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 fentanyl 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-tetrahydrocannabinol, 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 • Stimulant-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., mephedrone), 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 depressant substances and tranquilisers (a.k.a., ‘Downer’/tranquilis- aimed at chronic heroin users, namely new syn- er-type drugs), which are designed to repli- thetic opioids 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 ketamine, 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 stimulants, or trol substances not explicitly mentioned in the as hallucinogens, 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