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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

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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

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‘Joint Action’ on New Synthetic Drugs (1997-2005)

• 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

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The Early Warning System (EWS)

Three stages:

1. Information collection/dissemination in MS

2. Risk assessment by EMCDDA scientific committee

3. Control in EU

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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

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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

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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

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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 1997

• 2007: 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

CH2 NHN N NH

ClBZP mCPP

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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

C

O

CH2

CH3

NH2

Cathinone

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Misused medicinal products

• Dextromethorphan (DMX)• Glaucine• Benzydamine• Phenazepam

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Plant products

• Salvia divinorum (Mexican Sage) - salvinorin A

• Mitragyna speciosa (Kratom) - mitragynine

• Piper methysticum (Kava) - kavalactones

• Argyreia nervosa (Hawaiian Baby Woodrose) -lysergamide

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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.

CH2Br

O

O

CH

CH3

NH2

Bromodragonfly

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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.

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‘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

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Synthetic cannabinoid agonists

1. Analogues of Δ9-THC (e.g. HU-210, Nabilone)

2. Cyclohexylphenols (Pfizer CP-compounds)

3. Naphthoylindoles, naphthoylpyrroles (JWH compounds)

4. Others (fatty acid amides?, etc.)

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Δ9-THC HU-210

CP 47,497 JWH-018

Δ9-THC and three synthetic cannabinoids

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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

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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

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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

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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