European Review for Medical and Pharmacological Sciences 2019; 23: 9681-9690 New psychoactive substances: concerted efforts and common legislative answers for stemming a growing health hazard

S. ZAAMI

Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy

Abstract. – OBJECTIVE: New psychoactive Introduction substances (NPS), are a range of drugs de- signed to mimic the effects of established illic- New psychoactive substances (NPS) are a it drugs, being legal at the time of their distribu- range of drugs that are designed, manufactured tion in illicit markets. The review aims to shed a light on the growing threat caused by NPS, and and marketed to replicate the effects of illegal on the dynamics and developments that have established substances (e.g., cannabis, cocaine, led to their spread, including the risk of new ecstasy and LSD1). At the time of their arrival adulteration practices which can cause a seri- on street and web markets, such substances are ous health threat, due to their increased toxicity, mostly not scheduled under the 1961 Single Con- e.g., through and its analogs. vention on Narcotic Drugs or the 1971 Conven- MATERIALS AND METHODS: An overview of statistical trends relative to NPS use has been tion on Psychotropic Substances. Manufacturers provided, in addition to regulatory and legisla- of these drugs deliberately develop new chemi- tive approaches in several countries and recom- cals to replace others that have been banned. In mendations and data from International institu- this concern, NPS chemical structures constantly tions: UN Office on Drugs and Crime, United Na- change and develop in an attempt to stay ahead of tions Commission on Narcotic Drugs, WHO, Eu- ropean Parliament, European Monitoring Centre the national and international banning laws, and for Drugs and Drug Addiction, Europol and inter- when a new substance is scheduled a new ana- national collaborative efforts such as the Trans log is created to restart the process of distribut- European Drug Information (TEDI) project and ing a free psychotropic substance. Over the past the Spanish Energy Control. decade, the emergence of hundreds of NPS has RESULTS: Given the elusive nature of NPS, represented a daunting challenge for public health spontaneous pharmacovigilance reporting sys- tems are needed to identify new trends of drug and drug policies on a global scale. Such drugs abuse. Broad-ranging legislative initiatives are are relatively new to recreational drug markets, needed in order to set common international and the definition encompasses all NPS, as well standards (e.g., the European Parliament Reg- as drugs that even though not newly synthesized, ulation 2017/2101, with information exchange, have recently seen a significant rise in terms of il- an early warning system and risk assessment legal use2,3. NPS may be categorized by chemical procedure for NPS) to tackle a potentially cata- strophic and growing threat. structure, psychoactive properties, biological tar- 4 CONCLUSIONS: By virtue of all the complex- gets, or by source (plant, synthetic, or combined ), ities and hurdles that have to be overcome in and can be subdivided into four main categories: the fight against NPS, and to assist national governments in their identification and report- • Synthetic cannabinoids – they mimic the can- ing, supranational organizations can come to play a key role. Only through international mea- nabis effects and are traded under various sures, supplementing national legislative initia- “street names”. They show no chemical rela- tives, can this multi-faceted problem be effec- tion to delta-9-, the psy- tively addressed and information about NPS be choactive principle of cannabis, but they act on gathered and disseminated in a timely fashion. cannabinoid brain receptors in a similar way to Key Words: that of cannabis. New psychoactive substances, Adulteration, Drug • -type drugs – they simulate the psy- of abuse, Legislative measures. choactive effects of substances such as am-

Corresponding Author: Simona Zaami, MD; e-mail: [email protected] 9681 S. Zaami

phetamine, cocaine and ecstasy and include phenomenon that has to be highlighted is given compounds such as e.g., benzylpiperazine, by the evidence that the most recent NPS started synthetic cathinones (e.g., ), meth- to be targeted to a different type of consumers, ylphenidate and analogs, methylenedioxypy- thus transitioning from being substances for rec- rovalerone, 5,6-methylenedioxy-2-aminoin- reational weekend music parties and casual sex- dane, ethylphenidate. New benzodiazepines ual scenes to narcotic and substances and tranquilisers (a.k.a., ‘Downer’/tranquilis- aimed at chronic users, namely new syn- er-type drugs), which are designed to repli- thetic and new benzodiazepines9-11. cate the effects of tranquilisers or anti-anxiety drugs, especially from the benzodiazepine family, including, among others, etizolam, pyr- Lawmakers and regulatory bodies azolam and flubromazepam. strive to keep up • Hallucinogenic drugs – these drugs simulate the central action of substances like lysergic The European new psychoactive substances acid diethylamide and include the substances (NPS) market has increased at a somewhat alarm- of 2-C phenetylamines (2-CB, 2-CE, 2C-I), ing rate, to such an extent that established drug , deschloro-N-ethyl-ketamine. control laws have struggled to keep up. Several countries have therefore devised and enacted new legal responses to this phenomenon, either based Broad-ranging variety only adds to on existing laws (mostly focused on consumer or the problem health protection or pharmaceuticals), or by pass- ing new and innovative pieces of legislation. As of NPS, sometimes incorrectly called “legal 2018, over 60 countries have implemented legal highs”, are being developed at an unprecedented responses to control NPS, many of which resorted rate since the beginning of the century. The two to the existing legislation, sometimes properly years which registered the highest number of NPS amended, while others decided to draw up and seized in the European Union have been 2014 and enact innovative legal instruments. Several Euro- 20155. In this concern, as of December 2015, a pean and non-European countries (Austria, Den- total of 643 new psychoactive substances were mark, France, Hungary, Hong Kong, Ireland, Is- reported in the United Nations Office of Drugs rael, Japan, Lithuania, Norway, the Russian and Crime (UNODC) Early Warning Advisory Federation, Switzerland, the United Arab Emir- on NPS6. The emergence of 75 NPS was reported ates, the United Kingdom and the United States12), for the first time in 2015, most of them belonging where a large number of different NPS has rapid- to synthetic cannabinoids (which act as Synthet- ly emerged, have adopted controls on entire sub- ic Cannabinoid Receptor Agonists, 21), synthetic stance groups of NPS using a so-called generic cathinones (β-keto phenethylamines and chemi- approach, or have introduced analogue legislation cally similar to amphetamine and methamphet- that invokes the principle of “chemical similarity” amine, 20) and phenethylamines (most of which to an already controlled substance in order to con- act as either central nervous system , or trol substances not explicitly mentioned in the as , 9), in addition to 21 more, that legislation. Legislation regulating known NPS are structurally diverse and do not belong to any varies internationally. In Germany, a draft law of the above mentioned groups7. After those two was adopted by the government in May 2016, to years, the yearly number of reported substances be eventually enacted by parliament in September started to decrease, mainly due to the fact that of the same year. Under this draft law, NPS are banning laws imposed more severe and specific defined as any substance or preparation which be- restrictions to the classes of prohibited psychotro- longs to a specified generic group definitions for pic drugs and to the seizing action of police forces. synthetic cannabinoids and compounds derived Nevertheless, by the end of 2018, the EMCDDA from 2-phenylethylamine. It should be noted how- was monitoring more than 730 new psychoactive ever that substances that are already listed in the substances, 55 of which were detected for the first Narcotics Act or Medicines Act have been ex- time in Europe in 2018. These include synthetic empted. Based on expert advice, the German cannabinoids, stimulants (including cathinones), Health Ministry has the authority to amend or up- hallucinogens and opioids that are designed to date such definitions. Manufacturing, trading, mimic the effects of established substances8. A importing, possessing and offering NPS is unlaw-

9682 NPS: concerted efforts and common legislative answers for stemming a growing health hazard ful under the legislation; law enforcement agen- necessary in order to prevent their distribution cies are entitled to confiscate and dispose of such and avoid ensuing health hazards. Two conditions substances, by virtue of their authority to protect must be fulfilled for any substance to fall within life and health. Customs officials may confiscate that definition: (1): it can be assumed that they substances that they have good reason to believe will be distributed for the purpose of being mis- are potentially harmful NPS. As for offences aris- used by certain groups of individuals for its ef- ing from smuggling and supply, penalties, up to fect…” and (2): “according to the current state of 10 years in prison are set in the law. Trade for rec- scientific knowledge and experience, they may ognized commercial, industrial or scientific uses pose a health hazard to the consumers or such is excluded13. In Romania, targeted NPS legisla- hazard cannot be ruled out when applied16”. tion was enacted in 2011, according to which any France, in the context of the governmental plan product likely to provoke psychoactive effects set up to tackle the spread of drugs and abusive similar to those caused by substances controlled behaviour, established in March 2014 a special- under drug law requires a specific permit to be ized working group made up of representatives of legally sold. Such effects are characterized as lia- the Ministries of the Interior, Justice, Economy ble to bring about ‘changes in functions and men- and Health within named MILDECA (Mission in- tal processes and behaviour’, or ‘causing addic- terministérielle de lutte contre les drogues et les tion’; it is worth noting, however, that no precise conduites addictives: Interministerial Mission for reference is made to ‘harmful’ substances. Un- the Fight against Drugs and Addictive Be- lawfully supplying NPS and their advertisement haviour17). Such a group has been tasked with ex- are punishable by detention and custodial sen- ploring and assessing all legal instruments that tences, whereas possession for personal use is could be fit to identify NPS that are potentially not14. In Finland, new legislation was enacted, harmful to public health18. NPS in France are reg- coming into force on 20th December 2014. Ac- ularly subjected to assessment and listed as nar- cording to the new set of norms, NPS are com- cotics. In that regard, seven families of synthetic prised in the Finnish Narcotics Act and listed in cannabinoids were defined as such by a decree of the government regulation on the consumer mar- the Minister for Health, on 19th May 2015. More- ket of psychoactive substances. It is noteworthy over, prosecutors strive to offset the existing legal that for a specific NPS to be banned in Finland, it vacuum by indicting, whenever and to the extent should be included that regulation. In addition, possible, traffickers for criminal association as( - the Finnish criminal statutes were amended so as sociation de malfaiteurs). Besides, if dealers or to provide for a general provision of subsidiary distributors purport NPS as bearing the same application, designed to effectively outlaw NPS characteristics (and eliciting the same effects) as manufacturing, import, storage and possession an illegal drug, they can be charged with the for sale (Chapter 44, Section 5a). Such a provision crime of “incitement to use or traffick illegal nar- applies only where the felony is not more severely cotics” (provocation à l’usage ou au trafic de punished by another criminal law provision. Since produits stupéfiants) through the Public Health most NPS-related criminal offences have to do Code (Article L.3421-4). That criminal offence is with importing, which is prosecuted and punished impactful in terms of online peddling19. In France, as smuggling (carrying harsher penalties under just over 300 substances in total were recorded in Chapter 46, Section 4), the provision has a limited France (as opposed to approximately 650 in Eu- range of application15. The Austrian Parliament rope), comprising 11 chemical classes. The num- enacted in 2011, the New Psychoactive Substanc- ber of new NPS detected appears to have dwin- es Act (Neue Psychoaktive Substanzen Gesetz), a dled in recent years (from 53 in 2015 to 44 in Federal Act on the Protection against health haz- 2016, and 15 in 2017). A mere 3 new compounds ards arising from new psychoactive substances. were detected in the first semester of 2018. Appar- The law characterizes a ‘new psychoactive sub- ently, such a decrease is unrelated to customs and stance’ as “a substance or preparation which has drug enforcement agencies, which on the contrary the capacity to cause a psychoactive effect in the have reported an increasing number of seizures human body when consumed…” (Article 1). The each year: nearly 900 in 2015, over 2,000 in piece of legislation vests in the Federal Minister 201720. In the UK distribution and sale of NPS are of Health the authority to define individual NPS illegal, whereas possession is not a criminal of- or classes of chemical substances through regula- fence. In the UK, the 2016 Psychoactive Sub- tion for control purposes, whenever this proves stances Bill21, based on recommendations from an

9683 S. Zaami

NPS Review Expert Panel, banned trading but not nervous system is remarkably similar to or great- possession of all current and future NPS, in an er than that caused by a controlled substance or attempt to stem the rapid proliferation of these (3) that the defendant represented the substance as compounds. The new legislation has been at the having a similar or greater effect on the central receiving end of criticism, and has been labeled nervous systems as a controlled substance. Prose- legally flawed22, especially in terms of establish- cutions under this legislation have generally been ing a total ban and associating penalties with sub- very resource intensive: judges and juries often stances whose harmfulness, in many cases, has hear differing expert evidence, which they are not yet been established23. Ireland has tackled supposed to thoroughly assess in order to deter- NPS through a general prohibition on the distri- mine whether it is warranted for a given substance bution of non-controlled substances. The 2010 to be treated as a controlled substance analogue28. Irish Republic’s Criminal Justice (Psychoactive The United States Federal Government has re- Substances) Act was passed on 23rd August 2010, cently taken up a “neurochemical approach”, as a reaction to the proliferation of retail premises aimed at controlling substances on the basis of selling various NPS. The Act makes it illegal un- their effects on the user’s brain. Those provisions der criminal law statutes to advertise, supply, im- are codified in the Synthetic Drug Abuse Preven- port, export or sell a psychoactive substance, tion Act 201229, which has effectively classified while being aware that it is meant for human con- several synthetic cannabinoids (or cannabimimet- sumption, and is applicable to substances that are ric agents) within the scope of the 1970 Controlled not explicitly prohibited under the Misuse of Substances Act. In New Zealand, the Psychoac- Drugs Acts. The Act does not contain any offence tive Substances Bill was turned into law by Par- for possession for personal use of these substanc- liament in July 2013 by 119 votes to one, thus be- es nor does it have a production offence: it is tar- coming the Psychoactive Substances Act30, in an geted at peddlers rather than users. As a result of effort to cope with the unregulated use of NPS. the new legislation, the head shop trade, selling in Under the legislation, manufacturers and provid- the past the so called “legal highs” namely NPS ers of any psychoactive substance including ener- not yet under banning legislation, in Ireland has gy pills, party pills, and herbal products are legal- almost vanished, with very few such outlets still ly bound to provide scientific evidence proving open for business, while being continuously mon- that their product is ‘low-risk’ to the consumer. itored by the authorities24. Further legislation was Apparently, a transition has been made by the also passed in Ireland in May 2011 under the Mis- government of New Zealand: from outright prohi- use of Drugs Act 1977 and 1984, controlling 200 bition to a new regulatory framework akin to psychoactive substances among which benzylpip- medicines regulations. The manufactures/sellers/ erazine derivatives, synthetic cannabinoids, me- importers of NPS are required to have their prod- phedrone, methylone and related cathinones, ket- uct either green-lighted or rejected by the govern- amine, , GBL and 1, 4 BD. The ment based on the company’s pre-clinical and proliferation of legal headshops in Ireland was so clinical data. That arguably constitutes a some- fast before the law that such outlets were opening what innovative approach to the legal high prob- at approximately one per week25, 26. In the United lem, with some analysts hailing the new law as States, the Federal Government has opted for “good example of the start of evidence-based pol- what could be characterized as an “analogue ap- icy31,32”. proach”: substances are controlled based on their Finally, in Italy, since July 2007, by separate “chemical similarity” to other drugs that are al- updated decrees of the Ministry of Health, many ready controlled. Under the Controlled Substance new psychoactive substances, have been included Analogue Enforcement Act 198627, it is unlawful in the Presidential Decree n. 309/9033, and sub- to peddle or provide a substance for human con- sequent amendments and additions which rule sumption that is listed as a controlled substance the banning of psychotropic substances. NPS analogue. A suspect is held criminally liable for have been progressively introduced as singles drug-trafficking under the 1986 Act if it is proven substances and only in case of synthetic cannabi- that the substance was meant for human con- noids and synthetic cathinones, analogs have been sumption and: (1) that substance’s chemical struc- indicated with a general chemical structure (e.g., ture is substantially similar to a controlled sub- for synthetic cathinones: analogs of 2-amine-1- stance’s and either (2) that the depressant, phenyl-1-propanone, for one or more substitution hallucinogenic, or stimulant effect on the central on the aromatic ring and/or on nitrogen and or

9684 NPS: concerted efforts and common legislative answers for stemming a growing health hazard on terminal carbon and for synthetic cannabi- Several cases of synthetic cannabinoids ingestion noids: structural analogs of indole 3-carboxam- have been linked to liver failure as well40. The ide, indazole 3 carboxamide, 1 naphtoylindole, use of NPS has often been associated with health phenylacetylindole and benzoylindole). Gener- problems, with side effects ranging from agitation ally speaking, NPS are not controlled under the to seizures, hypertension, tachycardia, aggres- International Drug Control Conventions, hence sion, acute psychosis and potential addiction41,42. their legal status can greatly differ from country The novel nature of NPS, the degree of ambigu- to country. At the international level, up to March ity surrounding their legal status, their ability to 2018, the United Nations Commission on Narcot- evade toxicological tests, their prompt adaptation ic Drugs decided to place 39 NPS under interna- to regulatory and legal efforts, the global Internet tional control34. These control measures need to marketing, and a low degree of public awareness be implemented into the national legal framework as to their harmful health effects are among the of each country. In 2014, the Court of Justice of key drivers of this twenty-first century phenom- the European Union ruled that substances are not enon. Effective responses need to be produced medicinal products if they do not have benefi- through multi-disciplinary research efforts in the cial effects on human health, thus restricting the areas of biology, epidemiology, prevention, and use of such laws for NPS control. Several recent web analytics, in a realm liable to overwhelm legislative responses have undoubtedly been suc- national drug control policies, as well as interna- cessful in reducing availability and sales of these tional conventions. substances in some settings (e.g., “legal highs” and research chemicals openly traded in the street and online), new challenges have come to the NPS adulterants: a potentially fore. This includes monitoring a growing num- deadly challenge ber of highly potent substances – including 179 synthetic cannabinoid receptor agonists and 28 The use of NPS as adulterants has not yet – that can pose a high risk of life-threat- gained much attention in terms of specific re- ening poisoning to users and can cause explosive search. European drug testing services in the type outbreaks35. The European Union has recently de- of adulterants detected several NPS types in ec- cided to put in place a faster process for regulat- stasy tablets (sold as such) or purportedly MDMA ing new psychoactive substances at the European powders. According to an analysis of some of the level. Regulation (EU) 2017/2101 of the European most frequently detected NPS in ecstasy across Parliament and of the Council, amending Regula- five European drug testing services, several sub- tion (EC) No 1920/2006 with reference to infor- stances appear to have sort of a geographic link mation exchange on new psychoactive substances to certain countries: 4-methylethcathinone (4- came into force on 23rd November 2018, including MEC) was marketed in Switzerland, Spain and an early warning system and risk assessment pro- Austria, whereas 4-Fluoroamphetamine (4-FA), cedure36. It is worth noting that NPS do not typ- 4-APB, 5-APB, 6-APB, PMMA and PMA and its ically come with a recommended dosage printed analogues only seemed to show up in the Neth- on the label. They are unregulated and untested, erlands43. Drug-checking services in Portugal which only adds to their potential harmfulness. reported in 2014 the presence of NPS as adul- Given that the chemicals in these drugs are con- terants in lysergic acid diethylamide (LSD), an- stantly changing to try to stay ahead of the law, other common party drug: out of 245 samples of it is possible for users to receive very different LSD analyzed, 24.1% did not contain LSD at all, products, varying from batch to batch, although but did contain another psychoactive substance, the packaging and name may read the same. At 11.4% of which were found to be 2,5-dime- this point, toxicity and health risks are unpredict- thoxyamphetamine derivatives and 9.8% N-ben- able. Indeed, there is limited information avail- zyl-2,5-dimethoxyphenethylamine derivatives44. able about NPS short and long-term effects37,38. A net increase has been registered over time in However, synthetic cannabis has been found to terms of the number of substances used as adul- have more serious side-effects than cannabis39; terants of ecstasy as well, according to findings cardiovascular, gastrointestinal, neurological, released by the Trans European Drug Informa- kidney, metabolic, ophthalmologic, pulmonary tion (TEDI) project, in which Spain, Switzerland, and psychoactive adverse side-effects have been Belgium, Austria, Portugal, and the Netherlands observed, including addiction and withdrawal. have partaken, providing data from their respec-

9685 S. Zaami tive drug testing systems45. According to the ditional and alternative matrices, which would go Spanish project Energy Control, which collects a long way towards clarifying drug metabolism and analyzes drug samples throughout Spain, the and ascribing consumption to clinical outcomes NPS adulterant most frequently observed was and ensuing possible intoxication symptoms60. 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine As supply has gone up, fentanyl overdose-related (2C-B) followed by 1-(4-fluorophenyl)propan-2- casualties have doubled from 2012 to 201461. The amine (4-FA) 46. Fentanyl, a potent, synthetic and substantial scope of the structural risk increase highly lipophilic, acting mostly on μ-opi- is reflected in the volume of seized fentanyl: data oid receptors47 first synthesized by Janssen Phar- from the White House Office of National Drug maceutica in the 1960s48, has been found to play Control Policy (ONDCP) show that 668 kg of fen- a major role as a heroine adulterant as well. Stud- tanyl powder, apparently smuggled from China, ies have shown that since 2001, deaths related to were seized in 2016, which accounts for a 426% heroin overdose have risen six-fold in the United increase from the amount seized in 201562. Even States49; such an increase cannot be accounted given conservative estimates of 5% purity and a for by the rising user population. Heroin use rose high 1:4 seizure to importation ratio, it is safe to 63%, from 2002 to 2013 and in 2015 an estimated assume that at least 134 kg of pure fentanyl en- 833,000 people had used heroin in the last year50. tered the US in 2016. That in turn would represent Reports of fentanyl and its analogs (such as Cro- 134 to 536 million replacement doses, i.e., about tonylfentanyl51 and Valerylfentanyl52), often con- one dose a day for the estimated million heroin cealed in or sold as heroin, have also increased users in the US, based on a 0.25 to 1.0 mg esti- sharply53. Fentanyl, fentanyl analogs and other mate as a replacement dose for a single dose of novel synthetic opioids are all full agonists of heroin63. Suppliers have been found to use fentan- varying potencies at the µ-, lead- yl to make up for heroin shortages and to height- ing to typical clinical effects of miosis and re- en overall opioid potency64-66. As pointed out by spiratory and central nervous system depression. the United States Drug Enforcement Agency, Due to their high affinity for µ-opioid receptors, although it is sometimes diverted from pharma- larger doses of are required to reverse ceutical sources, most recent cases of fentanyl-re- the effects than commonly used54. Fentanyl is le- lated harm, overdose, and death in the U.S. are gally prescribed and used as a synthetic opioid linked to illegally made fentanyl, manufactured pain reliever, approved for treating severe pain, and smuggled from Mexico and China67. Similar typically advanced cancer pain, for which it is trends have been observed in European markets68, prescribed in the form of transdermal patches or 69. Reports from the Swedish Police show that fen- lozenges and can be diverted for abuse. Its poten- tanyl analogues were introduced into the illegal cy is 50-100 higher than that of ; since drug market in Sweden in 2014; since then, simi- fentanyl and heroin are approximately 100 and lar seizures have become increasingly common in 2.5 times the potency of morphine, respectively, the country. During 2014, a total of 11 seizures of fentanyl is roughly 40 times stronger than hero- fentanyl analogues were executed by the Swedish in per mg55. Overdose outbreaks in the US have customs and the police; in 2016-2017, however, long been ascribed to fentanyl and its analogs56,57. the number had risen to roughly 200 seizures per According to data from the National Forensic year. Before that, from 2006 to 2015, the original Laboratory Information System, confiscations, or fentanyl molecule was predominant and was de- seizures, of fentanyl have risen nearly 7 fold from tected in a total of 227 seizures, which have been 2012 to 2014. 4,585 fentanyl confiscations oc- analysed by the National Forensic Centre (NFC). curred in 2014, which suggests that the sharp rise 80 per cent of these seizures consisted of fentanyl in fentanyl-related deaths may be due to increased patches, and as described earlier, they appear on availability of illegally made, non-pharmaceutical the illegal market through diversions from legal fentanyl, and not prescribed fentanyl58. Although sources70. toxicological testing for fentanyl has proven somewhat uneven in terms of outcomes, an anal- ysis of 27 states has shown an increase in fatal- Economic and social sea-change may ities associated with fentanyl in 2014 over 2013 play into the hands of traffickers levels: from 392 to 140059. Hence, it is of utmost importance to develop and validate analytical Fentanyl and other synthetic opioids are like- methods for the determination of NPS both in tra- ly to become mainstays and recurrent aspects of

9686 NPS: concerted efforts and common legislative answers for stemming a growing health hazard the heroin supply, even to the extent of becoming GHB, or its prodrug Gamma-butyrolactone the “new norm”, not unlike the role of levamisole (GBL), often used as an alternative74, is abused by in the cocaine supply: an ever-spreading adul- teens and young adults at parties and rave parties terant designed to heighten the stimulant effect followed by sexual intercourse. Two instances of and which has come to be sort of a normalized GHB adulteration by sindenafil, a sexual enhanc- aspect of illicit cocaine abuse71. A further decline ing drug, have recently been found in individuals in illicit production may be brought about who had consumed the adulterated drug for the by economic and civil growth and development purpose of enhancing its sexual effects, but even- in source countries. While there used to be four tually ended up facing severe intoxication75. sources of heroin competing for retail US mar- kets, it is now down to two, with the oligopolistic trade of heroin manufactured and smuggled from Conclusions: legislative harmonizing Mexico and Colombia potentially turning into a will go a long way towards providing monopolistic trade of opioids, including fentan- new effective standards yl, solely supplied from Mexico. It is also worth noting how the forces of globalization and neolib- Many European Union Member States and the eral economic policies have come to play a prom- international community, in an effort to safeguard inent role in shaping such dynamics, leading to public health, have striven to devise a wide range ever-growing flows of licit and illicit goods while, of legislative responses to grapple with the new at the same time, inhibiting or greatly hampering the dynamics of the NPS market; the issue appears cross-border drug trafficking72. to be extremely complex and multifaceted, espe- As for NPS themselves, they have become a cially in light of their rapid rise and attempts by global phenomenon: 119 countries and territo- NPS manufacturers and traffickers to circumvent ries from all world regions have reportedly had legislation, and a dearth of scientific evidence and one or more NPS-related incident. A total of 888 data that would allow for a thorough assessment substances have been reported to the UNODC of the NPS hazard. By virtue of all the complex- Early Warning Advisory (EWA) on NPS as of ities and hurdles that have to be overcome in the December 2018, by Governments, laboratories fight against NPS, and to assist national govern- and partner organizations. NPS available on the ments in the identification and reporting of NPS, market have similar effects as substances under supranational organization can come to play a international control such as cannabis, cocaine, key role. To that end, the United Nations Office heroin, LSD, MDMA (ecstasy) or methamphet- on Drugs and Crime (UNDOC) established the amine. Looking at the effects of NPS that have Early Warning Advisory (EWA) on NPS, which is been reported until December 2018, the majority meant to serve as a valuable monitoring tool and are stimulants, followed by synthetic cannabinoid knowledge hub, gathering organizing and pre- receptor agonists and classic hallucinogens. senting relevant information on NPS trends, haz- It seems safe to say that the phenomenon of ards, national legislative initiatives and response, adulteration has undergone a radical change in in addition to technical standards for law- and the 21st century, in lockstep with the rise of NPS, policy-makers, laboratories and law enforcement and that has given rise to previously unheard-of agencies. Moreover, the UNODC has laid out a health hazards. Furthermore, it is noteworthy that set of manuals pertaining to the identification and new psychoactive substances can themselves be analysis of fentanyl and its analogues, piperazines, subject to “cutting”, or adulteration, which adds synthetic cathinones and synthetic cannabinoids. to the risk of potentially deadly toxicity. A telling Such indications are valuable in enhancing and instance of such a trend is that of GHB or Gam- fine-tuning the forensic capabilities of national ma Hydroxybutyrate (C4H8O3), a central nervous drug laboratories76. Selected chemical reference system depressant that is illegally traded as a “club standards are also distributed to forensic labora- drug”, a “date rape” drug or a “chemsex” drug. tories as part of the UNODC International Qual- GHB is also a naturally-occurring metabolite of ity Assurance Program. In addition, training and the inhibitory neurotransmitter gamma-aminobu- awareness raising workshops for laboratories and tyric acid (GABA) found in the brain. Nonethe- law enforcement are provided77. As mentioned be- less, the naturally-occurring metabolite GHB is fore, the number and type of NPS that have been present in much lower concentrations in the brain identified as well as their patterns of emergence than those levels found when the drug is abused73. greatly vary among nations. In an effort to live up

9687 S. Zaami to that challenge, countries have adopted a broad 4) Madras BK. The growing problem of new psycho- range of legal measures devised and laid out in active substances (NPS). Curr Top Behav Neuro- order to control NPS. That approach clearly re- sci 2017; 32: 1-18. flects the diversity of the problem as well as the 5) early Warning System on NPS. Available at: http:// www.emcdda.europa.eu/publications/topic-over- differences that exist in legal and policy frame- views/eu-early-warning-system. works and priorities. Despite that diversity at the 6) Negrei C, Galateanu B, Stan M, Balalau C, Dumitru national level, the global organization of the NPS MLB, Ozcagli E, Fenga C, Kovatsi L, Fragou D, Tsat- market is a common feature of the phenomena. sakisl A. Worldwide legislative challenges related The international drug control system serves as to psychoactive drugs. Daru 2017; 25: 14. a common, shared frame of reference in order 7) United Nations Office on Drugs and Crime (UN- to devise and develop an international response DOC). World Drug Report 2016. to the problem. One of the crucial responsibili- 8) European Drug Report. Trends and Developments. ties will be the identification of the most wide- EMCDDA, Lisbon, June 2019. Available at: http:// spread, noxious and persistent NPS, for which an www.emcdda.europa.eu/edr2019_en. international tackling effort may be needed. Only 9) European drug report. Available at: http://www.em- through international measures, supplementing cdda.europa.eu/edr2019_en. United Nations Office on Drugs and Crime (UN- national legislative initiatives, can this multi-fac- 10) DOC). Early warning advisory on new psychoac- eted problem be effectively addressed and infor- tive substances. Categories of NPS sold in the mation about NPS be gathered and disseminated market. 2019 UNODC ITS. 78 in a timely fashion . The number of NPS unre- 11) Marchei E, Pacifici R, Mannocchi G, Marinelli E, Bu- mittingly grows, and such a growth calls for a sardò FP, Pichini S. New synthetic opioids in biolog- thorough understanding of such substances, the ical and non-biological matrices: a review of cur- chemical profiles and complexities in addition to rent analytical methods. Trends Anal Chem 2018; 102:1-15. reliable and updated spectral databases. Institu- 12) Commission on Narcotic Drugs. Changes in the tions such as the EWS of the EMCDDA, which scope of control of substances new psychoactive are focused on collecting spectral data (nuclear substances: overview of trends, challenges and magnetic resonance, GC/MS, infrared) relative to legal approaches. Released on 8th March 2016. 79 such compounds from all over the world . Cru- 13) European Monitoring Centre for Drugs and Drug Ad- cial input for the EWS database is delivered by diction (EMCDDA) New psychoactive substances the different European forensic institutes and also in Europe Legislation and prosecution — current customs laboratories, which provide the majority challenges and solutions. of the information. 14) Legea 194/2011 privind combaterea operatiunilor cu produse susceptibile de a avea efecte psiho- active, altele decat cele prevazute de acte norma- tive in vigoare, republicata 2014. 15) Narcotics Act (amended 2014), Criminal Code Conflict of Interest (amended 2014), Finnish government decree 2014. The Authors declare that they have no conflict of interests. 16) Neue Psychoaktive Substanzen Gesetz, BGBl. 1 Nr. 146/2011. BGBl. 1 Nr. 48/2013. 17) La MILDT devient la MILDECA. Publié le References 13/03/2014. Available at: https://www.drogues. gouv.fr/actualites/toutes-les-actualites/mildt-devi- 1) Orsolini L, Chiappini S, Corkery JM, Guirguis A, Pa- ent-mildeca. panti D, Schifano F. The use of new psychoactive 18) Available at https://www.drogues.gouv.fr. substances (NPS) in young people and their role 19) Roussel O, Tensorer L, Bouvota X, Baltera C, Sabinia in mental health care: a systematic review. Expert S, Groves Carlin M. The development of new psy- Rev Neurother 2019; 19: 1253-1264. choactive substances in France. Toxicol Anal Clin 2) Hassan Z, Bosch OG, Singh D, Narayanan S, Ka- 2017; 29: 90-95. sinather BV, Seifritz E, Kornhuber J, Quednow BB, 20) Magali M, Néfau T, Cadet-Taïrou A. New psychoac- Müller CP. Novel psychoactive substances-re- tive substances - ten-year overview of the situa- cent progress on neuropharmacological mecha- tion in France. OFDT - Observatoire français des nisms of action for selected drugs. Front Psychia- drogues et des toxicomanies. Tendances 2018; try 2017; 8 :152. 127: 1-8. 3) Busardò FP, Kyriakou C, Cipolloni L, Zaami S, Frati 21) Bates M, May T. Psychoactive substances bill P. From clinical application to cognitive enhance- [HL] 2015-2016. http://services.parliament.uk/ ment: the example of methylphenidate. Curr Neu- bills/2015-16/psychoactivesubstances.html (ac- ropharmacol 2016; 14: 17-27. cessed 25 Nov 2015).

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