1. Opinion of the Scientific Committee regarding the scientific aspects of the risk assessment exercise R. Sedefov & A. Gallegos, 33th Meeting of the Scientific Committee, 15 November 2010 Assessment of the functioning of the Council Decision on information exchange, risk-assessment and control of new psychoactive substances

2. 2 2010 Risk Assessment Guidelines Mephedrone 33 NPAS Designer medicines Assessment of the functioning of the Council Decision

3. 3 NPAS 2010 1. 2C-B-BZP (1-(4-bromo-2,5-dimethoxybenzyl)piperazine) – January – Germany 2. N,N-dimethylphenethylamine – February – Norway 3. N-benzyl-1- phenethylamine – February – Norway 4. β-Me-PEA (2-phenylpropan-1-amine) – February – Norway 5. MDAI (5,6-methylenedioxy-2-aminoindane) – February – Sweden 6. 4-FMA (4-fluoromethamphetamine) – March – Norway 7. JWH-081 (1-pentyl-3-(4-methoxy-1-naphthoyl)indole) – June – Latvia 8. (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone – May – Hungary 9. Naphyrone (naphthylpyrovalerone) – June – Sweden (UK, Ireland) 10. Iso-ethcathinone – June – Ireland 11. DMAA (dimethylamylamine) – June – Ireland 12. Dimethocaine – June –Ireland 13. 1-butyl-3-(1-(4-methyl)naphthoyl)indole (deriv. JWH-073) – June – Germany 14. Buphedrone – July – Finland 15.4-methylethcathinone – July – UK 16.AM-694 –July – Ireland

4. 4 NPAS 2010 17.JWH-122 (1-pentyl-3-(4-methyl-1-naphthoyl)indole) ) – 23 July – Latvia 18.MPBP – July – Bulgaria 19.JWH-015 – July – Austria 20.4-MBC – August – UK 21.MPPP – August – UK 22.CP47,497 (C8 + C2) variant – August – UK 23.1-naphthalen-1-yl-2-pyrrolidin-1-yl-pentan-1-one – August – UK 24.Pentylone – September – UK 25.M-ALPHA –September – UK 26.5-MeO-DPT (5-methoxy-N,N-dipropyltryptamine) – September – Finland 27.β-Ethyl-Methcathinone (2-methylamino-1-phenyl-1-pentanone) – September – Austria 28.JWH- 210 (4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone) – September – Germany 29.3,4-Dimethylmethcathinone – October – Hungary 30.JWH-203 (2-(2-chlorophenyl)-1-(1-pentylindol-3-yl)ethanone) – October – Latvia 31.JWH-019 (1-hexyl-3-(1-naphthoyl)indole) – October – Finland 32.Methoxetamine – November – UK 33.3-(4-Hydroxymethylbenzoyl)-1-pentylindole – November – UK

5. 5 PhTrPpCathS.CB?Fent. 1980s mid-1980s 1990s2000smid-2000s2008-92010s

6. 6 2010 and beyond? Synthetic cocaine derivatives Fluorotropacocaine (pFBT) – 2008 Dimethocaine – 2010 Designer medicines MDPV – 2008 (pyrovalerone) o-desmethyltramadol (ODT) – 2009 (tramadol) Etaqualone – 2009 (methaqualone) 2009 - 2-DPMP (desoxypipradrol) (methylphenidate and pipradrol) Methoxetamine – 2010 (ketamine) Other Aminoindanes: MDAI – 2010 Simple aliphatic amine: DMAA – 2010

7. 7 Gophers…as a metaphor & instead of conclusion

8. 8 Questionnaire Sent on 11 October, 10 respondents out of 16 SC members Q1. Is this time frame foreseen for the risk assessment sufficient? (12 weeks for preparation and day risk assessment meeting) Q2. Is there a need for additional research? What additional research is feasible? Is there a need for post-risk assessment research, what research? Q3. Is the current format of extended Scientific committee appropriate? Is there need for additional expertise? Q4. Currently only one substance is being assessed at a time - is feasible that in the future a group (class) of substances are assessed within one risk assessment exercise? Would that be a sound scientific practice? Q5. Is the current format of the risk assessment report appropriate? Q6. The scoring system was implemented for the first time in 2010 - was is helpful and how could it be improved?

9. 9 Q1. Is this time frame foreseen for the risk assessment sufficient? (12 weeks for preparation and day risk assessment meeting) In general, the timeframe foreseen for the risk assessment is considered to be sufficient. Remarks: The timeframe should be flexible, and should depend on the data available

10. 10 Q2. Is there a need for additional research? What additional research is feasible? Is there a need for post-risk assessment research, what research? There is a need for short-term (and feasible) additional scientific research. The kind of research depends on the specific substance. There is a need for post-risk assessment research and for assessing the impact of control measures. Remarks: The interpretation of missing data should be carefully considered.

11. 11 Q3. Is the current format of extended Scientific committee appropriate? Is there need for additional expertise? The current format of the extended Scientific Committee is in general appropriate and there is no need for additional expertise. Remarks: There are too many participants for a Delphi / focus group risk assessment meeting. Although additional expertise is considered when appropriate, the possibility of appointing individuals for specific additional expert fields should be considered.

12. 12 Q4. Currently only one substance is being assessed at a time - is feasible that in the future a group (class) of substances are assessed within one risk assessment exercise? Would that be a sound scientific practice? The assessment of a group (class) of substances within one risk assessment exercise should be considered when appropriate, depending on the substances considered, the data available, etc. Remarks: Although this kind of risk assessment would be more cost-effective, it might be also more difficult. Substantial variations (on the effects, potential harms, etc) among different substances of the same class should be carefully assessed. The size of the group or class to be risk-assessed should be considered on individual basis. Semi-generic definitions of psychotropic classes of substances should be considered.

13. 13 Q5. Is the current format of the risk assessment report appropriate? The current format of the risk assessment report is in general appropriate.

14. 14 Q6. The scoring system was implemented for the first time in 2010 - was is helpful and how could it be improved? The scoring system is in useful in reaching consensus, although it has a number of limitations. Remarks: More time is needed for the Delphi approach. Missing information should be appropriately scored. Subjective interpretations of the scores may led to pseudo-objectivity.

15. 15 Generic definition Purpose of the definition Generic definition for the purpose of law & law enforcement: a precise definition of a family of substances e.g. by describing substitution patterns in a parent molecule. Generic definition for the purpose of risk assessment does not exist so for this discussion we use the one above (defined by the EMCDDA through analysis of the existing laws) For comparison only: Analogue: a more general definition of similarity in pharmacological activity, as well as similarity in chemical structure. B Hughes, T Blidaru (2009) Legal Responses to New Psychoactive Substances in Europe

16. 16 Misuse of Drugs Act 1971 (Amendment) Order 2010: mephedrone In Part 2 of Schedule 2, which specifies the drugs which are subject to control under that Act as Class B drugs (valid as of 16 April 2010) (a) in paragraph 1(a), after Methcathinone, insert - 4-Methylmethcathinone; (b) after paragraph 1(a), insert - (aa) Any compound (not being bupropion, cathinone, diethylpropion, pyrovalerone …) structurally derived from 2– amino–1–phenyl–1–propanone [cathinone] by modification in any of the following ways, that is to say, (i) by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents; (ii) by substitution at the 3–position with an alkyl substituent; (iii) by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure..

17. 17 Misuse of Drugs Act 1971 (Amendment No.2) Order 2010: naphyrone Naphthylpyrovalerone analogues (including naphyrone) were not covered by the generic definition, which was amended (enforced on 23 July 2010) In Part 2 of Schedule 2, after paragraph 1(aa), insert - (ab) Any compound structurally derived from 2–aminopropan–1–one by substitution at the 1 position with any monocyclic, or fused polycyclic ring system (not being a phenyl ring or alkylenedioxyphenyl ring system), whether or not the compound is further modified in any of the following ways, that is to say, (i) by substitution in the ring system to any extent with alkyl, alkoxy, haloalkyl or halide substituents, whether or not further substituted in the ring system by one or more other univalent substituents; (ii) by substitution at the 3–position with an alkyl substituent; (iii) by substitution at the 2 amino nitrogen atom with alkyl or dialkyl groups, or by inclusion of the 2 amino nitrogen atom in a cyclic structure..

18. 18 Questions for discussion Identification and analysis: (central) laboratory, active purchase of products, synthesis of reference samples Active monitoring (before Risk Assessment) Type of research: pharmacology, toxicology, epidemiology… Post Risk Assessment active monitoring, incl. research (impact of control?) Generic context vs. generic risk assessment

19. 19 EWS@emcdda.europa.eu

20. 20 Commissions proposal a Council Decision on submitting 4- methylmethcathinone (mephedrone) to control measures Article 1 Member States shall take the necessary measures, in accordance with their national law, to submit 4- methylmethcathinone (mephedrone) to control measures and criminal penalties as provided for under their legislation by virtue of their obligations under the 1971 United Nations Convention on Psychotropic Substances. Article 2 This Decision shall enter into force on the day following that of its publication in the Official Journal of the European Union.

21. 21 Types of systems for controlling new substances Individual Listing System: specifying the chemical definitions of controlled substances individually in the legislation. Standard procedure Emergency procedure: fast but temporary listing of individual substances Rapid procedure: fast and permanent listing of individual substances Substances are controlled after the procedure finishes Generic System: legislation includes a precise definition of a family of substances (e.g. by describing substitution patterns in a parent molecule). E.g. Ireland and the United Kingdom Analogue System: legislation includes a more general definition of similarity in pharmacological activity, as well as similarity in chemical structure. E.g. Latvia and Norway Substances within the definition are automatically controlled B Hughes, T Blidaru (2009) Legal Responses to New Psychoactive Substances in Europe.

22. 22 Individual Listing System: specifying the chemical definitions of controlled substances individually in the legislation. Standard procedure Emergency procedure: fast but temporary listing of individual substances Rapid procedure: fast and permanent listing of individual substances Substances are controlled after the procedure finishes Generic System: legislation includes a precise definition of a family of substances (e.g. by describing substitution patterns in a parent molecule). E.g. Ireland and the United Kingdom Analogue System: legislation includes a more general definition of similarity in pharmacological activity, as well as similarity in chemical structure. E.g. Latvia and Norway Substances within the definition are automatically controlled B Hughes, T Blidaru (2009) Legal Responses to New Psychoactive Substances in Europe. Individual Listing System Generic System Rapid procedure Standard procedure Emgcy control: limited Rapid control: permanent Standard ctrl: permanent Analogue System Identification of substance Time Emergency procedure

23. 23 An example An example is the definition of: any compound (…) structurally derived from fentanyl by modification in any of the following ways, that is to say: (i) by replacement of the phenyl portion of the phenethyl group by any heteromonocycle whether or not further substituted in the heterocycle; (ii) by substitution in the phenethyl group with alkyl, alkenyl, alkoxy, hydroxy, halogeno, haloalkyl, amino or nitro groups; (iii) by substitution in the aniline ring with alkyl, alkoxy, alkylenedioxy, halogeno or haloalkyl groups. B Hughes, T Blidaru (2009) Legal Responses to New Psychoactive Substances in Europe

24. 24 An example Description of group-generic substances can occur by illustrating the modifications in the parent molecule without referring to structural derivation, as in the following case: DMT (dimethyltryptamine) analogues, in which the 3-(2 aminoethyl)indole nucleus has additional radicals, either alone or in combination, attached as follows: (a) 1 or 2 alkyl radicals, each with up to 6 carbon atoms, including cyclic radicals, attached to the amino nitrogen atom; (b) 1 or 2 methyl groups, or an ethyl group, attached to the carbon atom adjacent to the amino nitrogen atom; (c) Any combination of up to 5 alkyl radicals and/or alkoxy radicals (each with up to 6 carbon atoms, including cyclic radicals) and/or halogen radicals, attached to the benzene ring. B Hughes, T Blidaru (2009) Legal Responses to New Psychoactive Substances in Europe