Faculty of Medicine & Faculty of Science, Prince of Songkla University

7 November 2011, Hat Yai, Songkhla, Thailand

Emerging and re-emerging drugs

The situation in Europe and Hungary

István Ujváry, PhD

iKem BT

&

Budapest University of Technology and Economics

Lisbon

European Union

Population: ~500 Million

European Monitoring Centre for Drugs and Drug Addiction

The hub of drug-related information in the EU since 1993

EMCDDA Reitox network:

27 EU Member States + Croatia + Turkey + Norway

Hungary

Population: ~10 Million

Budapest

EMCDDA

The illicit drug situation in the European Union & Hungary annual use prevalences (15–64 years old); with regional differences

EU average % in million

Hungary % in thousand

cannabis

6.8

23

2.3

cocaine

1.3

4

0.2

Ecstasy

0.8

2.5

0.5

amphetamines

0.6

2

0.5

opioids*

0.4

1.2–1.5

< 0.1 2800–3400

*Current “problem/injecting drug users”

http://www.emcdda.europa.eu/stats11

Estimates of drug use in Europe data from surveys conducted between 2004 and 2008

Number of users (million)

Drug (street price, EUR / g)

cannabis (7)

cocaine (60)

Ecstasy (70)

heroin (100)

amphetamines (18)

EMCDDA (2010) Annual Report 2010.The state of the Drugs Problem in Europe

stimulants

%

last year use

lifetime use

lifetime use

lifetime use

lifetime use

Hibell, B. et al. (2009) The 2007 ESPAD Report; http://www.espad.org

Substance use among students in 35 European countries

data from surveys conducted during spring 2007

15–16 year old students, ntotal > 100,000; nHungary = ~10,200

last month

Hibell, B. et al. (2009) The 2007 ESPAD Report; http://www.espad.org

Substance use trends among students in Hungary, 1993–2007 lifetime use, 15–16 year old students, n = 8,000–10,200

Regional differences!

Have you ever used new substances

– sold legally as powders, pills, or herbs –

that imitate the effect of illicit drugs?

Young people and new substances (‘designer drugs’ or ‘legal highs’) n = 12,000; 15–24 years old; with regional differences; May 2011

Gallup (2011) Flash Eurobarometer: Youth attitudes on drugs.

5 %

95 %

Yes, I have used

No, I have never used

DESIGNER DRUGS (1985)

Chemical analogues of controlled substances that produce effects similar to the

illicit substances they mimic.

• ‘designed’ by slightly altering the chemical structure of an illicit drug to evade

existing regulations

• selected from the scientific literature; hitherto unknown substances are rare

“LEGAL” HIGHS

A wide range of unregulated products, incl. herbal mixtures & synthetic designer

drugs, frequently with concealed ingredients.

• often agressively advertised and marketed over the Internet & in special shops as

incense, room odouriser, plant food, bath salt or research chemical

• misleadingly labelled “NOT FOR HUMAN CONSUMPTION”, though the plant mixes,

powders, tablets or capsules are intended for smoking, snorting or oral ingestion

• due to innovative marketing strategies and rapidly changing compositions,

suppliers can circumvent existing regulations

‘Designer drugs’ and ‘legal highs’ §

ALL are poorly characterised pharmacologically & toxicologically: legal safe

Scientific literature: a rich source of new drugs

Risk identification / Information exchange / Early-warning

A new psychoactive

drug is detected in

the EU Member States

and described

in the Reporting Form

EMCDDA

Europol Europol national units

Reitox focal points

Early-warning system on new psychoactive substances 2005/387/JHA Council Decision

NCH

3

O

The appearance of new psychoactive drugs in the EU by activity type

Number of new drugs

others 9

synth. cannabinoids 21

stimulants 54

hallucinogens 25

Altogether 2005-2010

7

3

7

2 3

1

4

6

89

1

3

2

3

3

26

11

9

1

0

5

10

15

20

25

30

35

40

2005 2006 2007 2008 2009 2010

EMCDDA, EUROPOL & EWS Reports 2006-2010

List of some new psychoactive drugs grouped by psychoactivity

• stimulants 4-fluoroamphetamine, p-methoxymethamphetamine (PMMA),

N-benzylpiperazine, 1,3-dimethylamylamine (DMMA),

mephedrone, 3,4-methylenedioxypyrovalerone (MDPV),

naphyrone, 2-aminoindan, 5,6-methylenedioxy-2-aminoindan,

4-fluorotropacocaine, 6-(2-aminopropyl)benzofuran (6-APB)

• hallucinogens N,N-dipropyltryptamine (DPT), 5-MeO-DPT, 5-MeO-DIPT,

DOM, DOI, 2C-B, 2C-I, bromo-dragonfly, DXM, ketamine,

3-MeO-PCP, Salvia divinorum, …

• sedative-narcotic etaqualone, kratom, O-desmethyltramadol (ODT)

• cannabinoids Spice, JWH-018, JWH-073, JWH-0122, JWH-398, RCS-4,

CP-47497+homologues, AM-694, AM-1220, WIN-48,098

• miscellaneous pregabalin, benzydamine, poppers, glaucine, kava, etc.

Examples from EMCDDA Database (several chemotypes) Psychoactivity

The appearance of new psychoactive drugs in Hungary in 2009 and 2010

Phenethylamines Cathinones Synthetic

cannabinoids Others Total

2009

4-fluoroamphetamine

methamphetamine

MDPV

butylone

mephedrone

JWH-018 2C-B

g-hydroxybutyrate 8

2010

4-fluoromethamphetamine

4-methylamphetamine

methylone

3,4-dimethylmethcathinone

4-methylethcathinone

pentylone

ethylcathinone

3-fluoromethcathinone

4-fluoromethcathinone

4’-methyl-2-pyrrolidinylpropiophenone

3’,4’-methylenedioxy-2-pyrrolidinyl-

butyrophenone

JWH-073

JWH-081

JWH-210

4-fluorophenyl-

piperazine

1-phenethylamine

mescaline

2-diphenylmethyl-

piperidine

18

Data source: Hungarian Institute for Forensic Sciences, Budapest

D9-THC

from Cannabis sativa

identified in 1964

JWH-018 described in 2000

report to EMCDDA in 2008

N

O

CH3

O

CH3

CH3

CH3

OH

CH3

N

O

indole ring naphthalene ring

R1 R2

Since 2008, 35 analogs have

been reported to EMCDDA

Herbal mixtures laced with synthetic cannabinoids

The Spice phenomenone: smokeable herbal mixtures sold as ‘incense’ contain synthetic cannabinoids as undisclosed active ingredients

different chemistry similar psychoactivity

unknown pharmacology & toxicology

EMCDDA (2009) Understanding the 'Spice' phenomenon. Thematic papers

Example Bioorg Med Chem 13,

89-112 (2005)

...designer drugs design...

N

O

JWH-018 (2000)

N

O

N

AM-1248 (2006) patent example

N

O

Hitherto not described in the scientific literature

OH

CH3

NH

CH3

(1S,2S)-(+)-pseudoephedrine alkaloid from Ma Huang, Ephedra sp.

Analogues of cathinone, a ‘natural amphetamine’ new synthetic psychostimulants

NH2

CH3

O

cathinone alkaloid from khat, Catha edulis

CH3

NH

CH3

O

CH3

NH

CH3

(S)-(+)-methamphetamine (as HCl salt)

methcathinone

semisynthetic stimulants

4-methylmethcathinone 4-MMC, mephedrone

NH

CH3

O

CH3

CH3

synthetic stimulant

O

N

R1

R2

R3

Since 2005, 35 new cathinones have been reported to EMCDDA

EMCDDA (2011) Report on the risk assessment of mephedrone

4

Brandt et al (2010) Analyses of second-generation ‘legal highs’ in the UK. Drug Test Anal 2, 377

NRG-2

mephedrone

benzocaine +

caffeine

mephedrone +

benzocaine

4-methyl-N- ethcathinone

All sold as „Legal Highs”

yet contain ingredients

controlled in the UK

since 16 April 2010!

Variations in undisclosed ingredients in ‘NRG’ products United Kingdom April 2010 - July 2010

NRG-3 pentylone

+ 4-methyl-N- pyrrolidine- cathinone

(MPPP)

NRG-1

mephedrone mephedrone

+ caffeine

mephedrone +

procaine flephedrone

naphyrone flephedrone

+ naphyrone

butylone +

MDPV

flephedrone +

MDPV

inorganic material caffeine

(S)-a,a-diphenylprolinol chiral catalyst in organic syntheses

pipradol (1953) methylphenidate (1950)

OH

NH

desoxypipradol (1954)

2-(diphenylmethyl)-

piperidine

2-DPMP

2008

NH

O

O

NH

NH

OH

Organic reagents, (obsolate) medicines and street

drugs

D2PM (1964)

diphenyl-(2-pyrrolidinyl)-

methanol

2007

NH

OH

desoxy-D2PM

2-(diphenylmethyl)-

pyrrolidine

A3A Methano

2010

NH

15x fortified kratom preparation 35x fortified kratom preparation

morphine

N

OH

O

OH

CH3

NH

N

OMe

MeOOC

MeO

mitragynine

NCH

3

CH3

OH

OH

O-desmethyltramadol

+ caffeine

50x fortified kratom preparation

‘Legal highs’ – Kratom preparations in Europe some, like Krypton, are laced with a synthetic opiopid

?

Dresen et al (2010) J Mass Spectrom 45: 1186-1194

unknown substance in a tablet, not seen before

structure similar to mephedrone

isolation and analysis by Mass Spectroscopy

Data source: Hungarian Institute for Forensic Sciences, Budapest

A newly identified cathinone in Hungary a methyl (CH3) homologue of mephedrone (4-MMC)

-CH2

191 14 + = 177 CH

3

O

CH3

NCH

3

N+

CH3

CH3

H

m/z 58

m/z 133

O+

CH3

CH3

2.33

2.33

CH

CH

CH

CH3

CH3

CH

O

CH3

NH

CH3

7.38

7.78

7.83

1.44

2.59

5.10 9.20

Data source: Hungarian Institute for Forensic Sciences, Budapest

analysis by Nuclear Magnetic Resonance spectroscopy

The newly identified cathinone is 3,4-DMMC a 3-methyl (CH3) homologue of mephedrone

§ individual control (according to UN conventions; universal)

lists specific substances named one by one

§ generic control (Austria, UK, Hong Kong, Ireland, Israel, Lithuania, New Zealand)

defines a family of substances based on substitution patterns in a parent molecule

where the type, number and position of substituents may be precisely specified

§ analogue control (Australia, Latvia, New Zealand, Norway, USA)

covers families of substances based on their

- similar chemical structure

- similar pharmacological activity

Regulatory options for ‘designer drugs’ and ‘legal highs’

§ ‘psychoactive substance control’ (Ireland)

covers all psychoactive substances based on their activity on the CNS

§ ‘substitute drug control’ (Poland)

covers essentially all psychoactive substances that are used like the already

regulated narcotic or psychotropic substances

(with examples)

Nature 469(6 January 2011), p. 7

awareness – preparedness – common sense

DRUG VIGILANCE

Summary – Challenges

Thank you

The appearance of new drugs

can be anticipated based on medicinal chemistry literature, old & new

can be noticed on the Internet

can be identified by regular analysis of seized or market samples

can be suspected by getting information from users

can trigger regulation once composition & risks are clarified

cannot probably be prevented but can be discouraged / deterred

will certainly cause some surprises & concerns