions, catatonia, lethargy, psychosis (including susceptible individuals)), cardiovascular (e.g. tachycardia, hypertension) and renal (e.g. acute kidney failure) features. The total number of cases reported in the scientific literature that make a causal link with AB-PINACA is very small. Intoxications and deaths associated with AB-PINACA have been reported but very few details are available. ‘Driving Under the Influence’ cases linked to AB-PINACA intoxication and ‘Drug Recognition Expert’ exams revealed significant impairment. Although not specific to just AB-PINACA, there are indications that socially vulnerable and stigmatized drug users for example found in homeless and prison populations, are increasingly associated with problematic use of SCRA products. Heavy use of SCRAs has been associated with problematic withdrawal symptoms even though further research is needed to investigate the underlying mechanisms. Epidemiological data, such as prevalence of use, abuse and dependence information specifically related to AB-PINACA could not be identified

N-Ethylnorpentylone. Critical Review Report.

Substance identification N-Ethylnorpentylone (IUPAC name: 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)pentan-1-one) is a ring-substituted synthetic cathinone analog. It originally emerged in the 1960s during pharmaceutical drug development efforts. Another common name used widely is N- ethylpentylone. On the streets, N-ethylnorpentylone is most likely available as the racemic mixture and it might be obtained from Internet retailers. In the United States of America (USA), this substance was detected for the first time in 2014 but began to emerge more prominently in 2016 both in the USA and other UN Member States. Seizures indicate that N-ethylnorpentylone is available in powder, crystal, rock, capsule, and tablet forms. Examples exist where this drug has been surreptitiously sold as ‘ecstasy’/MDMA. WHO Review History N-Ethylnorpentylone has not been previously pre-reviewed or critically reviewed. Chemistry There is no specific information available about the routes of synthesis employed for the N- ethylnorpentylone products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. Ease of convertibility into controlled substances There is no specific information available but it appears unlikely that N-ethylnorpentylone is converted into a substance currently controlled under the UN conventions. Similarity to known substances / Effects on the central nervous system The information currently available suggests that N-ethylnorpentylone is a psychomotor stimulant and that its molecular mechanism of action is also shared by other ring-substituted synthetic cathinones of the pyrovalerone type, such as MDPV (1-(2H-1,3-benzodioxol-5-yl)-2-(pyrrolidin-1- yl)pentan-1-one) and α-PVP (1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one), which are both listed in Schedule II of the Convention on Psychotropic Substances of 1971. General pharmacology The number of systematic studies available at this time is limited but it seems clear that N- ethylnorpentylone is a psychomotor stimulant. In vitro, it has been demonstrated to block the reuptake of dopamine, norepinephrine and serotonin using rat brain synaptosomal preparations with preference for the dopamine system, thus, behaving cocaine- and MDPV-like rather than amphetamine-like. Animal studies confirmed that N-ethylnorpentylone increases locomotor activity and that it substituted for methamphetamine and cocaine in drug discrimination studies. Toxicology The LD50 value for N-ethylnorpentylone in the mouse (route of administration not reported) was determined at 240 mg/kg. Adverse reactions in humans The detection of N-ethylnorpentylone in biological fluids collected from cases involving adverse effects (including deaths) confirmed that this drug is circulating on the market and used recreationally. Not all of the reported adverse effects could be causally linked to N- ethylnorpentylone alone but there are indications that the observed effects are consistent with those seen with other psychomotor stimulants. The fact that N-ethylnorpentylone has been identified in products believed by users to represent ‘ecstasy’/MDMA means that users may be unaware of the additional risks of harm (e.g. potential exacerbation of a psychostimulant toxidrome) associated with the consumption of N-ethylnorpentylone either alone or in combination with other drugs. Dependence potential No studies carried out in humans or animals could be identified. Abuse potential In rodents, N-ethylnorpentylone fully substituted for methamphetamine and cocaine when using the drug discrimination paradigm. Mechanistically, results obtained from in vitro investigations confirmed that N-ethylnorpentylone inhibited the reuptake of the monoamines dopamine, norepinephrine and, to a lesser extent, serotonin, which is consistent with closely related pyrovalerone-type synthetic cathinones and cocaine with known abuse liability. The currently available data suggest that N-ethylnorpentylone might be liable to abuse. Therapeutic applications / usefulness N-Ethylnorpentylone is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines N-Ethylnorpentylone is not listed. Marketing authorizations N-Ethylnorpentylone is not known to have any marketing authorizations. Industrial use N-Ethylnorpentylone is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Non-medical use The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). The information currently available suggests that N-ethylnorpentylone has been found in products sold as ‘ecstasy’/MDMA but there have been instances where other drugs have been detected in addition to N-ethylnorpentylone. N-Ethylnorpentylone may also be available in its own right and is advertised for sale by Internet retailers. Nature and magnitude of public health problems Use of N-ethylnorpentylone appears to be limited to recreational substance users rather than the general population. The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). The fact that N-ethylnorpentylone has been identified in products believed by users to represent ‘ecstasy’/MDMA means that users may be unaware of the additional risks of harm (e.g. potential exacerbation of central nervous system effects resulting in a psychostimulant toxidrome) associated with the consumption of N-ethylnorpentylone either alone or in combination with other drugs. Licit production, consumption, and international trade N-Ethylnorpentylone is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Illicit manufacture and traffic A dramatic increase in seizures and reports linked to the detection of N-ethylnorpentylone has been predominantly reported in the USA from 2016 onward. Purchase and importation of N- ethylnorpentylone is unproblematic in UN Member States that do not exercise legislative control measures. Increasing numbers of reports have appeared that document the detection of N- ethylnorpentylone on the drug market where it has been sold in the form of ‘ecstasy’/MDMA-like products. Current international controls and their impact N-Ethylnorpentylone is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls N-Ethylnorpentylone is controlled in some UN Member States

4-Fluoroamphetamine (4-FA). Critical Review Report.

1-(4-Fluorophenyl)propan-2-amine (4-fluoroamphetamine, 4-FA) is a psychomotor stimulant that was first synthesized in the early 1940s. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) received the first formal notification of the detection of 4-FA in Europe in December 2008 although its presence has been noted since at least 2007. In Europe, it has been found in tablets sold as ‘ecstasy’/MDMA, paste or powder sold as amphetamine. In addition, it can be obtained from Internet retailers as a ‘research chemical’ and it has also been detected as an adulterant present in other illicit controlled substances. 4-FA appears to be most commonly administered orally or by nasal insufflation (snorting). The EMCDDA has been notified of seizures from various locations in Europe since 2008. Data indicate that 4-FA may be able to inhibit monoamine oxidase and that it functions as a substrate-type releasing agent of dopamine, norepinephrine and serotonin. It has been shown to display amphetamine-like features in vivo and in vitro and further research is warranted to investigate the extent to which 4-FA displays a potential for abuse and dependence in both animals in humans that is comparable to substances such as amphetamine, cocaine or related psychostimulants. Case report data in the scientific literature that unambiguously confirm a causal relationship between adverse effects of 4-FA and its presence in biofluids are limited to only a relatively small number of cases. In cases where this information is available, reported clinical features were associated with those of a sympathomimetic toxidrome. The EMCDDA has received reports from positive identifications in biofluids samples from 2009 onward. It has been reported that 4-FA might have established itself as a drug of choice in a surveyed convenience sample of 249 life-time users of 4-FA in one European country. Surveys that systematically assess the prevalence of use 4-FA within the general population are not available

1-Phenyl-2-(pyrrolidin-1-yl)pentan-1- one (α-PVP). Critical Review Report.

1-Phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP) is a psychomotor stimulant that has originally been explored in the 1960s. It is the desmethyl analogue of pyrovalerone, which is listed in Schedule IV of the 1971 United Nations Convention on Psychotropic Substances. A closely related derivative of α-PVP gives rise to 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one (3,4-methylenedioxypyrovalerone, MDPV) that has recently been placed in Schedule II of the UN Convention on Psychotropic Substances (1971). The first official notification of α-PVP detection in the European Union was received in February 2011. α-PVP is a synthetic cathinone derivative and commonly referred to as a new psychoactive substance (NPS), ‘research chemical’, ‘bath salt’ or ‘designer drug’. α-PVP appears to act as a potent blocker at the dopamine and norepinephrine transporter and pre-clinical research into areas of abuse liability, psychomotor activity and drug discrimination suggests that the properties of α- PVP are reminiscent of MDPV, methamphetamine and cocaine. Data indicate that α-PVP is most commonly encountered in powdered and tablet form. In addition to being available from Internet vendors in both wholesale and consumer amounts, α-PVP has also been encountered in products destined for the traditional illicit drugs market, for example, in form of ‘ecstasy’ tablets. More than 130 deaths have been associated with α-PVP and among the non-fatal acute intoxications reported, hospitalizations were required. In cases where α-PVP use was established unambiguously, neurological and cardiovascular effects consistent with an extensive psychostimulant toxidrome have been observed and included cardiotoxicity, violent behavior and display of psychotic behavior. In addition to use by traditional recreational drug users it appears that α-PVP is also used by high-risk drug users including those who inject

Critical Review Report: p-Fluoro-butyrylfentanyl

Substance identification p-Fluoro-butyrylfentanyl (IUPAC name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4- yl]butanamide) is a synthetic analog of the opioid analgesic fentanyl. In Europe, it was first reported in 2014 followed by the Untied States of America in 2015. Samples obtained from seizures and collections suggest that p-fluoro-butyrylfentanyl appears in powder, tablet, nasal spray and e-liquid form. Examples exist where it might be found in samples mixed with heroin. WHO Review History p-Fluoro-butyrylfentanyl has not been previously pre-reviewed or critically reviewed. Chemistry There is no specific information available about the routes of synthesis employed for the p-fluoro- butyrylfentanyl products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. Routes of synthesis also exist that might require the use of a controlled precursor. Ease of convertibility into controlled substances p-Fluoro-butyrylfentanyl could be converted to its isomer p-fluoro-isobutyrylfentanyl (IUPAC name: N-(4-fluorophenyl)-2-methyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide), which is listed in Schedule I of the Single Convention on Narcotic Drugs of 1961, as amended by the 1972 Protocol. Similarity to known substances / Effects on the central nervous system Data from human studies are not available but the information available so far suggests that the effects induced by p-fluoro-butyrylfentanyl are also shared by other synthetic opioids such as fentanyl and heroin. General pharmacology Pharmacological studies have shown that p-fluoro-butyrylfentanyl is qualitatively similar to fentanyl and heroin. p-Fluoro-butyrylfentanyl binds to μ-opioid receptors (MOR) with high selectivity over the κ- and δ-opioid receptors and has been shown to act as a partial agonist at MOR in a [35S]GTPγS binding assay. Similar to both fentanyl and morphine, p-fluoro- butyrylfentanyl was also shown to induce locomotor activity and antinociceptive effects in mice. Antinociceptive effects were attenuated by pre-treatment with naltrexone. Toxicology Data on the toxicology of p-fluoro-butyrylfentanyl could not be identified. Adverse reactions in humans p-Fluoro-butyrylfentanyl has been detected in biological samples obtained from fatal intoxication cases although unambiguous differentiation from the p-fluoro-isobutyrylfentanyl isomer was not always possible. A report detailing an acute intoxication revealed that clinical features included disorientation, slurred speech and hypotension. Dependence potential No studies available. Experience with fentanyl and other synthetic opioids suggest that the dependence potential might extend to p-fluoro-butyrylfentanyl but further studies are warranted to explore this. Abuse potential Whilst no formal studies exist, the limited available information indicates that p-fluoro- butyrylfentanyl is used by experimental users (psychonauts) and people who also use synthetic opioids and opiates. It is likely that p-fluoro-butyrylfentanyl will be associated with abuse liability. Therapeutic applications / usefulness p-Fluoro-butyrylfentanyl is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines p-Fluoro-butyrylfentanyl is not listed. Marketing authorizations p-Fluoro-butyrylfentanyl is not known to have any marketing authorizations. Industrial use p-Fluoro-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Non-medical use The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Similar to other fentanils, p-fluoro-butyrylfentanyl may be administered as a solution (e.g. using nasal sprays), orally as a powder (including in capsules or tablets), or by insufflation of a powder; it can also be administered sublingually or intranasally via a spray; administered by injection (intramuscular or intravenous) or inhaled by vaporizing. Nature and magnitude of public health problems Use of p-fluoro-butyrylfentanyl appears to be limited to recreational substance users rather than the general population. Marginalized and vulnerable opioid users including those who inject such substances also use fentanyl analogs. However, users may not be aware of using them and the high potency associated with fentanyl analogs might result in increased risks of life-threatening overdoses. At the same time, fentanyl and its analogs pose a serious risk of accidental exposure to such products with the potential for subsequent poisoning of the public, law enforcement and emergency personnel, as well as medical/laboratory personnel. Licit production, consumption, and international trade p-Fluoro-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Illicit manufacture and traffic So far the total number of reports describing the identification of p-fluoro-butyrylfentanyl seems comparatively low but it an increase in detections has been reported in the US. p-Fluoro- butyrylfentanyl can be purchased from Internet retailers. Current international controls and their impact p-Fluoro-butyrylfentanyl is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls p-Fluoro-butyrylfentanyl is controlled in some UN Member States

4‐Methylethcathinone (4‐MEC). Critical Review Report. Agenda item 4.15. (R/S)-2‐(Ethylamino)‐1‐(4‐methylphenyl) propan‐1‐one (4‐methyl‐N‐ethylcathinone, 4‐MEC). Expert Committee on Drug Dependence. Thirty‐sixth Meeting. Geneva, 16‐20 June 2014 (World Health Organization).

(R/S)- 2-(Ethylamino)-1-(4-methylphenyl)propan-1-one, also known as 4-methylethcathinone or 4-MEC, has emerged in recent years as a recreational psychostimulant. Its synthesis was first published in 2010 as part of an analytical confirmation related to test purchases from online retailers. The first official notification submitted to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) by a European member state was 2010. Since then, it has been detected across the globe as a reflection of modern forms of trade within a globalised world. As was the case with many other emerging substances with psychoactive properties, commonly used terms include "legal highs", "bath salts" or "new psychoactive substances" (NPS) in the attempt to highlight the fact that many, if not most, did not originally fall under any legislative control and that detailed data on both pre-clinical and clinical levels were normally less well explored. 4-MEC appears to be among the most seized cathinone representatives. Currently, the available pre-clinical in-vitro data are limited but it is suspected that further studies may be underway. So far, 4-MEC was found to inhibit dopamine, norepinephrine and serotonin uptake transporters with equal potency. In addition, first evaluations have shown that it may also function as a serotonin releasing agent but not dopamine and norepinephrine. Further studies are needed to assess abuse liability and dependence potential