Synthetic Cathinones: Novel Addictive and Stimulatory Psychoactive Substances (Current Topics in Neurotoxicity Book 12)

Over the last decade, and particularly during the recent five years, a rapidly increasing number of novel psychoactive substance (NPSs), often marketed as “designer drugs”, “legal highs”, “herbal highs”, “research or intermediate chemicals” and “laboratory reagents”, has appeared on the drug market in an effort to bypass controlled substance legislation. NPSs encompass a wide range of different compounds and drug classes but had been dominated by synthetic cannabinomimetics and psychostimulatory synthetic cathinones, so-called β-keto amphetamines. Compounds from the later class were first detected in Europe in 2004, and since then 103 new cathinones have been identified and reported to the European Monitoring Centre for Drugs and Drug Addiction, with 57 during the last two years. **Synthetic cathinones – novel addictive and stimulatory psychoactive substances** is the first publication of this kind that provides readers with background on chemical structures, detection, prevalence and motivation of use of the very popular group of NPSs. This book also presents comprehensive overview of the mechanisms of action, pharmacological activity, and main metabolic pathways of synthetic cathinones, followed by a detailed discussion of the acute and chronic toxicity associated with the use of these substances. Written by international experts in the field, this multi-authored book is a valuable reference not only for scientists, clinicians and academics, but also for readers representing different professional background who are involved in educational-prophylactic activities directed to harm reduction of psychoactive compounds. Preface 6 Contents 8 Contributors 10 1 Synthetic Cathinones: Neurotoxic Health Hazards and Potential for Abuse 12 Abstract 12 References 18 2 Novel Psychoactive Substances: Classification and General Information 22 Abstract 22 2.1 Introduction 23 2.2 The Number of NPS Is Rapidly Growing Around the World 24 2.3 Classification of NPS 25 2.4 NPS—Where Do They Originate from? 29 2.5 Why Are NPS Attractive to Their Users? 30 2.6 Pharmacological Properties of NPS 30 2.7 NPS Exert Various Adverse Effects 31 2.8 Concluding Remarks 32 Acknowledgements 33 References 33 3 Khat—A Natural Source of Cathinone 36 Abstract 36 3.1 Khat and Its Consumption 36 3.2 Distribution and Cultivation of Khat 38 3.3 Identification and Isolation of Cathinone 39 3.4 Biosynthetic Pathway in Catha edulis Forsk 42 3.5 Neurochemistry of Cathinone 44 3.6 Effects of Khat in Humans 45 3.7 Dependence and Addiction to Khat 46 3.8 Conclusions 47 References 48 4 Analytical Methods Used for Identification and Determination of Synthetic Cathinones and Their Metabolites 52 Abstract 52 4.1 Introduction 54 4.2 Analysis of Seized Materials 55 4.2.1 Presumptive Tests 55 4.2.2 Preliminary Identification by Gas Chromatography–Mass Spectrometry Method 56 4.2.3 Confirmatory Analysis by Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry Method 60 4.2.4 Other Analytical Methods Used in Identification of Cathinones 62 4.3 Analysis of Synthetic Cathinones in Biological Material 64 4.3.1 Immunochemical Detection 64 4.3.2 Chromatographic Methods 65 4.3.2.1 Gas Chromatography–Mass Spectrometry Detection 66 4.3.2.2 High-Performance Liquid Chromatography with Diode Array Detection 66 4.3.2.3 Liquid Chromatography–Mass Spectrometry Detection 67 4.3.3 Other Techniques 76 References 77 5 Metabolism of Synthetic Cathinones 81 Abstract 81 5.1 Chemical Structures of Synthetic Cathinones—A Basis to Understand Their Metabolic Pathways 81 5.2 Outline of Major Metabolic Pathways for Synthetic Cathinones 83 5.2.1 Phase I Metabolism 83 5.2.1.1 Reduction of the β-Ketone Moiety 84 5.2.1.2 N-Dealkylation 84 5.2.1.3 Demethylenation Followed by O-Methylation Pathways for 3′,4′-Methylenedioxyphenyl Cathinone Derivatives 85 5.2.1.4 Hydroxylation Followed by Dehydrogenation, and Ring Opening for the N-Pyrrolidine Cathinone Derivatives 85 5.2.1.5 Metabolism of Benzene Ring Substituents 85 5.2.2 Phase II Metabolism 86 5.3 Details of Metabolism for Each Compound 86 5.3.1 N-Alkylated Cathinone Derivatives with/Without Ring Substituents 86 5.3.1.1 Cathinone, Methcathinone (N-Methylcathinone, Ephedrone), Ethcathinone (N-Ethylcathinone), Dimethylpropion (N,N-Dimethylcathinone) and Diethylpropion (N,N-Diethylcathinone, Amfepramone) 86 5.3.1.2 4′-Methylmethcathinone (Mephedrone, 4-MMC) 87 5.3.1.3 4′-Methoxymethcathinone (Methedrone) 88 5.3.1.4 3′,4′-Dimethylmethcathinone (3,4-DMMC) 88 5.3.1.5 3′-Fluoromethcathinone and 3′-Bromomethcathinone 89 5.3.2 3′,4′-Methylenedioxy-N-alkylated Cathinones (3′,4′-Methylenedioxycathinones, bk-MDAs) 90 5.3.2.1 3′,4′-Methylenedioxymethcathinone (bk-MDMA, Methylone) 90 5.3.2.2 2-Methylamino-1-(3′,4′-methylenedioxyphenyl)butan-1-one (bk-MBDB, Butylone) and 2-Ethylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (bk-MDEA, Ethylone) 91 5.3.3 N-Pyrrolidine Cathinone with/Without Ring Substituents 92 5.3.3.1 α-Pyrrolidinopropiophenone (PPP, α-PPP) 92 5.3.3.2 α-Pyrrolidinobutiophenone (PBP, α-PBP) 92 5.3.3.3 α-Pyrrolidinovalerophenone (PVP, α-PVP) 92 5.3.3.4 α-Pyrrolidinohexanophenone (PHP, α-PHP, PV-7) 94 5.3.3.5 α-Pyrrolidinoheptanophenone (PV-8) 94 5.3.3.6 α-Pyrrolidinooctanophenone (POP, α-POP, PV9) 95 5.3.3.7 4′-Methyl-α-pyrrolidinopropiophenone (MPPP) 95 5.3.3.8 4′-Methyl-α-pyrrolidinobutiophenone (MPBP) 96 5.3.3.9 4′-Methyl-α-pyrrolidinovalerophenone (MPVP, Pyrovalerone, O-2371) 97 5.3.3.10 4′-Methyl-α-pyrrolidinohexiophenone (MPHP) 98 5.3.3.11 4′-Methoxy-α-pyrrolidinopropiophenone (MOPPP) 98 5.3.4 3′,4′-Methylenedioxy-N-pyrrolidine Cathinone Derivatives 99 5.3.4.1 3′,4′-Methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) 99 5.3.4.2 3′,4′-Methylenedioxy-α-pyrrolidinobutiophenone (MDPBP) 100 5.3.4.3 3′,4′-Methylenedioxy-α-pyrrolidinovalerophenone (MDPVP, MDPV) 101 5.3.5 Other N-pyrrolidine Cathinone Derivatives 102 5.3.5.1 Naphthylpyrovalerone (Naphyrone, β-Naphyrone, O-2482, NRG-1) 102 5.3.5.2 α-Pyrrolidinopentiothiophenone (α-PVT) 102 References 103 6 Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones 107 Abstract 107 6.1 Introduction 108 6.2 Pharmacological Profiling of New Synthetic Cathinones In Vitro 109 6.2.1 Pharmacological In Vitro Data 110 6.2.2 In Vitro Assays 111 6.3 In Vitro Screenings for Predictions of Acute Effects and Toxicity 112 6.3.1 Advantages of In Vitro Pharmacological Assessment 112 6.3.2 Limitations of In Vitro Pharmacological Assessment 113 6.3.3 Well-Known Psychoactive Substances as Reference Compounds 113 6.3.4 Clinical Effects Arising from Elevated Dopaminergic, Serotonergic, and Noradrenergic Transmission 114 6.4 Pharmacological Diversity of Synthetic Cathinones 117 6.4.1 Synthetic Cathinones with Selective and Nonselective Serotonergic Action 117 6.4.2 Dopaminergic and Noradrenergic Cathinones 119 6.4.3 Potent Uptake Inhibitors 122 6.5 Conclusion 122 Acknowledgements 123 References 123 7 Effects of Synthetic Cathinones on Brain Neurotransmitters 126 Abstract 126 7.1 Introduction 127 7.2 Effects of Methcathinone, Methylone, and Mephedrone on Extracellular DA and 5-HT Levels in Rat Brain Regions 127 7.3 Effects of 3,4-Methylenedioxypyrovalerone (MDPV) on Extracellular DA and 5-HT Levels in Rat Brain Regions 128 7.4 Effects of Para-Substituted Methcathinone Analogs on Extracellular DA and 5-HT Levels in Rat Brain Regions 129 7.5 Effects of Trifluoromethyl Ring-Substituted Methcathinone Analogs on Extracellular DA and 5-HT Levels in Rat Brain Regions 129 7.6 Concluding Remarks 130 Acknowledgements 132 References 132 8 Behavioral Profiles and Underlying Transmitters/Circuits of Cathinone-Derived Psychostimulant Drugs of Abuse 134 Abstract 134 8.1 Introduction 136 8.2 Psychostimulant Effects of Synthetic Cathinones in Human Abusers 136 8.3 Reward and Reinforcement from Cathinone-Derived Drugs: Preclinical Evidence 138 8.3.1 Locomotor Activity, Behavioral Sensitization, and Drug Discrimination 138 8.3.2 Place Conditioning as a Measure of Passive Reward-Context Association 148 8.3.3 Intravenous Drug Self-administration Captures Volitional Aspect of Drug Taking 149 8.3.4 Intracranial Self-stimulation (ICSS) of Reward Pathways 150 8.3.5 Other Behavioral Effects of Synthetic Cathinones in Animals Mapped Against User Accounts 151 8.4 Transmitter Systems and Circuits Underlying Behavioral Effects of Synthetic Cathinones 153 8.4.1 Cathinone 153 8.4.2 First-Generation Synthetic Cathinones: Mephedrone, Methylone, and MDPV 153 8.4.3 Second-Generation Synthetic Cathinones: α-PVP, 4-MEC, and Others 155 8.5 Pharmacotherapeutic Avenues for Treating Abuse of Synthetic Cathinones 155 Contributions and Acknowledgements 156 References 157 9 Synthetic Cathinones—Prevalence and Motivations for Use 162 Abstract 162 9.1 Introduction and Background 162 9.2 Availability of Synthetic Cathinones 164 9.2.1 Legal Status of Cathinones 164 9.2.2 Number of Synthetic Cathinones 166 9.2.3 Number and Quantities of Cathinones Confiscated 166 9.3 Prevalence of Use 167 9.3.1 International Sources 168 9.3.2 Mixmag/Global Drug Survey 170 9.3.3 Additional United Kingdom Data 171 9.4 Investigating Motivations for Using Psychoactive Substances 173 9.4.1 Motivations for Use of Any Drug 174 9.4.1.1 Reasons Why Individuals Use Synthetic Cathinones 178 9.4.1.2 Consumption with Other Substances 179 9.4.1.3 Comparison of Synthetic Cathinones with Other Stimulants 180 9.4.1.4 Use of Specific Types of Synthetic Cathinones 181 9.5 Stopping Use of Cathinones 183 9.6 Injecting Behaviours and Blood-Borne Infections 185 9.7 Morbidity and Mortality 186 9.7.1 Intoxications, Hospital Admissions 186 9.7.2 Fatalities 187 9.8 What Challenges Might the Future Hold? 187 9.9 Conclusions 188 Acknowledgements 188 References 189 10 The Effects and Risks Associated with Synthetic Cathinones Use in Humans 199 Abstract 199 10.1 Introduction 200 10.2 History of Synthetic Cathinones 201 10.3 Routes of Administration 203 10.4 Clinical Pharmacology 203 10.5 Reported Adverse Effects 204 10.5.1 Physical Adverse Effects 206 10.5.2 Psychiatric Adverse Effects 206 10.6 Fatalities 207 10.7 Addictive Potential 207 References 208 11 Concluding Remarks: Where We Are and Where Do We Go from Here? 211 Abstract 211 Index 213 Front Matter ....Pages i-x Synthetic Cathinones: Neurotoxic Health Hazards and Potential for Abuse (Trevor Archer, Richard M. Kostrzewa)....Pages 1-10 Novel Psychoactive Substances: Classification and General Information (Jolanta B. Zawilska, Jakub Wojcieszak)....Pages 11-24 Khat—A Natural Source of Cathinone (Nilesh B. Patel)....Pages 25-40 Analytical Methods Used for Identification and Determination of Synthetic Cathinones and Their Metabolites (Dariusz Zuba, Piotr Adamowicz)....Pages 41-69 Metabolism of Synthetic Cathinones (Kei Zaitsu)....Pages 71-96 Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones (Linda D. Simmler)....Pages 97-115 Effects of Synthetic Cathinones on Brain Neurotransmitters (Krystyna Gołembiowska, Katarzyna Kamińska)....Pages 117-124 Behavioral Profiles and Underlying Transmitters/Circuits of Cathinone-Derived Psychostimulant Drugs of Abuse (Steven J. Simmons, Erin Kim, Taylor A. Gentile, Ali Murad, John W. Muschamp, Scott M. Rawls)....Pages 125-152 Synthetic Cathinones—Prevalence and Motivations for Use (John M. Corkery, Amira Guirguis, Duccio G. Papanti, Laura Orsolini, Fabrizio Schifano)....Pages 153-189 The Effects and Risks Associated with Synthetic Cathinones Use in Humans (Laurent Karila, Amine Benyamina)....Pages 191-202 Concluding Remarks: Where We Are and Where Do We Go from Here? (Jolanta B. Zawilska)....Pages 203-204 Back Matter ....Pages 205-207 Over the last decade a rapidly increasing number of novel psychoactive substance (NPSs), often marketed as "designer drugs", "legal highs", "herbal highs", "research or intermediate chemicals" and "laboratory reagents", has appeared on the drug market worldwide in an effort to bypass controlled substance legislation. NPSs encompass a wide range of different compounds and drug classes but had been dominated by synthetic cannabinomimetics and psychostimulatory synthetic cathinones, so-called b-keto amphetamines. Compounds from the later class were first detected in Europe in 2004, and since that time more than 130 new cathinones have been identified and reported to the European Monitoring Centre for Drugs and Drug Addiction. The rapid and extensive worldwide rise of synthetic cathinone abuse is attracting increasing attention, due to many intoxications and overdose deaths