The appearance of new psychoactive substances (NPS) within the recreational drug market is not a new phenomenon 1. These substances, also named ‘smart drugs’, ‘legal highs’ or ‘designer drugs’, are a large group of plant derivatives and synthetic compounds that are not controlled under the international drug laws 2. In recent years, this phenomenon has dramatically increased in terms of availability of both number of substances and chemical families 2. The Internet has significantly contributed to the spread of these substances to an ample public, and it has also contributed to induce a false sense of safety among drug users promoting these new drugs as ‘natural products’, ‘herbal incense’, ‘bath salts’ or ‘plant food’ 3. A survey conducted by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has shown that Web stores offering for sale at least one psychoactive drug have quadrupled from January 2010 to January 2012. They grew from 170 to 693 in two years 4. In 2013, a survey conducted by the EMCDDA on Internet stores selling NPS to European drug users has identified 651 shops 5. Prevalence data are unknown; however, a survey conducted by the United Nations Office On Drugs And Crime (UNODC) among member states has shown that, in 94 countries, there has been an emergence of legal highs 6. Moreover, a flash Eurobarometer survey performed on more than 12,000 people aged 15–24 years estimated that about 5% of young Europeans had used NPS at least once. In the United Kingdom (UK), Latvia and Poland, the percentage was higher (10%) while Ireland was the country where the NPS were most used (16%). Conversely, Finland, Greece and Italy were the countries with the lowest percentage of use (3%) 7. Overall, 2.9 million of Europeans aged 15–64 years have used legal alternatives to traditional and illicit drugs of abuse 7. In 2013, the NPS officially notified for the first time to the EMCDDA via the early warning system were 81, up from 73 in 2012, 49 in 2011, 41 in 2010 and 24 in 2009 8. Furthermore, the UNODC via the World Drug Report 2014 has also demonstrated that NPS represent a concern in North America and Oceania. In particular, in the first six months of 2012, NPS signalled in these geographical areas were 141 and 44, respectively 6. The most popular NPS belong to two principal groups: synthetic cannabinoids and synthetic cathinones. However, other compounds belonging to the phenethylamines, tryptamines, piperazines, arylcyclohexylamines, benzodiazepines and hormones have also been found in recreational products marketed as legal highs 2. In November 2012, 4,4′‐Dimethylaminorex (4,4′‐DMAR), a novel synthetic stimulant, was first detected in the Netherlands 9. Subsequently, this stimulant was detected in many samples seized across Europe 9. 4,4‐DMAR is a derivative of aminorex and 4‐methylaminorex, both synthetic anorexigenic stimulants controlled under the 1971 United Nations Convention on Psychotropic Substances 9 and associated with misuse 10, 11. 4,4′‐DMAR is sold online in products labelled with various brand names such as ‘Speckled Cherry’ and ‘Speckled Cross’ 9. After its appearance within the recreational drug market, 4,4′‐DMAR has been associated with numerous analytically confirmed cases of severe intoxication and deaths signalled by some European countries 9. Considering the paucity of toxicological information about this stimulant, the aim of this MiniReview was to summarize the chemical, pharmacological and toxicological knowledge currently available.

Chemical and physical characteristics 4,4′‐DMAR, IUPAC name 4‐methyl‐5‐(4‐methylphenyl)‐4,5‐dihydrooxazol‐2‐amine, is a synthetic substituted oxazoline derivative classified as an analogue of both aminorex and 4‐methylaminorex (fig. 1) 10. Aminorex is listed in Schedule I, and 4‐MAR is listed in Schedule IV of the 1971 United Nations Convention on Psychotropic Substances 10. Chemical differences among these stimulants are related to the presence of methyl groups. Aminorex has no methyl groups, while 4‐methylaminorex has a 4‐position methyl group located on the oxazoline ring 11. 4,4′‐DMAR contains an additional methyl group in para‐position on the phenyl ring 11. 4,4′‐DMAR, molecular formula C11H14N2O, has two chiral centres within the oxazoline ring leading to four enantiomers 11. Cis‐ and trans‐free base racemates prepared from the same 4′‐methyl‐norephedrine precursor performed with cyanogen bromide or cyanate to synthesize both products have been described as colourless solids 12. Cis‐ and trans‐free base forms show a melting point of 136–138°C and 101–103°C, respectively, while the water‐soluble cis‐4,4′‐DMAR hydrochloride form shows a melting point of 163–165°C 12. The cis‐4,4′‐DMAR hydrochloride salt is a white crystalline powder available as research chemical in online research chemical stores 12. Figure 1 Open in figure viewer PowerPoint Chemical structure of 4,4′‐dimethylaminorex, 4‐methylaminorex and aminorex (12, 13).

Pharmacology No study has investigated the effects of 4,4′‐DMAR in human beings, and no pharmacokinetic studies are available. Recently, a pharmacodynamic study performed in male Sprague–Dawley rat synaptosomes has investigated the monoamine release induced by (+/−)‐cis‐4,4′‐DMAR comparing the activity of these racemates with that of d‐amphetamine, aminorex and (+/−)‐cis‐4‐methylaminorex 12. The study showed that (+/−)‐cis‐4.4′‐DMAR, d‐amphetamine, aminorex and (+/−)‐cis‐4‐methylaminorex were potent dopamine, noradrenaline and serotonin releasers (table 1). Dose–response curve highlighted that (+/−)‐cis‐4,4′‐DMAR elicited a potent releasing activity at dopamine (DAT), noradrenaline (NET) and serotonin transporters (SERT) with a EC50 of 8.6 (+/−) 1.1 nM, 26.9 (+/−) 5.9 nM and 18.5 (+/−) 2.8 nM, respectively (table 1). The study also demonstrated that the DAT/SERT ratio for (+/−)‐cis‐4,4′‐DMAR, d‐amphetamine, aminorex and (+/−)‐cis‐4‐methylaminorex was 2, 473, 45 and 31, respectively 12. In another recent study performed in rat brain synaptosomes, monoamine release activity of both cis‐4,4′‐DMAR and trans‐4,4′‐DMAR isomers was compared to that of (S)‐(+)‐3,4‐methylenedioxymethamphetamine (MDMA) 13. The study showed that cis‐4,4′‐DMAR and trans‐4,4′‐DMAR isomers exerted a dopamine‐ and noradrenaline‐releasing activity more potent than that of MDMA (table 1). Regarding the activity at SERT, cis‐4,4′‐DMAR showed to be a fully efficacious releasing agent, while trans‐4,4′‐DMAR acted as a fully efficacious uptake blocker (table 1) 13. The study has also highlighted that the DAT/SERT ratio for (S)‐(+)‐MDMA, cis‐4,4′‐DMAR and trans‐4,4′‐DMAR was 0.6, 1.6 and 2.5, respectively 13. Table 1. EC50 at DAT, NET and SERT for (+/−)‐cis‐4,4′‐DMAR, d‐amphetamine, aminorex, (+/−)‐cis‐4‐methylaminorex, cis‐4,4′‐DMAR, trans‐4,4′‐DMAR and (S)‐(+)‐MDMA DAT (nM) NET (nM) SERT (nM) (+/−)‐cis‐4,4′‐DMAR 8.6 ± 1.1 26.9 ± 5.9 18.5 ± 2.8 d‐amphetamine 5.5 ± 0.5 8.2 ± 1.6 2602 ± 494 aminorex 9.1 ± 0.9 15.1 ± 3.5 414 ± 78 (+/−)‐cis‐4‐methylaminorex 1.7 ± 0.2 4.8 ± 0.9 53.2 ± 6.8 cis‐4,4′‐DMAR 10.9 ± 0.7 11.8 ± 2.0 17.7 ± 2.3 trans‐4,4′‐DMAR 24.4 ± 2.7 31.6 ± 4.6 59.9 ± 17.2 (S)‐(+)‐MDMA 143 ± 16 98.3 ± 15.0 85.0 ± 13.3

Toxicology No pre‐clinical or clinical study has evaluated the toxicological effects of 4,4′‐DMAR in human beings. Since October 2013, 4,4′‐DMAR has been analytically confirmed in biological samples of thirty‐one deaths and one severe intoxication reported to the EMCDDA via the early warning system 11. Poland signalled a non‐fatal intoxication which occurred in September 2013 and that involved a 16‐year‐old female admitted to the hospital after legal high consumption. She felt ill, collapsed and vomited after smoking an unknown herbal mixture. In a blood sample collected 24 hr after admission 4,4′‐DMAR was found at a concentration of 0.448 mg/L 11. Regarding the thirty‐one deaths (table 2), twenty‐two were reported in the United Kingdom between June 2013 and June 2014, eight in Hungary between June and October 2013 and one in Poland in July 2013 11. Except for a case in the United Kingdom, sex and age data were collected for all deceased people. They were twenty‐two males and eight females with a middle age of 27.93 years. In twenty‐seven cases, 4,4′‐DMAR was quantified in blood samples, and in three of them, it was also quantified in urine samples. In one case, 4,4′‐DMAR was the only detected substance, while in all the other cases, additional drugs were found, including cocaine, amphetamines, cannabis, benzodiazepines, antidepressants, second‐generation antipsychotics, opioids and synthetic cathinones. Clinical examination demonstrated high body temperature, pupil dilation, muscular spasm, seizure, increased perspiration, cardiac and respiratory arrest, agitation, confusion, unconsciousness and paranoia. Autopsy revealed bleeding in muscles and organs, brain and pulmonary oedema, right atrial and ventricular dilation 11. Table 2. Demographic information, blood and urine concentration of 31 deaths related to the consumption of 4,4′‐DMAR Dead patients: 31 Demographic information: 30 Male: 22 Female: 8 Age Mean age: 27.93 Standard deviation: 7.88 Range: 16–43 Mean age male: 30.45 Mean age female: 22.25 4,4′‐DMAR blood concentration: 27 Male: 20 Female: 7 Mean: 2.041841 mg/L Standard deviation: 3.42 Range: <0.02–18.68 mg/L Mean male: 2.22 mg/L Mean female: 1.53 4,4′‐DMAR urine concentration: 3 Male: 1 Female: 2 Mean: 27.45 mg/L Standard deviation: 250.25 mg/L Range: 5.93–43.49 mg/L

Routes of administration and doses Information obtained from both European countries and user websites suggest that the nasal insufflation and the oral consumption are the main routes of administration 10, 11. However, the consumption of 4,4′‐DMAR via inhalation and injection has also been signalled 10, 11. Information provided by the user websites suggest that the oral doses range from 10 to 200 mg, while the doses for insufflation range from 10 to 65 mg 10, 11. Repeated use up to 360 mg in the same session has also been reported 10, 11.

Availability and prevalence of use An Internet monitoring of psychoactive substance retailers conducted in May 2014 by the EMCDDA and an Internet snapshot survey undertaken in April 2014 by Nizar and colleagues have permitted the identification of two Web stores selling 4,4′‐DMAR 11, 14. Other four stores identified had discontinued the sale of 4,4′‐DMAR for unclear reasons 11. Regarding the prevalence of use, no study has investigated the spread of this stimulant among the general population and in targeted subgroups 11. In nine European countries have been reported numerous seizures of tablets and white or coloured powder in which was found the presence of 4,4′‐DMAR as unique substance or a combination of 4,4′‐DMAR with other psychotropic drugs such as synthetic cathinones, synthetic cannabinoids, α‐Pyrrolidinopentiophenone (α‐PVP), 5‐(2‐Aminopropyl)‐2,3‐dihydrobenzofuran (5‐APDB, RH‐34 and ethylphenidate 11.

Medical use To the best of our knowledge, there is no approved medical indication for the 4,4′‐DMAR, and it must be considered a drug for research and forensic utilization 11, 12. The (4S,5S)‐trans‐4,4′‐DMAR enantiomer has been used in some patients related to the preparation of anti‐inflammatory medicines based on phospholipase A2 inhibitors 15.