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Acknowledgements

Tis report was produced by the Laboratory and Scientic Section (headed by Justice ettey) under thesupervision of Sandeep Chawla, Director, Division for Policy Analysis and Public Affairs.

Core team: Beate Hammond (coordination), Conor Crean, Sabrina Levissianos, Deniz Mermerci , un Nay Soe,akako Otani, Meejung Park, Diego Pazos, Kristal Pieros, Akara Umapornsakula, Yen Ling Wong.

Te report also beneted from the work and expertise of many other UNODC staff in Vienna and in eld officesaround the world.

UNODC would like to specically acknowledge the Government of Japan for providing funding that made itpossible to prepare this report.

UNODC reiterates its appreciation and gratitude to Member States and to the drug analysis laboratories thatform part of the UNODC International Collaborative Exercise network for the reports and information thatprovided the basis of this report as well as to the International Narcotics Control Board (INCB) and the EuropeanMonitoring Centre on Drugs and Drug Addiction (EMCDDA).

UNODC would also like to thank Dr. Kalman Szendrei for comments provided on an earlier draft of this report.

DISCLAIMERTe publication has not been formally edited. Te boundaries, names and designations used in all maps do notimply official endorsement or acceptance by the United Nations.

Comments on this report are welcome and can be sent to:Laboratory and Scientic SectionUnited Nations Office on Drugs and CrimePO Box 500

1400 Vienna, AustriaE-mail: [email protected] Nations Publication


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The challenge ofnew psychoactive substances

A Report from the Global SMAR Programme

March 2013

United Nations Office on Drugs and Crime


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Table of Contents

Te Global SMAR Programme ................................................................................................................iAbbreviations ............................................................................................................................................iiNotes to the reader ................................................................................................................................... ivBackground .............................................................................................................................................viMethodology ...........................................................................................................................................vi

1. INRODUCION ..............................................................................................................................11.1 Emergence of new psychoactive substances ........................................................................................... 1

1.2 Denition and categories of new psychoactive substances ..................................................................... 1

2. MAIN NEW PSYCHOACIVE SUBSANCES ENCOUNERED IN ILLICI MARKES AND HEIR EFFECS ................................................................................................................................3

2.1 Synthetic cannabinoids ........................................................................................................................ 3 2.2 Synthetic cathinones ............................................................................................................................ 5 2.3 Ketamine ............................................................................................................................................. 8 2.4 Phenethylamines .................................................................................................................................. 9 2.5 Piperazines ......................................................................................................................................... 11 2.6 Plant-based substances ....................................................................................................................... 13 2.6.1 Khat .......................................................................................................................................... 13 2.6.2 Kratom ...................................................................................................................................... 14 2.6.3 Salvia divinorum........................................................................................................................ 15 2.7 Miscellaneous substances .................................................................................................................... 15 2.7.1 Aminoindanes............................................................................................................................ 15

2.7.2 Phencyclidine-type substances ................................................................................................... 16 2.7.3 ryptamines ............................................................................................................................... 17

3. GLOBAL SPREAD OF NEW PSYCHOACIVE SUBSANCES ...................................................... 19 3.1 Emergence of new psychoactive substances......................................................................................... 19 3.2 Legal situation .................................................................................................................................... 26 3.2.1 Te international drug control system ........................................................................................ 26 3.2.2 Regional responses: the European Union ................................................................................... 27 3.2.3 National responses to new psychoactive substances .................................................................... 28 3.2.4 Other regulatory frameworks ..................................................................................................... 30

4. USE OF NEW PSYCHOACIVE SUBSANCES ..............................................................................33 4.1 Global use estimates ........................................................................................................................... 33 4.2 Regional use estimates ........................................................................................................................ 33 4.3 National use estimates ........................................................................................................................ 34 4.4 National treatment data estimates ...................................................................................................... 38 4.5 Internet surveys on the use of new psychoactive substances ................................................................ 39

5. SOURCES OF NEW PSYCHOACIVE SUBSANCES ....................................................................43 5.1 Countries reporting seizures of new psychoactive substances .............................................................. 43 5.2 Number of new psychoactive substances in global markets ................................................................. 49 5.3 Perceived sources of new psychoactive substances and the role of internet .......................................... 52

5.4 Identication of new psychoactive substances ..................................................................................... 53


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ANNEXES ..............................................................................................................................................57 New psychoactive substances reported in 2012......................................................................................... 59 Synthetic cannabinoids ............................................................................................................................ 67 Synthetic cathinones ................................................................................................................................ 73

Ketamine ................................................................................................................................................. 77 Phenethylamines ...................................................................................................................................... 79 Piperazines ............................................................................................................................................... 85 Plant-based substances ............................................................................................................................. 87 Aminoindanes .......................................................................................................................................... 89 Phencyclidine-type substances .................................................................................................................. 91 ryptamines ............................................................................................................................................. 93 Others ...................................................................................................................................................... 95

References ..................................................................................................................................................... 99


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The Global SMART ProgrammeUNODC launched the Global Synthetics Monitoring:

Analyses, Reporting and rends (SMAR) Programme

in September 2008. Te Programme seeks to enhancethe capacity of Member States and authorities inpriority regions, to generate, manage, analyse andreport synthetic drug information, and to applythis scientic evidence-based knowledge to designthe policies and programmes. Te Global SMARProgramme is being implemented in a gradual phasedmanner, with East Asia being the rst focus priorityregion. Operations in Latin America started in 2011.

Tis report is the rst global situation assessment

on new psychoactive substances put forward underthe Global SMAR Programme and pursuant toCommission on Narcotic Drugs Resolution 55/1 onPromoting international cooperation in respondingto the challenges posed by new psychoactivesubstances, which requested the United NationsOffice on Drugs and Crime to provide an update toits 2011 report entitled Synthetic cannabinoids inherbal products, addressing a wider range of newpsychoactive substances, in addition to syntheticcannabinoids, and to take into consideration the

creation of a compilation of new psychoactivesubstances encountered by Member States, to serve asan early warning advisory.

It constitutes the rst step in providing consolidatedup to-date analysis, based primarily on the information

shared by Member States and the InternationalCollaborative Exercise network of drug analysislaboratories. It is hoped that the information onnew psychoactive substances presented in this reportwill make a practical contribution to addressing thesignicant threat posed by the manufacture, traffickingand use of these substances throughout the world, andplace policymakers in a better position to evaluate thedrug situation, and to make informed decisions onintervention and prevention strategies.

Tis report provides an overview of the situationthroughout the world. It outlines the emergence ofdifferent groups of new psychoactive substances in theregions and highlights several key issues associatedwith these substances, including reported adverseeffects associated with their use, the challenges forthe identication of these substances and theirsubsequent control through legislation. While theinformation presented points towards increasingefforts by the countries to address the NPS problem,it also highlights the need for continued and joint

efforts, both at the national as well as regional levels.It is hoped that this report will contribute to a betterunderstanding of the NPS problem and in developingeffective strategies to address it.


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Abbreviations2-AI 2-Aminoindane3-MeO-PCE 3-Methoxyeticyclidine4-AcO-DiP 4-Acetoxy-N,N-diisopropyltryptamine4-AcO-DM 4-Acetoxy-N,N-dimethyltryptamine4-FA 4-Fluoroamphetamine4-FMA 4-Fluoromethamphetamine4-MeO-PCP 4-methoxyphencyclidine5-APB 5-(2-Aminopropyl)benzofuran5-HP 5-Hydroxytryptophan5-IAI 5-Iodo-2-aminoindane5-MeO-DAL 5-Methoxy-N,N-diallyltryptamine5-MeO-DM 5-Methoxy-N,N-dimethyltryptamine

5-MeO-DP 5-Methoxy-N,N-dipropyltryptamine6-APB 6-(2-Aminopropyl)benzofuran-PPP -Pyrrolidinopropiophenone-PVP -Pyrrolidinopentiophenone

ARQ UNODC Annual Reports QuestionnaireAS Amphetamine-type stimulantsBCS British Crime Survey (UK)BZP BenzylpiperazineCP compounds cyclohexylphenols or 3-arylcyclohexanolsCSA Controlled Substances Act (USA)DAINAP Drug Abuse Information Network for Asia and the PacicDEA Drug Enforcement Administration (USA)DE 3-[2-(diethylamino)ethyl]indoleDOB BrolamphetamineDOC 2,5-dimethoxy-4-chloroamphetamineDOI 2,5-dimethoxy-4-iodoamphetamineDOM / SP 2,5-dimethoxy-alpha,4-dimethylphenethylamineEACD Expert Advisory Committee on Drugs (New Zealand)EDND European database on new drugsEDRS Ecstasy and Related Drugs Reporting System (Australia)EMCDDA European Monitoring Centre for Drugs and Drug Addiction

EMEA European Agency for the Evaluation of Medicinal ProductsEAI N-Ethyl-5-triuoromethyl-2-aminoindaneEU European UnionEUROPOL European Police OfficeFIR Fourier transform infrared spectroscopyGC-MS Gas chromatography - mass spectrometryGHB Gamma-hydroxybutyrateHPLC High performance liquid chromatographyICE International Collaborative ExercisesINCB International Narcotics Control BoardLCMS Liquid chromatographymass spectrometry LSD d-lysergic acidMBZP 1-Benzyl-4-methylpiperazine


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mCPP 1-(3-Chlorophenyl)piperazineMDA 3,4-methylenedioxyamphetamineMDAI 5,6-Methylenedioxy-2-aminoindaneMDBP Methylenedioxybenzylpiperazines

MDE N-ethyl--methyl-3,4-(methylenedioxy)phenethylamineMDMA 3,4-methylenedioxymethamphetamineMDMAI 5,6-Methylenedioxy-N-methyl-2-aminoindaneMDPV 3,4-MethylenedioxypyrovaleroneMephedrone (4-MMC) 4-methylmethcathinoneMMAI 5-Methoxy-6-methyl-2-aminoindaneNFLIS National Forensic Laboratory Information SystemNMR Nuclear magnetic resonanceNPS New Psychoactive Substancesnp-SAD National Programme on Substance Abuse Deaths (UK)NA National reatment Agency for Substances Misuse (UK)PCE EticyclidinePCP PhencyclidinepFPP 1-(4-Fluorophenyl)piperazinePHP/PCPY RolicyclidinePMA p-methoxy-alpha-methylphenethylaminePMMA 1-(4-methoxyphenyl)-2-methylaminopropaneSMAR Global Synthetics Monitoring: Analyses, Reporting and rendsAI 5-triuoromethyl-2-aminoindaneCP enocyclidineFMPP 1-(3-riuoromethylphenyl)piperazine

HC 9

-tetrahydrocannabinolUK United KingdomUS United States of America UNODC United Nations Office on Drugs and Crime

WHO World Health OrganizationYSS Youth Smoking Survey (Canada)

Weights and measurements

kg Kilogrammt Metric tons


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Notes to the readerTis report has not been formally edited.

Te designations employed and the presentationof the material in this publication do not imply theexpression of any opinion whatsoever on the part ofthe Secretariat of the United Nations concerning thelegal status of any country, territory, city or area orof its authorities, or concerning the delimitation ofits frontiers or boundaries. Countries and areas arereferred to by the names that were in official use at thetime the relevant data were collected.

Te following notes describe certain terms, regional

designations, data sources and timeframes usedthroughout this document.

NPS New psychoactive substances are substancesof abuse, either in a pure form or a preparation, thatare not controlled by the 1961 Single Convention onNarcotic Drugs or the 1971 Convention on Psycho-tropic Substances, but which may pose a public healththreat. In this context, the term new does not neces-sarily refer to new inventions but to substances thathave been recently become available.

Data sources Unless indicated specically, datacontained in this report draws upon official sourcesas reported in the UNODC questionnaire on newpsychoactive substances by Member States and bythe International Collaborative Exercise networkof drug analysis laboratories, data reported in theUNODC Annual Reports Questionnaire (ARQ) byMember States, annual and technical reports of officialgovernment and inter-governmental entities (e.g.Europol, EMCDDA, World Health Organization,

UNODC reports) and scientic literature.Annexes Any compound or substance reportedthrough the UNODC questionnaire on newpsychoactive substances under control in theinternational drug control conventions or whose namewas not provided in full or only as an analogue withoutfurther indication was excluded from the annexes tothis report. Individual reports on active ingredientsof plant-based substances were merged with thecorresponding plant/herb. Substances with severalpositional isomers in which the specic isomer was not

indicated were merged into the generic compound.

Data time frame Te statistical data contained inthis report cover the 2009-2012 period, except ininstances where a longer historical frame is necessaryto provide a clear explanation of emergence and use of

new psychoactive substances. Data for 2012 should beconsidered preliminary as the UNODC questionnaireon NPS was circulated in July 2012. Data are subjectto change for a variety of reasons, such as new or latedata being added or revisions in data already providedby Member States. Tus, some gure may differ frompreviously published gures. All data reported hereinreect the most up-to-date and precise informationavailable at the time of publication.

Symbols In the tables throughout this report arrowsindicate an increase or decrease in the trend of use or

availability of a specied new psychoactive substanceduring the previous year - () an increase, () a decrease,() a stable and (-) indicates that the information isnot available, not known, or was not reported.

erms Since there is some scientic and legalambiguity about the distinctions between drug use,misuse and abuse, this report uses the neutral terms,drug use or consumption.

Country names and geographical names In

various sections, this report uses a number of regionaldesignations. Tese are not official designations. Teyare dened as follows:

Africa

Algeria, Angola, Benin, Botswana, Burkina Faso,Burundi, Cameroon, Cape Verde, Central AfricanRepublic, Chad, Comoros, Congo, DemocraticRepublic of Congo, Cte dIvoire, Djibouti, Egypt,Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia,

Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho,Liberia, Libya, Madagascar, Malawi, Mali, Mauritania,Mauritius, Morocco, Mozambique, Namibia, Niger,Nigeria, Rwanda, Sao ome and Principe, Senegal,Seychelles, Sierra Leone, Somalia, South Africa, SouthSudan, Sudan, Swaziland, ogo, unisia Uganda,United Republic of anzania, Zambia and Zimbabwe.

Americas

Antigua and Barbuda, Argentina, Bahamas, Barbados,Belize, Bermuda, Bolivia (Plurinational State of),Brazil, Canada, Chile, Colombia, Costa Rica, Cuba,Dominica, Dominican Republic, Ecuador, El Salvador,


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Grenada, Guatemala, Guyana, Haiti, Honduras,Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru,Saint Kitts and Nevis, Saint Lucia, Saint Vincent andthe Grenadines, Suriname, rinidad and obago,

United States of America, Uruguay and Venezuela(Bolivarian Republic of).

Asia

Afghanistan, Armenia, Azerbaijan, Bahrain,Bangladesh, Bhutan, Brunei Darussalam, Cambodia,China, Democratic Peoples Republic of Korea,Georgia, India, Indonesia, Iran (Islamic Republicof), Iraq, Israel, Japan, Jordan, Kazakhstan, Kuwait,Kyrgyzstan, Lao Peoples Democratic Republic,Lebanon, Malaysia, Maldives, Mongolia, Myanmar,

Nepal, Oman, Pakistan, Philippines, Qatar, Republicof Korea, Saudi Arabia, Singapore, Sri Lanka, Syrian

Arab Republic, ajikistan, Tailand, imor-Leste,urkmenistan, the United Arab Emirates, Uzbekistan,Viet Nam and Yemen

Europe

Albania, Andorra, Austria, Belarus, Belgium, Bosniaand Herzegovina, Bulgaria, Croatia, Cyprus, CzechRepublic, Denmark, Estonia, Finland, France,

Germany, Greece, Hungary, Iceland, Ireland, Italy,Latvia, Liechtenstein, Lithuania, Luxembourg, Malta,Monaco, Montenegro, Netherlands, Norway, Poland,Portugal, Republic of Moldova, Romania, RussianFederation, San Marino, Serbia, Slovakia, Slovenia,Spain, Sweden, Switzerland, the former YugoslavRepublic of Macedonia, urkey, Ukraine and UnitedKingdom of Great Britain and Northern Ireland.

Oceania

Australia, Cook Islands, Fiji, Kiribati, Marshall Is-lands, Micronesia (Federated States of), Nauru, NewZealand, Palau, Papua New Guinea, Samoa, SolomonIslands, onga, uvalu and Vanuatu.


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BackgroundTe amphetamine-type stimulants (AS) markethas always been characterized by a large variety of

substances. However, in recent years, new psychoactivesubstances (NPS) have rapidly emerged in this marketpurportedly as legal alternatives to internationallycontrolled drugs, causing similar effects to the latter,with the potential to pose serious risks to public healthand safety. Te fast-paced nature of this market, theincreased availability of these substances and thereports of increased and emerging use of and tradein such substances have drawn concerns among theinternational community as there is the potential fortransnational organized criminal groups to exploit the

market for these substances.

As a response, the Commission on Narcotic Drugs,recalling its resolution 48/1 of 11 March 2005 onpromoting the sharing of information on emergingtrends in the abuse of and trafficking in substancesnot controlled under the international drug controlconventions, and noting the increasing number ofreports about the production of synthetic cannabinoidsin herbal products, adopted resolution 53/11 of 12March 2010, on promoting the sharing of informationon the potential abuse of and trafficking in syntheticcannabinoid receptor agonists. In that resolution, theCommission requested the United Nations Office onDrugs and Crime to share information on the issueof cannabinoid receptor agonists with the ExpertCommittee on Drug Dependence of the WorldHealth Organization to increase its understanding andawareness of the issue. Pursuant to this resolution,UNODC prepared the 2011 report Syntheticcannabinoids in herbal products.1

Te continued high number and wide range of new

psychoactive substances of diverse origin, effect andrisk prole, identied as posing serious risks to publichealth, as well as the challenges that identicationand control of such substances pose to effectivehealth and law enforcement regulation, resulted inCommission on Narcotic Drugs resolution 55/1,which in paragraph 13 requests UNODC to providean update to its 2011 report entitled Syntheticcannabinoids in herbal products, addressing a widerrange of new psychoactive substances, in addition to

synthetic cannabinoids, and to take into considerationthe creation of a compilation of new psychoactivesubstances encountered by Member States, to serve asan early warning advisory.

Tis report was prepared pursuant to resolution55/1. Its aim is to provide an overview of the maingroups of new psychoactive substances present inillicit AS markets, their chemistry, mode of useand reported adverse effects associated with theiruse. It reects the situation as of February 2013 andprovides information about the emergence of NPS,the prevalence of use, the origins of these substancesand the different approaches in regulation that havebeen taken by some Governments. It nally suggestsways that could be potentially used to detect, identify

and monitor NPS, in order to facilitate States makingeffective evidence-based decisions to counteract thechallenges posed by such substances.

MethodologyTe information and data presented in this reportwere obtained primarily through an electronicquestionnaire on NPS, which was sent to all MemberStates as well as to the drug analysis laboratories

that participate in the UNODC InternationalCollaborative Exercises (ICE) in July 2012. Tequestionnaire covered a wide spectrum of issuesrelated to NPS, inter alia, legislation, seizures ofNPS, substances detected and analyzed, identicationof NPS, sources, trafficking, distribution and the useof NPS. Additional information was obtained fromGovernment reports, scientic literature and dataextracted from the UNODC ICE Portal.

1


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Introduction

1. INTRODUCTION

1. 1 Em er gence o f new psy choac t i ve sub -

s t ances

New psychoactive substances that fall outside interna-tional drug control conventions are not a novel phe-nomenon. Many of these substances were synthesizedand patented in the early 1970s or even earlier, butonly recently their chemistry or process of synthesishave been slightly modied to produce effects similarto known illicit substances.

NPS have been known in the market by terms suchas designer drugs, legal highs, herbal highs, bathsalts. Te term designer drugs had been tradition-ally used to identify synthetic substances but has re-cently been broadened to include other psychoactivesubstances that mimic the effects of illicit drugs andare produced by introducing slight modications tothe chemical structure of controlled substances to cir-cumvent drug controls. Legal highs, herbal highs,research chemicals and bath salts are also commonnames used to refer to NPS offered as a legal alter-native to controlled drugs. Tese substances are fre-quently labelled as not for human consumption.

Over the last decade these substances have been in-troduced in AS markets through various modes ofdistribution, including the Internet, head or smartshops which sell drug paraphernalia, or street-leveldrug traffickers as legal alternatives to illicit drugs, ac-counting for an increasingly signicant share of illicitdrug markets in some countries and becoming a mat-ter of great concern and a threat to public health.

Ketamine is one of the oldest NPS. Its abuse was rec-

ognized in the United States since the beginning ofthe 1980s and started to be noticed in Europe in the

1990s.2Other NPS such as those belonging to the fam-

ily of phenethylamines and piperazines appeared in themarket through the 1990s and at the beginning of the2000s respectively.3From 2004 onwards synthetic can-nabinoids such as spice, started to be seen in the mar-ket, followed by synthetic cathinones and other emerg-ing groups of NPS, as identied in this report.

psy choac t i ve subs t an ces

For the purposes of this document, NPS are dened assubstances of abuse, either in a pure form or a prepa-ration, that are not controlled by the 1961 Conven-tion on Narcotic Drugs or the 1971 Convention onPsychotropic Substances, but which may pose a publichealth threat. In this context, the term new does notnecessarily refer to new inventions but to substancesthat have recently become available.

Te information and analysis of NPS presented throu-ghout this report is based on the identication of sixmain groups of substances present in this market, i.e.synthetic cannabinoids, synthetic cathinones, ketamine,

phenethylamines, piperazines, plant-based substances,and a seventh group of miscellaneous substances thatcontain recently identied NPS which do not t intothe aforementioned groups.

Given the almost innite possibilities of altering struc-

2 European Monitoring Center for Drugs and Drug Addiction, Reporton the risk assessment of ketamine in the framework of the joint ac-tion on new synthetic drugs, Belgium, 2002

3

an alternative and a legal drug in New Zealand around the year 2000.Bassindale, T., Benzylpiperazine: the New Zealand legal perspective, Europe around 2004


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Global SMART Programme 2013

tures of chemicals, the list of substances mentioned ineach of the NPS groups is not exhaustive but offerssome guidance on the most common substances as re-ported by respondents to the UNODC questionnaire

on NPS.Substances that are not covered in this report includesubstances that are subject to international control un-der the 1961 Convention on Narcotic Drugs or underthe 1971 Convention. Benzodiazepines, for instance,or any other prescription drugs that are prone toabuse, such as opioids, central nervous system depres-sants and stimulants are not the subject of this report.


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Main New Psychoactive Substances Encountered In Illicit ATS Markets And Their Effects

2. MAIN NEW PSYCHOACTIVE SUB-STANCES ENCOUNTERED IN ILLICITATS MARKETS AND THEIR EFFECTS

Many of the substances that are available on the mar-

ket for NPS contain unfamiliar molecules that mayor may not share similar risk effects and proles tothe illicit substances they are designed to mimic. As aresult, they may pose serious challenges to researchersand policy-makers that try to assess the risk of harmand to take appropriate measures to control them.

Research on most NPS is very limited. Tere are nocomprehensive scientic studies on their toxicityand most studies are based on work in animals, fa-tal poisonings in humans or clinical observations inintoxicated patients. oxicity, abuse liability and risksassociated with long-term use in particular remain un-known. Most NPS have little or no history of medicaluse.

2 .1. Sy n t he t i c can na b i n o i d s

Background

Te appearance of herbal highs in the market is nota new phenomenon. Such products usually consistedof plant mixtures with little psychoactive effects. Since

2004, however, the composition of these herbal prod-ucts seems to have substantially changed to includepotent new psychoactive compounds known as syn-thetic cannabinoids.

Research on the mechanism of cannabis activity datesback several decades when molecules with similar be-haviour to 9-tetrahydrocannabinol (HC) were rstexamined. A synthetic analogue of HC , HU-210,was rst synthesized in Israel in 19884 and is consid-

ered to have a potency of at least 100 times more than

HC. Due to its similar chemical structure to HC,HU-210 is regarded as a classical cannabinoid andhas been found in synthetic cannabinoids sold in theUnited States and other countries.

Non-classical cannabinoids include cyclohexylphe-nols or 3-arylcyclohexanols (CPcompounds). CPcompounds were developed as potential analgesics bya pharmaceutical company in the 1980s. Respondentsto the UNODC questionnaire on NPS have reported

4 Mechoulam, R., Lander, N., Breuer, A., Zahalka, J., Synthesis of theindividual, pharmacologically distinct, enantiomers of a tetrahydro-cannabinol derivative, Tetrahedron: Asymetry, 1990, 1 (5), 315-18

O

OHH

H

A

O

OHH

H

OH

B

Chemicalstructure ofclassicalcannabinoids: 9-tetrahy-drocannabinol (A), and of the synthetic cannabinoidHU-210 (B). Te differences between the synthetic

cannabinoid and the controlled substance tetrahydrocan-nabinolare highlighted inred.


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the emergence of CP-47,497 and CP-47,497-C8 innumerous countries in all regions except Africa since2009.

Other structurally dissimilar varieties of syntheticcannabinoids unrelated to HC have also emerged onthe market. Tese include aminoalkylindoles, such asnaphtoylindoles (e.g. JWH-018), phenylacetylindoles(e.g. JWH-250), and benzoylindoles (e.g. AM-2233).5

JWH-018, arguably the best known synthetic can-nabinoid, belongs to the group of aminoalkylindolesand is considered to be three times as potent as HC.Te JWH-compounds had been previously developedas test compounds in the research of receptor-drug in-

teractions by Professor John William Huffman6andhis team in the United States.

While cannabis and HC are controlled under the in-

ternational drug control treaties, none of the syntheticcannabinoids are under international control. However,several have been subject to control measures at the na-tional level. Respondents to the 2012 UNODC surveyon NPS identied JWH-018 as the most widespreadsynthetic cannabinoid, followed by JWH-073, JWH-250 and JWH-081, all of which are aminoalkylindoles.

5

in herbal products, Vienna, 2011, 5; see also Hudson, S., Ramsey, J., -ing and Analysis, 2011, 3, 466478

6 John W. Huffman is a US chemist and a retired professor of organic led to the synthesis of non-cannabinoid cannabimimetrics in the -

- html; accessed in: October 2012)

N

R3'

R2'O

R1'

N

R1'''

O

R2'''

R3'''

R4'''

N

R4''

R3''

O

R1''

R2''

B DC

OH

R2

R3

R4

OH

R1

A

Generic chemicalstructure ofnon-classicalcannabinoids and aminoalkylindoles: generic chemicalstructure ofsyntheticnon-classicalcannabinoids (A), and three groups ofaminoalkylindoles, i.e. naphthoylindoles (B), phenacetylindoles (C),and benzoylindoles (D). Manycannabinoid derivatives and analogues could be synthesized bythe additionofa halogen,alkyl, alkoxyorothersubstituent to one ofthe aromatic ring systems. Othersmallchanges, suchas variations ofthe lengthand congurationofthe alkylchain, canalso be made to synthesize othercompounds.


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Description

Most synthetic cannabinoids are functionally similar toHC. Synthetic cannabinoids are usually available in

powder form and are sold asSpice Gold, Spice Silver,Spice Diamond, K2, Bliss, Black Mamba, BombayBlue, Blaze, Genie, Zohai, JWH -018, -073, -250,Kronic, Yucatan Fire, Skunk, Moon Rocks, Mr. Smi-ley. Tey are usually smoked, but oral use has also beenreported. Labels on packages and actual constituents ofthe product are often mismatched.

Reported adverse effects

While side effects of cannabis are well documented,7data on human toxicity related to the use of synthetic

cannabinoids remains limited. As with other NPS,products sold as synthetic cannabinoids often containseveral chemicals in different concentrations, mak-ing it very difficult to determine substance-speciceffects. Available knowledge on the toxicity of thesecompounds comes from scientic reports and clinicalobservations.

Health-related problems associated with the use ofsynthetic cannabinoids include cardiovascular prob-lems and psychological disorders,8and it appears that

there may be carcinogenic potential with some of themetabolites of the substances contained in these prod-ucts.9

A study published in 2011 on the severe toxicity fol-lowing synthetic cannabinoid ingestion suggested that

JWH-018 could lead to seizures and tachyarrhythmia(irregular heartbeat).10In a recent review of clinical re-ports, addiction and withdrawal symptoms similar to

those seen with cannabis abuse were also linked to theuse of synthetic cannabinoids.11An analysis of syntheticcannabinoids in spice-like herbal blends highlightedthe increasing number of reports on suicides associated

with preceding use of these products.

12

2 .2 . Sy n t he t i c c a t h i n on es

Background

Cathinone and its derivatives are closely related to thephenethylamine family (which includes amphetamineand methamphetamine), but with a lower potencythan the latter.13Tey are characterised by the presenceof a -keto group on the side chain of the phenethyl-amines. Cathinone, the principal active ingredient in

the leaves of the khat plant (catha edulis), can be con-sidered as the prototype from which a range of syn-thetic cathinones have been developed.

Synthetic cathinones appeared in drug markets inthe mid 2000s. In 2005, methylone, an analogue ofMDMA, was the rst synthetic cathinone reported tothe European Monitoring Centre on Drugs and Drug

Addiction (EMCDDA). In 2007, reports of 4-methyl-methcathinone (mephedrone) use emerged, rst in Is-rael and then in other countries and regions, including

Australia, Scandinavia, Ireland and the United King-dom.14Mephedrone was reportedly rst synthesized in1929.15

ypically, synthetic cathinones have an amphetamine-type analogue, i.e.cathinone, ephedrone, and methy-lone are structurally related to amphetamine, meth-amphetamine and MDMA respectively. However,little is known about the mechanism of action and thepotential harms of mephedrone, but it has been sug-gested that mephedrone is likely to act in a similar way

to other stimulants (e.g. cocaine, amphetamine and7

cannabis and cannabinoids, British Journal of Anaesthesia, 1999, 83(4), 637-49

8 Mller, H., Huttner, H.B., Khrmann, M., Wielopolski, J.E., Kornhu- use of the synthetic cannabinoid K2, Jounal of Pediatrics, 2011, 128,6, 1622-1627; Every-Palmer, S., Synthetic cannabinoid JWH-018 and 117 (2-3), 152-157

9 - Nitro-naphthalene, Toxicology, 2009, 260, 16-27

10 -

11 -ter, 2010, 197, 157-162

12 Ludger, E., Krueger, K., Lindigkeit, R., Schiebel, HM., Beuerle, T., Forensic Science International, 2012, 222 (1), 216-222

13 -

14 -

45315 Saem de Burnaga Sanchez, J., Sur un homologue de lephedrine, Bul-


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MDMA).16Up to 2010, methylone and mephedrone(4-methylmethcathinone) were identied as the mostcommon substances of use in this group in Europe.17

Other synthetic cathinones recently identied in thedrug market are analogues of pyrovalerone (3,4-meth-

ylenedioxypyrovalerone and naphyrone). For instance,3,4-methylenedioxypyrovalerone (MDPV), rst syn-thesized in 1969,18emerged in 2007 as a new psycho-active substance in Germany.19In 2008, it was rst re-ported to the European Early Warning System by theUnited Kingdom and by Finland, after being associ-ated with adverse health effects.20Initially unregulated,many countries, including countries of the EuropeanUnion as well as Australia, Israel and the United Stateshave introduced control measures over the substance.Other synthetic cathinones, inter alia, ephedrone and

naphyrone also became available in the drug market as

NPS from 2008 onwards.21

Responses to the UNODC questionnaire on NPS in-dicated that other synthetic cathinones, includingmethylone, butylone, 4-methylethcathinone, 4-u-oromethcathinone, naphyrone, 3-uoromethcathi-

none, methedrone, and, to a lesser extent, 3,4-di-methyl-methcathinone, -pyrrolidinopentiophenone(-PVP), buphedrone, pentedrone and -pyrrolidi-nopropiophenone (-PPP), have increasingly beenused as NPS from 2010 onwards.

While some synthetic cathinones such as methylonehad been patented as antidepressant and antiparkinso-nian agents,22 very few have been exploited clinicallypredominantly on account of their abuse and depen-dence potential. For instance, whereas diethylcathinone

(amfepramone) is used as an appetite suppressant, py-rovalerone, rst synthesized in 1964 and marketed foruse as an appetite suppressant and in the treatment ofchronic fatigue, was later withdrawn due to abuse anddependency in users.23Apart from cathinone, the only

16 -cathinone (mephedrone), 2010

17 -

18 -

19 F., Junge, T., Rosner, P., Sonnichsen, F., Schuster, F., Mass and NMRspectroscopic characterization of 3,4-methylenedioxypyrolvalerone: a International, 2009, 190, 1-8

20 -

21 -

22 Neurobiological Technologies Inc, USA

23 (4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) ana-

logues: a promising class of monoamine uptake inhibitors, Journal of such as amfepramone and bupropion are or have also been used asactive pharmaceutical ingredients.

Chemicalstructures ofcathinone (A), mephedrone (B), MDMA(C) and methylone (D). Differences betweencontrolledsubstances (i.e. cathinone and MDMA) and synthetic derivatives of cathinones (i.e. mephedrone and methylone) arehighlighted inred. Te molecularstructure ofgeneric cathinone derivatives is represented instructure (E). Te R groupsindicate locations ofthe molecule where modications canoccurto produce a wide range ofcathinone derivatives.

O

NH2

OHN

OHN

A B

C D

O

O

HNO

O

CH3 CH3

CH2

N

O R1

R2

R3

R4

E

CH3


19/1227


cathinone derivatives under international drug controlare amfepramone, methcathinone and pyrovalerone.24

Description

Synthetic cathinones are frequently found in productssold as research chemicals, plant food, bath saltsor glass cleaner and are usually sold in powder, pillor capsule form. Mephedrone (m-cat, meph, droneor miaow) and methylone (explosionor top cat) areusually available as white or brown powders or in theform of pills that are often sold as ecstasy. Most syn-thetic derivatives are ingested but may be injected.Mephedrone is commonly nasally insufflated, inject-ed, ingested by swallowing a powder wrapped in paper(bombing), or mixed in a drink.


Few reports on the toxicity of synthetic cathinones ex-ist to date. Much of the current knowledge on health-related effects comes from user reports and clinicalobservations. Further research is needed to provideevidence of short and long-term health risks and theaddiction potential associated with the use of thesesubstances.

Whereas cardiac, psychiatric, and neurological signsare some of the adverse effects reported by syntheticcathinone users, agitation, ranging from mild agita-tion to severe psychosis, is the most common symp-tom identied from medical observations.25Studies ofpatients under the apparent inuence of mephedronehave also shown that synthetic cathinones presentsimilar sympathomimetic effects (including tachycar-dia and hypertension as well as psychoactive effects)to similar amphetamine derivatives.26 In a studentsurvey, more than half of those who had taken me-

phedrone reported adverse effects associated with thecentral nervous system, nasal/respiratory system and

cardiovascular system.27 Te rst fatality related tothe sole use of mephedrone, conrmed by toxicologi-cal analysis, was reported in Sweden in 2008.28Mostfatalities associated with the use of mephedrone in-

volved the use of other substances.

29

Deaths associatedwith the use of other synthetic cathinones include twodeaths related to methedrone30and two other deathsrelated to butylone.31

Te Finnish Poisons Information Centre reported 33calls regarding exposures to MDPV during the pe-riod of January 2008 to October 2009. Post mortemtoxicological analysis conrmed 6 deaths related toMDPV between 2009 and 2010, although in most ofthe cases the presence of other drugs was also detect-ed.32A report from the United States provided details

on the case of 35 patients who visited an EmergencyDepartment over a 3-month-period after ingesting,inhaling or injecting substances sold as bath salts andasserted that these products could contain stimulantcompounds such as MDPV or mephedrone. Oneperson was dead upon arrival at the emergency de-partment. Te toxicological analysis revealed a highlevel of MDPV, along with cannabis and prescriptiondrugs, but the autopsy results revealed MDPV toxicityto be the primary factor contributing to death.33

24 -

25 of synthetic cathinones, The Journal of Medical Toxicology, 2012, 8(1), 33-42

26 - sympathomimetic refers to a pharmacologic agent that mimics the

effects of stimulation of organs and structures by the sympatheticnervous system. It functions by occupying adrenergic receptor sitesand acting as an agonist or by increasing the release of the neurotrans-mitter norepinephrine at postganglionic nerve endings.

27 adverse effects in school and college/university students before theUK legislation change, Oxford Journal of Medicine, 2010, 103 (10),875-9

28 - (43), 2769-71

29 -tion of mephedrone and heroin. Other cases reported from Scotland toxicity caused by the coadministration of 4-methylmethcathinone

(mephedrone) and heroin, Journal of Analytical Toxicology, 2010, 34 (4-methylmethcathinone) in 4 fatalities in Scotland, Forensic ScienceInternational, 2010, 202 (1-3), 62-3

30 -thoxymethcathinone), Journal of Analytical Toxicology, 2010, 34,594-98

31 - 16870

32 - Finland.pdf)

33

salts--- Michigan, November 13, 2010--March 31, 2011 ( http:/ /


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2 .3 . K et am i n e

Background

Ketamine is closely related to the internationally con-trolled drug phencyclidine (also known as PCP orangel dust) which is listed in Schedule II of the 1971Convention (see section 2.7.2).

Phencyclidine was investigated as an intravenous an-aesthetic in the 1950s but was later withdrawn due to

undesired hallucinogenic and delirium effects.34

Fol-lowing the withdrawal of phencyclidine, ketamine wassynthesized as an anaesthetic in 1962, patented in 1963in Belgium and three years later in the United States. Inthe early 1970s, ketamine was marketed as a medicalalternative to phencyclidine.

Te use of ketamine as a new psychoactive substancedates back to the 1980s and 1990s. At the internationallevel, ketamine was subject to a series of risk assess-ments. Te Expert Committee on Drug Dependence

of the WHO pre-reviewed ketamine in 2003 and con-ducted critical review in 2006. After reviewing the in-formation contained before it, the Committee conclud-ed that this information was not sufficient to warrantscheduling.35It also requested an updated version ofthe critical review to be presented at the next meeting ofthe Committee which was held in 2012. At that meet-ing, the Committee decided that bringing ketamine

34

-

35 -

under international control is not appropriate.36 Atthe level of European Union, in 2000, growing con-cern over the use of ketamine as a NPS prompted arisk assessment in the framework of the joint action on

new synthetic drugs.

37

Te European Commission con-cluded that it was not appropriate to introduce controlmeasures and recommended further monitoring of theuse of ketamine.

Description

Ketamine and phencyclidine have similar modes ofaction, affecting a range of central neurotransmitters.Ketamine is frequently sold as ecstasy in illicit ASmarkets. Street names for ketamine include K, spe-cial K,kit kat,tac,tic,cat valium,cat tranquilizer,vitamin K,ket,super K.38

Pharmaceutical preparations of ketamine are usu-ally found in liquid form, but powder and capsulesare also available. Te powder prepared by evapora-tion of the original solution is often nasally insufflated(bumping), smoked or swallowed.Reported adverse effects

Ketamine appears to stimulate the cardiovascular sys-

tem, producing changes in the heart rate and bloodpressure. As such, tachycardia is one of the most com-mon symptoms identied in recreational users.

Findings of neurotoxicity in animal studies have raisedconcerns on the consumption of ketamine by recre-ational users, for a number of reasons: unlike when itis clinically administered, substance users will not takeketamine in combination with protective agents. More-over, substances which may increase the neurotoxic po-tency of ketamine might be co-administered (including

PCP, tiletamine as well as alcohol). Furthermore, recre-ational use usually implies repeated exposure, whereasclinical use is mostly incidental.39

36 -

37 -

38 -

39

-tional Journal of the Addictions, 1990, 25, 133-139, in World Health -

Chemical structures of phencyclidine (A) (controlledsubstance) and ketamine (B). Asignicant portionofthemolecule is common to both compounds (the phenylcy-clohexyl), while the differences betweenthemare highlight-ed inred.

N

A

NH

Cl

O

B


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Chemicalstructure ofamphetamine (A), two substitutedphenethylamines: 2C-B (B) and Bromo-Dragony (C),and the generic structure of phenethylamines (D). Tedifferences betweenamphetamine and two ofthe pheneth-ylamine derivatives (i.e. 2C-B (internationally controlledsubstance) and Bromo-Dragony) are highlighted inred.Te eight positions ofthe phenethylamine core that canbe

modied to generate a wide range ofsubstituted pheneth-ylamine derivatives are also highlighted instructure (D).

B

NH2H3CO

Br OCH3

NH2

Br

O

O

C

NH2

A

HN

R1

R2

R3

R5

R6

R4

R7

R8

D

Side effects related to the use of ketamine in conjunc-tion with other drugs include hypertension and pul-monary oedema. Psychological dependence in someusers has also been identied. Adverse effects in long-

term users of ketamine have been reported albeit scarce.Tese included persistent impairment of attention andrecall, and a subtle visual anomaly. Other reported ef-fects include anxiety, changes of perception, an impair-ment of motor function and rhabdomyolysis.

Between 1987 and 2000, 12 fatal cases in which ket-amine was identied were reported, but only three ofthem involved ketamine alone. Chronic ketamine usehas been reported to result in potential lasting memo-ry and cognitive dysfunction.40

2 .4 . Phene t h y l am i n es

Background

Phenethylamines refer to a class of substances withdocumented psychoactive and stimulant effectsand include amphetamine, methamphetamine andMDMA, all of which are controlled under the 1971Convention.41Te phenethylamines also include ring-substituted substances such as the 2C series, ring-substituted amphetamines such as the D series (e.g.

DOI, DOC), benzodifurans (e.g. Bromo-Dragony,2C-B-Fly) and others (e.g. p-methoxymethamphet-amine (PMMA)).

Seizures of phenethylamines were rst reportedfrom the United States and European countries andsince 2009 substances such as 2C-E, 2C-I, 4-FA andPMMA have been commonly reported by severalcountries in different regions. Other phenethylaminesincreasingly reported in the UNODC questionnaireon NPS since 2011 include 4-FMA, 5-APB, 6-APB

and 2C-C-NBOMe.

A number of studies have reported the synthesis ofsome phenethylamines and amphetamine substitutes.In the 1980s and 1990s, Alexander Shulgin, a bio-chemist and pharmacologist, reported the synthesisof numerous new psychoactive compounds.42 Tis

included the D series (e.g. DOC, DOI) and the 2Cseries (e.g. 2C--7, 2C--2) of phenethylamines.

Simple variations on the mescaline molecule (a natu-ral phenylethylamine) led to the synthesis of powerfulhallucinogenic substances, e.g. 4-bromo-2,5-dime-thoxyphenethylamine (2C-B), synthesized by Shulginin 1974. Te 2C series differs from the D series

only by a slight modication in the chemical struc-ture, and their psychoactive effects have been reportedto be dose dependant, ranging from mere stimulant

40 and palliative medicine physician, Pain Physician, 2007, 10, 493-500

41

42 Alexander Shulgin research institute, Alexander Sasha Shulgin (http:/ /


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effect at lower doses, with hallucinogenic and entacto-genic effects at higher doses.44

Over two decades later, a new generation of phenethyl-amines was researched by Professor David Nichols andhis research team at Purdue University in the UnitedStates. Te team found the potency of synthetic ana-

logues of mescaline such as 2C-B and DOB, to exceedthat of many naturally occurring hallucinogens.45 Sever-al substances were synthesized, including a wide range ofbenzodifuranyl substances, later known as the FLY.46Benzodifurans, such as FLY (tetrahydrobenzodifura-nyl) and Dragony (benzodifuranyl aminoalkanes)are potent hallucinogens. Bromo-Dragony is the mostcommon and potent substance in this sub-group.

Other phenethylamines such as PMMA, rst synthe-sized in 1938,47are also sold in the drug market as a sub-

stitute for ecstasy. PMMA, in combination with PMA

(a substance listed in Schedule I of the 1971 UnitedNations Convention on Psychotropic Substances), hasbeen frequently found in tablets that carry a similar logoto ecstasy.48

Whereas some phenethylamines such as 2C-B, brolam-phetamine (DOB), SP/DOM, MDE, 4-MA, arelisted in Schedules I and II of the 1971 Convention,most of the new substances such as the 2C series, theD-Series and others such as PMMA are not under in-ternational control. Some phenethylamine derivativesare controlled in some countries.

Description

Street names for some phenethylamines include Euro-pafor 2C-E; 4-FMP, para-uoroamphetamine, RDJfor 4-FA; and 4-MMA, Methyl-MA for PMMA.Phenethylamines are usually available in form of pills,but FLY compounds are commonly sold in powderform, while oral doses (on a slip of blotter paper) areusually available for D substances. Ingestion is themost common route of administration of phenethyl-amines.


Phenethylamines included in the D series are de-scribed to be longer lasting, more potent and report-edly more liable to induce vasoconstriction than othermembers of the phenethylamine family.49

Reported adverse effects associated with the use of theD series derivatives include agitation, tachycardia, my-driasis, hallucinations, severe limb ischemia, seizures,liver and renal failure.50Bromo-Dragony has also beenassociated with a number of deaths in Scandinavia.51A

43 p-methoxy-alpha-methylphenethylamine (PMA) is controlled in Schedule

44 Huang, H.H. and Bai, Y.M. Persistent psychosis after ingestion of a

-

45 analogues of hallucinogens. 4. Mescaline derivatives, Journal of Me-

46 3 (7-8), 404-16

47

A preliminary behavioral investigation of PMMA, the 4-methoxy ana-log of methamphetamine, Pharmacology Biochemistry and Behavior,1988, 31 (1), 9-13

48

49

50 - -cal Toxicology, 2009, 5, 226

51 Andreasen, M.F., Telving, R., Birkler, R., Schumacher, B. and Jo-

- Toxicology, 2008, 46, 379-80

Chemical structures of other synthetic phenethylamines:PMA (A) and PMMA (B). Structure (B) shows how thederivativePMMAis produced byintroducing a smallmodi-cation in the structure ofPMA (internationally controlledsubstance).43

HN

AH3CO

H

HN

CH3

H3CO

B


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52 Neurosciences, 2008, 62, 243

53

- - Toxicology, 2003, 27, 493-98

54 of 4-methylthioamphetamine (4-MTA) intoxication: clinico-pathological - -phetamine (4-MTA), Journal of Analytical Toxicology, 2000, 24, 85-9; -cent paramethoxyamphetamine deaths, Journal of Analytical Toxicol-

Territory, Medical Journal of Australia, 2008, 188, 42655 -

choactive substances, 2011, 3, 401-403

case of acute psychosis after ingestion of 2C--4 wasreported in Japan.52 Tree fatal cases associated withthe use of 2C--7 have been identied, two of whichinvolved poly-drug use.53

PMA, PMMA and 4-methylthioamfetamine have beenmore often associated with incidental deaths than otherphenethylamines. PMA and PMMA are known to havea particularly high toxicity but there is no data availableon fatalities associated with their use. Clinical obser-vations have reported severe hyperthermia followingthe use of these substances.54Studies in animals havesuggested that some metabolites may be exposed to in-creased toxicity from 4-MA.

2 .5. P ip er az i n es

Background

Piperazines have been described as failed pharmaceu-ticals, as some had been evaluated as potential thera-peutic agents by pharmaceutical companies but neverbrought to the market.55While the best known pipera-zine that has been used as a new psychoactive substance

56 laboratories in 2012.

57 - -bon, 2009, 23

58

- - - - pdf; accessed in: September 2012)

59 - -bon, 2009, 23

60 EU, as part of the illicit ecstasy market, containedm

emcdda.europa.eu; accessed in: September 2012)

is 1-benzylpiperazine (BZP), during the last decadeother compounds such as 1-(3-chlorophenyl) pipera-zine (mCPP), 1-(3-triuoromethylphenyl) piperazine(FMPP) and, to a lesser extent, 1-Benzyl-4-methyl-piperazine (MBZP) and 1-(4-Fluorophenyl)piperazine

(pFPP) have been identied on the market.56

BZP was initially developed as a potential antidepres-sant drug, but was found to have similar propertiesto amphetamine and therefore liable to abuse. In the1980s, it was used in Hungary to manufacture pibera-line, a substance marketed as an antidepressant, but laterwithdrawn.57In the late 1990s, BZP emerged in NewZealand as a legal alternative for MDMA and metham-phetamine.58In Europe, its use was rst reported in Swe-den in 1999, but it only became widespread as a NPS

from 2004 onwards until controls over the substancewere introduced in 2008, in the European Union.59

MCPP, reportedly more widespread than BZP in someregions of the world,60 was developed during the late

Chemicalstructures of BZP(A), mCPP(B) and FMPP(C).

NHN

Cl

HN N

A B

NHN

CF3

C


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1970s and is used as an intermediate in the manufactureof several antidepressants, e.g. trazodone and nefazodo-ne.61FMPP is almost always seen in combination withBZP to produce the entactogenic62effects of MDMA.63

Neither BZP nor any other piperazines are under in-ternational control, although several (BZP, FMPP,mCPP, MDBP) were pre-reviewed by the WHO Ex-pert Committee on Drug Dependence in 2012. Severalcountries have introduced national control measuresover piperazines.

Description

Piperazines are frequently sold as ecstasy. Some of thegeneric names for these substances include, pep pills,

social tonics or simply party pills. Te latter term wasused to commercialize BZP in New Zealand.64Otherstreet names includeJax,A2, Benny Bear, Flying Angel,Legal E or Legal X, and Pep X, Pep Love or Nemesis.65

MCPP is known as3CPP,3C1-PPor CPP.

Piperazines are usually available in the form of pills(regularly pressed with logos similar to ecstasy pills),capsules or loose powders, and are mainly consumedby ingestion. Liquid forms are rarely seen, but injec-

tion, smoking and snorting is also possible.Reported adverse effects

Information on the toxicological aspects of many pi-perazines listed in this group remain limited. Furtherresearch is required to provide evidence on short andlong term health-effects associated with the use ofthese substances. Current knowledge comes from userreports, studies in animals, limited human studies, andclinical observations.

Piperazines have been found to act as stimulants as aresult of dopaminergic, noradrenergic, and predomi-nantly serotoninergic effects produced in the brain. BZPproduces toxic effects similar to amphetamine and othersympathomimetics, although, according to animal stud-ies, its effects are less potent than amphetamine, meth-amphetamine and MDMA.66FMPP, used in conjunc-tion with BZP, has been reported to produce some ofthe effects of MDMA, but with a lower potency,67whilemCPP has been indicated to produce similar stimulantand hallucinogenic effects as MDMA.68

In New Zealand, toxic seizures and respiratory acidosisafter the use of BZP alone or in conjunction with oth-er drugs were reported from three patients.69Anotherstudy of 61 patients reported toxic effects of BZP, withtwo cases presenting life-threatening toxicity.70Hyper-

61 active metabolite common to the psychotropic drugs trazodone, eto-peridone and mepiprazole, Journal of Pharmacy and Pharmacology,1982, 34, 674-5

62 feelings of happiness, increased empathy, and closeness to others.

- - -ence in humans, Progress inNeuro-Psychopharmacology - M., Huber,T., Psychological and cardiovascular effects and short-term

of Psychedelic Research, 2001, 2, 64-72

63 - Social and Health Outcomes Research and Evaluation (SHORE),

64 Stargate International, Party pills: successful safety record (http:/ /

65 - -

psychoactive substances, Risk Assessments Issue 8, Lisbon, 2009; World -

66 -

67

- piperazines abused by humans mimic the molecular mechanism of -ropsychopharmacology, 2005, 30 (3), 550-60

68 m 430-8)

69 -fects of BZP-based herbal party pills in humans: a prospective study 118, U1784

70

-fects of BZP-based herbal party pills in humans: a prospective study 118, U1784


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thermia, rhabdomyolysis and renal failure associatedwith BZP ingestion have also been reported.71 In theUnited Kingdom, self-terminating grand mal seizures72after the use of BZP have also been reported.73

Between 2004 and 2008, six fatal cases involving pi-perazines use were reported in Europe. wo of the casesinvolved the use of BZP in conjunction with FMPPand none referred to the use of piperazines alone.74BZP and FMPP were also associated with 19 fatali-ties between 2007 and 2010.75While reported effectsof mCPP include the serotonin syndrome, no fatal poi-sonings from mCPP have been reported so far.76Simi-larly, toxic effects from the use of FMPP alone havenot been documented.77

2 . 6 . Pl an t - based sub s t an ces

2.6.1. Khat

Background

Te khat shrub (Catha edulis) of the celastraceae fam-ily is a plant native to the horn of Africa and the Ara-bian peninsula. Khat chewing is a social custom inthe communities living in these areas. Te psychoac-tive effects resulting from the release of cathinone and

cathine alkaloids after chewing of khat are well-docu-

mented.78Te khat shrub became known to Europe-ans in the late 18th century and in the 19th century,and the active constituents of the plant were isolatedin the 19th and 20th century. A katin alkaloid was

identied rst in 1887, cathine in 1930 and cathi-none in 1975.79

In Europe and North America, khat was consideredto be traditionally used by migrant communities fromEthiopia, Kenya, Somalia and Yemen, but in recentyears its use has spread beyond these communities.Respondents to the UNODC questionnaire on NPSfrom Bahrain, Canada, Finland, Ireland, Italy, NewZealand, Norway, Oman, United States and HongKong (China) reported that khat emerged on theirmarkets in 2009, and was the second most popular

plant based substance, after salvia divinorum, reportedby Member States from 2009 to 2012.

Catha edulisis not under international drug control,but cathinone and cathine are listed in Schedules Iand III, respectively, of the 1971 Convention. Khat isunder national control in several countries.

Description

Street names for khat include qat, gat, chat, miraa,

murungu and Arabianor Abyssinian tea. Due to thedegradation of cathinone, khat leaves need to be con-sumed soon after harvesting and therefore fresh leavesof khat are the preferred form of use, but dried leaves(graba) are also available. Khat is usually consumedby chewing the leaves and shoots of the plant, but in-fusions are also possible. Recently, alcoholic extracts ofkhat sold as herbal highs have been reported.80


It has been estimated that a typical chewing session ofkhat results in the absorption of its active constituentswith an activity equivalent to that of approximately 5mg of amphetamine.81 Te pharmacological effects of

71 - (Philadelphia), 2010, 48, 230-3

72 - tonic-clonic seizures. United States, National Library of Medicine

73 -

piperzine (BZP), Journal of Medical Toxicology, 2008, 4, 254-774 - 3-TFMPP, Journal of Analytical Toxicology, 2008, 32, 172; Wik- Fatal brain edema after ingestion of ecstasy and benzylpiperazine,

75 - -tion of fatal and non-fatal cases related to the use of BZP is available -ing, 2012

76

77 -

78 -its aetiological background, International Journal of EnvironmentalHealth Research, 2007, 17, 185-95

79 See Szendrei, K., The chemistry of khat, Bulletin on Narcotics, 1980,32, 3, 5-35 for further information.

80

81

amphetamine, Biomedical Papers, 2004, 148, 11-5


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khat resemble those of amphetamine use, and includesincreased alertness, euphoria, hyperthermia, anorexia, in-creased respiration rate, heart rate and blood pressure.82

Fatalities associated with the sole consumption of khathave not yet been reported. However, prolonged useof khat has been linked to adverse effects that rangefrom psychiatric disturbances (from psychosis to de-pression) to damage of major organs of the body, aswell as to similar neurological disorders to those as-sociated with amphetamine and cocaine use.83

2.6.2. Kratom

Background

Mitragyna speciosaKorth (of the Rubiaceaefamily) is alarge tree found in tropical and sub-tropical regions ofSouth-East Asia. In Tailand, the tree known as Kra-tom is found throughout the country but predomi-nantly in the southern region, although the growingand harvesting is prohibited.

Kratom contains many alkaloids including mitragynine,mitraphylline, and 7-hydroxymitragynine. raditional-ly, kratom had been used in Malaysia and Tailand bylabourers and farmers to enhance productivity, but also

as a substitute to opium and in traditional medicine,allegedly due to its morphine-like pharmacological ef-fects. However, its use as a new psychoactive substancein the global market has been recently reported.

In the early 2000s, products labelled as kratom acetate ormitragynine acetatebecame available in Europe, althoughit was found that neither of them contained mitragynine.Caffeine and synthetic O-desmethyltramadol (an activemetabolite of tramadol) were found in products underthe name krypton.84More recently, products containing

kratom have been sold as incensefor their psychoactiveeffects, but concentrations of the active components mi-tragynine and 7-hydroxymitragynine in these productsdiffer depending on the variety of the plant used, the en-

vironment and the time of harvesting.

Internet surveys conducted by the EMCDDA in 2008and 2011 revealed that kratom is one of the most

widely offered NPS.

85

Respondents to the UNODCquestionnaire on NPS reported kratom among thetop three plant-based substances, along with khat andsalvia divinorum.86As kratom is often not monitoredin national drug abuse surveys, there is little informa-tion on prevalence of its use.

Neither kratom nor any of its active alkaloids are list-ed under the 1961 and 1971 Conventions, but severalcountries have adopted control measures on kratom,mitragynine and 7-hydroxymitragynine.

Description

Street names for kratom include thang, kakuam,thom, ketum and biak. Kratom leaves are usuallyconsumed fresh, although dried leaves in powder formare also available. Te fresh leaves are chewed whilethe powder form is often either swallowed or brewedinto tea. Dried leaves are rarely smoked.


In spite of the increasing use of this substance, scienticliterature about the effects and toxicity of kratom aloneremains very scarce.

Kratom is a central nervous system stimulant, fromwhich over 40 alkaloids have been isolated. In low dosesit is reported to have stimulant effects (used to combatfatigue during long hours of work), while at high doses,it can have sedative-narcotic effects.87In 1921, the ma-

jor alkaloid found in this plant, Mitragynine, was rstisolated. Mitragynine has an opioid agonistic activity

and its derivative 7-hydroxymitragynine (7-OH-mi-tragynine) is reported to be more potent than mitragy-nine or morphine.88

82 -

83 Hoffman, R. and Alabsi, M., Khat use and neurobehavioural func-tions: suggestions for future studies, Journal of Ethnopharmacol-ogy, 2010, 132, 554; Morrish, P.K., Nicolaou, N., Brakkenberg, P. Journal of Neurology, Neurosurgery, and Psychiatry, 1999, 67, 556;

the literature and future prospects, Sucht, 2007, 53, 9-2284 -

85 -

86

87 -

88

- - Mitragy-na speciosa


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Nine fatal cases of intoxication associated with the use ofkrypton, a mixture of mitragynine and O-desmethyltra-madol, have been described in scientic literature. How-ever, these fatalities have been attributed to the addition

of O-desmethyltramadol to the dried kratom leaves.

89

2.6.3. Salvia divinorum

Background

Salvia divinorum(of the mint family Lamiaceae), is apsychoactive plant indigenous to forest areas in Oxa-ca, Mexico. It was traditionally used by the MazatecIndians for religious practices and medical purposes,although there is no approved medicinal use for salviadivinorumor its active ingredient salvinorin A. Te

use of salvia divinorum as a new psychoactive sub-stance dates back to the 1990s but respondents to theUNODC questionnaire on NPS identied this plantas the most common plant-based substance in 2009,and the third, after khat and kratom, in 2012.

Neoclerodane diterpene (i.e. salvinorin A) is the activecomponent responsible for the psychoactive effects ofthe plant in the 1980s. Te concentration of salvino-rin A in salvia divinorumleaves varies and depends onthe stage of development of the plant and the type of

preparation.

Neither salvia divinorumnor salvinorin A are underinternational control. However, due to the increasinguse of this plant as a new psychoactive substance, theplant and its active constituent salvinorin A are in-creasingly controlled in several countries under differ-ent regulatory frameworks.

Description

Street names for salvia divinorum include Maria Pas-tora, Sage of the Seers, Diviners Sage, Salvia, Sally-D,Magic Mint, Purple Sticky, Shepherdesss Herb.90

Salvia divinorumis usually sold as seeds or leaves, buta liquid extract purported to contain salvinorin A anda combination of dried leaves and extracts of salvino-

rin A (known as the fresh-man selectionor the starterpack) are also available on the market.91Recent studiesof products containing salvia divinorumhave shown amismatch between the label and the actual constituent

of the products. Vitamin E and caffeine have also beenreported as adulterants.

Salvia divinorum is traditionally consumed by suckingand chewing the fresh leaves from a cigar-like roll or al-ternatively the fresh leaves are crashed to make a drink-able infusion. Many users reportedly inhale vaporized sal-vinorin A extract, or smoke the dried leaves of the plant.Smoking of the dry leaves is reported to produce shortbut intense hallucinations, and the effects of salvinorin Ahave been compared to those of LSD or DOB.92


Animal studies have shown low toxicity and low addic-tive potential for salvia divinorum.93Like other plant-based substances, there are limited scientic studies inhumans that report acute or chronic toxicity associatedwith its use, but clinical observations have indicated last-ing psychosis in vulnerable individuals. Tus far, thereare no reports on fatalities from use of salvia divinorum.However, toxicological analyses have proved difficult assalvinorin A and other diterpenoids of the plant are not

detected by conventional drug screening methods.94

2 . 7. M i sce l l an eous sub s t an ces

2.7.1. Aminoindanes

Background

In the 1970s, aminoindanes were reported to possesssignicant bronchodilating and analgesic properties, butrecent research has indicated that they also have potent

effects on serotonin release and re-uptake.95

Tese sub-

89 - from the herbal blend krypton, Journal of Analytical Toxicology, 2011,35 (4), 242-7

90

Salvia divinorumand - Addiction, Salvia divinorum

91 legal highs: Salvia divinorum -delphia), 2008, 46 (2), 146-52

92 Salviadivinorum

93 - -

94 Salviadivinorum

95 Solomons, E. and Sam, J, 2-aminoindans of pharmacological inter-

M.P., Frescas, S.P., et al., Synthesis and pharmacological examination of1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-meth-yl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine


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stances have been sold as NPS for their ability to produceempathogenic and entactogenic effects of serotonin re-leasing drugs, such as MDMA.96

2-Aminoindane (2-AI) is a rigid analogue of amphet-amine. Its basic ring structure can be modied to producediverse chemical substances such as 5-Iodo-2-aminoin-dane (5-IAI) and 5,6-methylenedioxy-2-aminoindane(MDAI). Analogues of aminoindanes are prepared us-ing indanone, indene or after intramolecular cyclizationof the acyl chloride derivative of 3-phenyl-2-propanoicacid.97Other aminoindanes sold as NPS include EAI(N-Ethyl-5-triuoromethyl-2-aminoindane) and AI(5-triuoromethyl-2-aminoindane) 98 which are ana-logues of fenuramine and norfenuramine, substancesused as appetite suppressants.99

MDAI, 5-IAI and 2-AI were reported by respondents tothe UNODC questionnaire on NPS as the most com-mon substances within this group. None of the aminoin-danes are under international control.

Description

Street names of MDAI include MDAI gold, while 2-AI hasbeen found in party pills known as Pink Champagnes.100

Aminoindanes are commonly found in powder form and

crystals and are usually ingested, but snorting is also possible.


Research conducted in animals and in in vitrocell culturesindicates that aminoindanes are relatively benign at rec-reational doses; however, the effects on humans have not

yet been reported.101 MDAI and 5-IAI are reported to behighly potent selective serotonin releasing agents. Animalstudies have shown that these analogues did not presentany long-term neurotoxicity at the levels administered,102but slight neurotoxicity on rodents was shown after ad-ministration of very high doses of 5-IAI.103

2.7.2. Phencyclidine-type substances

Background

Another group of NPS that has recently appeared inthe market include phencyclidine-type substances.Phencyclidine (PCP) and ketamine (see section 2.3)show structural similarity and are classied as arylcy-cloalkylamines.104

PCP was rst synthesized in the 1950s and sold until1967 as an injectable anaesthetic in the United Statesunder the trade names Sernyl and Sernylan. It waswithdrawn from the market due to intensely negativepsychological effects, such as dysphoria, confusion,

96 examination of benzofuran, indan, and tetralin analogs of 3,4-(methylene-

97

98 Ibid99 -

proved for the treatment of obesity by the United States Food and - - N. J., Appetite suppressants and valvular heart disease, The AmericanJournal of the Medical Sciences, 2001, 321 (4), 285-91

100

-

101

102 Johnson, M.P., Frescas, S.P., et al., Synthesis and pharmacologicalexamination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylene-

- and pharmacological examination of benzofuran, indan, and tetralinanalogs of 3,4-(methylenedioxy)amphetamine, Journal of Medicinal -inforcing effects of certain serotonin-releasing amphetamine deriva-tives, Pharmacology Biochemistry and Behavior, 1996, 53, 99-105

103 -dan, a nonneurotoxic analog of para-iodoamphetamine, Pharmacol-

104 Baldridge, E.B., Bessen, H.A., Phencyclidine, Emergency Medicine behavioral pharmacology of phencyclidine, in H.Y. Meltzer (Eds.), 1987, 15739; The structure-activity relationships among arylcycloal-

-logical and molecular properties of phencyclidine-like compounds bychemometrics, Arzneimittelforschung, 1993, 43 (10), 1029-32

Chemical structures ofAmphetamine (A) and 2-AI (B).Te differences between amphetamine (internationallycontrolled substance) and 2-AIare highlighted inred.

NH2

A

NH2

B


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delirium, and psychosis.105 Its use as a recreationaldrug started in the mid-1960s, but its unpredictabledysphoric reactions made the drug infamous.

PCP-type substances appeared for the rst time in Eu-rope as research chemicals in 2010, when the UnitedKingdom reported 3-methoxyeticyclidine (3-MeO-PCE) to the European Early Warning System.106 In2011, 4-methoxyphencyclidine (4-MeO-PCP) wasidentied in Norway, Russian Federation and theUnited Kingdom.107 Respondents to the UNODCquestionnaire on NPS reported 4-MeO-PCP as themost common PCP-type substance.

PCP and phenylcyclohexyl analogues, including eticy-clidine (PCE), rolicyclidine (PHP, PCPY), tenocycli-

dine (CP) are controlled in Schedule I of the 1971Convention but derivatives such as 3-MeO-PCE and4-MeO-PCP are not under international control.Description

3-MeO-PCE and 4-MeO-PCP are frequently sold asresearch chemicals and usually in powder form.


Tere is very limited information on the PCP ana-logues. Acute PCP intoxication results in a wide rangeof behavioural/psychological effects, from mild neu-rologic and physiologic abnormalities, stupor or lightcoma to deep coma. Manifestations of behaviouraltoxicity resemble psychiatric syndromes. PCP has alsobeen claimed to cause violent behaviour.108

2.7.3. ryptamines

Background

ryptamine, the prototype of the tryptamines group, isa primary amine alkaloid. Some tryptamines are naturalneurotransmitters while most are psychoactive halluci-nogens found in plants, fungi and animals.109 Naturaltryptamines include serotonin, melatonin, bufotenin,110

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DM)and dimethyltryptamine (DM). Other tryptamineshave been synthesized for pharmaceutical purposes tocombat medical conditions (e.g. sumatriptan and zolmi-triptan to treat migraine), but they have also been usedas NPS.

Te use of psilocybin,111a natural hallucinogen foundin certain species of mushrooms that contain thetryptamine structure, became widespread in the late1950s in the United States, but synthetic tryptaminesappeared on illicit drug markets only throughout the1990s. Te use of tryptamines remains limited but ap-pears to have increased over the past ve years. Forexample, the Drug Enforcement Administration ofthe United States reported that the estimated numberof tryptamine reports to State and local laboratoriesin the United States rose from 42 reports in 2006 to

474 reports in 2010. Respondents to the UNODCquestionnaire on NPS reported the incidence of bothnatural and synthetic tryptamines including, 5-MeO-DM, 5-MeO-DP, AM, 4-AcO-DM, 4-AcO-DiP, and 5-HP.

Psilocin, psilocybin, DE, DM, and etryptamine arethe only tryptamines under international control (listedin Schedule I of the 1971 Convention). Some othersare restricted at the national level in several countries.

105

responding schedules, Psychopharmacology, 1991, 103, 121-8106 - - 2005/387/JHA, Lisbon, 2011

107

108 Wong, H. and Morgan, J.P., Phencyclidine and violence: clinical and

report of the American Psychiatric Association, American Psychiatric

109 3 (7-8), 404-16

110 found by Wieland in the 1930s. Wieland, H., Konz, W. and Mittash, 1-25

111 Hoffmann et al. in 1959. Hoffmann, A., Heim. R., Brack, A. and Ko-

bel, H., Experientia, 1958, 14, 107-9; Hoffmann, A., Heim, R., Brack,A., Kobel, H., Frey, A., Ott, H., Petrzilka, T. and Troxler, F., Psilo-


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Description

Street names for some tryptamines include Foxy-Me-thoxy(5-MeO-DIP); alpha-O, alphaand O-DMS(5-MeO-AM); 5-MEO (5-MeO-DM). Naturaltryptamines are commonly available in preparationsof dried or brewed mushrooms, while tryptamine de-rivatives are sold in capsule, tablet, powder or liquidform. ryptamines are generally swallowed, sniffed,smoked or injected.


oxicological studies on tryptamines remain limited.Reported adverse effects related to the use of foxy me-thoxyinclude restlessness, agitations, gastrointestinaldistress, and muscle tension.112Rhabdomyolosis afteringestion of Foxy has also been described in a casestudy.113 Other fatalities associated with the use ofFoxy and other tryptamines have also been describedin scientic literature.114

112 - Proceedings, 2006, 81 (4), 550-1

113 - Proceedings, 2006, 81 (4), 550-1

114Einosuke, T., Tooru, K., Munehiro, K., Hitoshi, T. and Katsuya, H., A Forensic Science International, 2006, 163, 1524; Sklerov, J., Levine,

-ing the ingestion of 5-methoxy-N,N-dimethyltryptamine in an aya-huasca preparation, Journal of Analytical Toxicology, 2005, 29 (8),838-41

Chemicalstructures ofDM(A), 5-MeO-DM(B) and the generic structure oftryptamine derivatives (C). Te structuraldifferences between5-MeO-DMand the related DM(internationallycontrolled substance) is highlighted inred. (C)Represents the generic structure oftryptamine derivatives, showing ve ofthe positions that have beenmodied so fartoproduce synthetic tryptamines.

HN

N

HN

N

O

A B

HN

N

R1

R2

R3

R4R5

C


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The Global Spread of New Psychoactive Substances

3. THE GLOBAL SPREAD OF NEWPSYCHOACTIVE SUBSTANCES

3 . 1. Em erg ence o f n ew psy choac t i ve

subs t ances

Prior to the present report, no information was avail-able on the global spread of NPS, due to the absenceof a global early warning system which monitorsthe appearance of new substances. Te UNODCquestionnaire on NPS, which was used to collectinformation on this issue, received more than 240responses from 80 countries and territories, indicat-ing a high level of interest in the subject.115 Mostquestionnaires were received from countries in Eu-

rope (33), which might be due to the high degree ofawareness of the problem in that region, followedby Asia (23 countries and territories), Americas (12countries), Africa (10 countries) and Oceania (2countries).

All 80 countries and territories from all regions

provided data on the emergence of NPS, with 70countries and territories116 (87%) indicating thatNPS had appeared on their drugs market, comparedto 10 countries117(13%) which reported otherwise.Responses indicate a worldwide spread of NPS, withcountries and territories reporting their appearancein Europe (31 countries or 94% of respondents),followed by Asia (19 countries and territories or86% of respondents), the Americas (11 countries or92% of respondents), Africa (7 countries or 70%of respondents) and Oceania (2 countries or all re-spondents).

With respect to the global emergence by NPSgroups, ketamine as well as plant-based substanceswere reported by 44 respondents (83%), followedby piperazines with 41 respondents (77%) and syn-thetic cannabinoids with 40 respondents (75%). Teleast reported NPS group were phenethylamines, re-ported by 32 respondents (60%).

115Multiple responses were received from some countries, as question-

naires were frequently circulated to various authorities working onthis issue. In the analysis of the data, only respondents that providedfull identifying information (institutions, country/territory) were con-sidered.

116 Countries and territories reporting emergence of NPS: Albania,Andorra, Angola, Argentina, Australia, Bahrain, Belgium, Bosniaand Herzegovina, Brazil, Brunei Darussalam, Bulgaria, Canada,Cape Verde, Chile, China, Colombia, Costa Rica, Croatia,

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