1 New drugs coming our way - - what are they and how do we detect them? Leslie A King UK Focal Point on Drugs EMCDDA Conference: Identifying Europe’s information needs for effective drug policy, Lisbon, 6-8 May 2009

2 The political-legal background of EU initiatives ‘Joint Action’ on New Synthetic Drugs (1997) The Early Warning System (EWS) Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances The ‘Phenethylamine/tryptamine period’ Recent developments

3 ‘Joint Action’ on New Synthetic Drugs ( ) Focus on substances (NSD) not already listed in UN1971 Convention, but with similar potential for harm as psychotropic drugs already in Schedules I or II New means newly-abused – not necessarily newly- discovered Before 1997 these substances were often known as designer drugs – e.g. fentanyl and α-prodine derivatives

4 The Early Warning System (EWS) Three stages: 1.Information collection/dissemination in MS 2.Risk assessment by EMCDDA scientific committee 3.Control in EU

5 The 2005 Council Decision: New Psychoactive Substances (NPAS) Extends scope to include both psychotropics (i.e. UN1971 candidates) and narcotics (i.e. UN1961 candidates) Not restricted to synthetic materials – plant products also covered (e.g. Salvia divinorum) Allows information collection (but not risk assessment) on misuse of medicinal products and their precursors

6 The ‘Phenethylamine/tryptamine period’ PIHKAL and TIHKAL Search for the ‘new ecstasy’ Tablets > powders > capsules Risk assessments (1999 – 2004): MBDB, 4-MTA, PMMA, TMA-2, 2C-T-2, 2C-T-7, 2C-I By 2004 over 20 illicit phenethylamine derivatives discovered in EU Tryptamines less common – all hallucinogens

7 Recent developments ‘Designer drugs’ now often called ‘legal highs’ Phenethylamines/tryptamines increasingly uncommon Wide diversity of new substances Substituted piperazines Substituted cathinones Misused medicinal products Plant products Miscellaneous synthetic drugs Spice

8 Substituted piperazines By 2006, 1(3-chlorophenyl)piperazine (mCPP) found in 10% of ‘ecstasy’ tablets in EU. More seizures, larger quantities than any other substance since : EMCDDA risk assessment on 1-benzylpiperazine (BZP) leads to expected EU-wide control in 2009 Others include TFMPP, DBZP, FPP Critical review of six piperazine derivatives by ECDD/WHO in 2009 BZP mCPP

9 Substituted cathinones Over 20 illicit substances derived from cathinone (e.g. mephedrone, methylone, MDPV) Available from websites and shops They are β-keto analogues of phenethylamines Mostly CNS stimulants Cathinone

10 Misused medicinal products Dextromethorphan (DMX) Glaucine Benzydamine Phenazepam

11 Plant products Salvia divinorum (Mexican Sage) - salvinorin A Mitragyna speciosa (Kratom) - mitragynine Piper methysticum (Kava) - kavalactones Argyreia nervosa (Hawaiian Baby Woodrose) - lysergamide

12 Miscellaneous synthetic drugs Indans, tetralines etc. - aryl-variants on the phenethylamine theme Difuranyl-phenethylamines (2CB-Fly and Bromodragonfly) Fluorotropacocaine – the first designer drug based on cocaine Many other synthetic psychoactive substances are being sold via websites, but misuse remains low, e.g. the phencyclidine derivative 4-Meo-PCP, the pipradrol derivative dipenylpyrrolidinylmethanol (D2PM), p-fluoroamphetamine, etc. Bromodragonfly

13 Spice Gold smoking mixture Marketed since ~ 2006; imported from China Contains unidentified herbal matter The claimed plant constituents are innocuous About €20 for 3g Produces a ‘cannabis-like’ effect Related products: Yucatan Fire, Spice Diamond etc.

14 ‘Spice’ – recent developments December 2008: Analysis by THC Pharma, Germany showed Spice contains JWH-018 and other synthetic cannabinoid receptor agonists January 2009: Germany controls JWH-018 and several CP compounds under narcotic laws. Similar action by Austria using medicines legislation February 2009: France controls 5 synthetic cannabinoids under narcotic laws May 2009: Controls planned in further MS

15 Synthetic cannabinoid agonists 1.Analogues of Δ 9 -THC (e.g. HU-210, Nabilone) 2.Cyclohexylphenols (Pfizer CP-compounds) 3.Naphthoylindoles, naphthoylpyrroles (JWH compounds) 4.Others (fatty acid amides?, etc.)

16 Δ 9 -THCHU-210 CP 47,497 JWH-018 Δ 9 -THC and three synthetic cannabinoids

17 Detecting new psychoactive substances Problem areas: Pure reference materials and analytical data are often not available in the early stages Not all forensic/toxicological laboratories in the EU have the means to identify new substances - the EWS often relies on those with NMR spectroscopy Examining non-scheduled drugs is not a priority for forensic science organisations in some countries Some substances may be active at doses below 1mg; detection in body fluids if not in dosage units may be challenging

18 Can new substances be anticipated? The Early Warning System is reactive But almost all new psychoactive substances were previously described in the scientific literature The Internet may provide information on new substances: drug ‘chat rooms’ purchases from websites selling ‘legal highs’ We could use this knowledge and devise a set of rules based on previous experience

19 A rule-based system for prediction? Synthetic drugs will continue to dominate – herbal products will remain uncommon Precursor chemicals or essential reagents should be commercially available or readily synthesised and not controlled The method of synthesis should be straightforward The end-product should be either a stimulant or have MDMA-like properties, but not be a synthetic hallucinogen The end-product should be active orally and the required dose should be no more than 100mg Further PIHKAL substances are unlikely to appear More synthetic cannabinoids can be expected

20 Summary A formal mechanism to monitor, assess and control new drugs has been in operation within the EU since 1997 In that time over 90 new psychoactive substances have been reported Most are synthetic compounds; plant/herbal products remain uncommon Most have not been widespread and most did not survive for long on the illicit market Risk assessments were carried out on 10 substances, of which 7 were recommended for control Nearly all presented analytical challenges when first encountered For many, little was and still is known about their pharmacology/toxicology Nearly all substances had been described in the scientific literature, often many years ago; they are effectively ‘failed’ pharmaceutical agents In the early years, most substances were either phenethylamine or tryptamine derivatives In the past 5 years there has been a great diversity of chemical structures, although most are stimulants, or are ‘MDMA-like’ or, less-commonly, hallucinogens Rather than be reactive, it should be possible to anticipate new substances given a knowledge of the literature and the use of rules