Cloud spectroscopy for identification and monitoring of ... · Nootropics “cognitive enhancers”...

Disclaimer: The contents of this presentation are the views of the author and do not necessarily represent an official position of the European Commission

C. Guillou, F.Reniero, M. Holland, J. Lobo Pereira Vicente, H. Chassaigne, K. Kamil, S. Tirendi

Joint Research Centre of the European Commission,Institute for Health and Consumer Protection (IHCP) via E. Fermi, 2749, I-21020 Ispra (VA)

and colleagues from the CLEN and other organisations or projects who contributed to this work

DG TAXUD for supporting the AA CLEN2SAND-DG TAXUD-Nr TAXUD/2014/DE/315, to the colleagues from organisations and projects above cited, and the manufacturers of scientific instrumentation who allowed the collection of spectra on their analytical devices.

Cloud spectroscopy for identification and monitoring of new psychoactive substances and beyond


What are the illicit drugs?

2

CANNABIS

HEROINE

COCAINE

AMPHETAMINES

(metamphetamine , MDMA/ Ecstasy)



3

CANNABIS

HEROINE

COCAINE

AMPHETAMINES

(metamphetamine , MDMA/ Ecstasy)

NEW PSYCHOACTIVE SUBSTANCES



4

NEW PSYCHOACTIVE SUBSTANCES

Gray zone ,

licit , illicit ?


New Psychoactive Substances ? NPS

Psychokiller qu’est ce que c’est? Talking Heads

Legal highs, spices

Research chemicals

5


6

Teenagers, young adultsPsychonauts

Body builders ,

Diet supplements

Nootropics “cognitive enhancers” Managers willing to improve their “ efficiency”

Self medication


Internet e-shops Headshops...

Wellness products

7


SYNTHETIC CATHINONES

• Usually sold as ‘Bath Salts’ or ‘plant fertilizers’

• Derivate from Khat, which is a plant • Usually snorted, taken as pills or

injected


Synthetic cathinones are related to the parent compound cathinone, one of the psychoactive principals in khat (Catha edulis) plant. Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine.

Cathinone derivatives are claimed to have effects similar to those of cocaine, amphetamine or MDMA (ecstasy), but little is known of their detailed pharmacology

Cathinone (R1,R2,R3,R4 = H) Amphetamine

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLubuN2RrsgCFcRWFAod5G0OQg&url=http://www.medicineonline.com/drugs/d/3963/DEXTROAMPHETAMINE-SACCHARATE-AMPHETAMINE-ASPARTATEDEXTROAMPHETAMINE-SULFATE-AND-AMPHETAMINE-SULFATE-TABLETS-CII-5-mg-10-mg-20-mg-and-30-mg%C2%A0.html&psig=AFQjCNE4PIZyXU9Zbr44TZyPpiSLQGgVVA&ust=1444230782673584

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLubuN2RrsgCFcRWFAod5G0OQg&url=http://www.medicineonline.com/drugs/d/3963/DEXTROAMPHETAMINE-SACCHARATE-AMPHETAMINE-ASPARTATEDEXTROAMPHETAMINE-SULFATE-AND-AMPHETAMINE-SULFATE-TABLETS-CII-5-mg-10-mg-20-mg-and-30-mg%C2%A0.html&psig=AFQjCNE4PIZyXU9Zbr44TZyPpiSLQGgVVA&ust=1444230782673584


Mephedrone (4-methylmethcathinone, 4-MMC)

Methylone (βk-MDMA, 3,4-methylenedioxy-N-methylcathinone)

Methcathinone (ephedrone)

MDPV (3,4-methylenedioxypyrovalerone)


SYNTHETIC CANNABINOIDS

• Most common familyof NPS

• Created in order to mimic THC effects

• Chemicals sprayed onto genericherbs

They are the second most used drug among teenagers after Marijuana.


Δ9-THCCP 47,497

JWH 018 5F CUMYL PINACA

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCMnq36r3r8gCFcg6FAod5SoIUQ&url=https://commons.wikimedia.org/wiki/File:(+)-(6aS,10aS)-%CE%949-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg&psig=AFQjCNGiRairA789PcgDhTgXPlqtd3NrNA&ust=1444292584266055

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCMnq36r3r8gCFcg6FAod5SoIUQ&url=https://commons.wikimedia.org/wiki/File:(+)-(6aS,10aS)-%CE%949-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg&psig=AFQjCNGiRairA789PcgDhTgXPlqtd3NrNA&ust=1444292584266055

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCOSPv4D4r8gCFQPDFAodewEJuQ&url=https://de.wikipedia.org/wiki/CP-47,497&psig=AFQjCNFUgN5a13f-DJKzvNFjJcoALZzvqQ&ust=1444292744708014

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCOSPv4D4r8gCFQPDFAodewEJuQ&url=https://de.wikipedia.org/wiki/CP-47,497&psig=AFQjCNFUgN5a13f-DJKzvNFjJcoALZzvqQ&ust=1444292744708014

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLnx8LGrsMgCFUy4FAodFbsOeA&url=http://countyourculture.com/2010/12/06/synthetic-cannabinoids-jwh-018-replacements/&psig=AFQjCNE-uELM8x2MoGOYz0fk77T0Uu1G-w&ust=1444306531482520

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLnx8LGrsMgCFUy4FAodFbsOeA&url=http://countyourculture.com/2010/12/06/synthetic-cannabinoids-jwh-018-replacements/&psig=AFQjCNE-uELM8x2MoGOYz0fk77T0Uu1G-w&ust=1444306531482520

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCKe63OassMgCFYjTFAod1uwPqw&url=http://www.officialbenzofury.net/products/5F%2dAB%2dPINACA.html&psig=AFQjCNEm_xcjDiR8mJesHubuLi0dRkWrwg&ust=1444306871048396

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCKe63OassMgCFYjTFAod1uwPqw&url=http://www.officialbenzofury.net/products/5F%2dAB%2dPINACA.html&psig=AFQjCNEm_xcjDiR8mJesHubuLi0dRkWrwg&ust=1444306871048396

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJCZ0tussMgCFclZFAodnbEGeQ&url=https://en.wikipedia.org/wiki/5F-CUMYL-PINACA&psig=AFQjCNEm_xcjDiR8mJesHubuLi0dRkWrwg&ust=1444306871048396

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJCZ0tussMgCFclZFAodnbEGeQ&url=https://en.wikipedia.org/wiki/5F-CUMYL-PINACA&psig=AFQjCNEm_xcjDiR8mJesHubuLi0dRkWrwg&ust=1444306871048396


How much pure drug is needed to make 10,000 doses?

Growing business

Drug Trends in EuropeA new concern synthetic opioids/ fentanyls

EMCDDA European Drug Report 2014


Launch of EU Drug Markets Report 5 April 2016

15

A large number of NPS are sold openly as

“legal” replacements for illicit drugs.

There are no signs of a slowdown in the

development of these substances.

Increase in number and diversity

2 new substances/week

Monitoring over 600 in 2016 ?

How?

Challenges for Customs, Forensic,

Law Enforcement laboratories

Hospitals, Anti-Poison Centres

and International Organisations

dealing with drugs and NPS

=> Need of appropriate tools


New Psychoactive Substances (NPS) Figures from the European Monitoring Centre for Drugs and Drug Addiction

EMCDDA

16


CHALLENGES

for law enforcement laboratories

ACCESS TO “REFERENCE” DATA

European Database on New Drugs EDND (EMCDDA)

SWDRUGS,

FORENDEX,

UNODC,

CAYMAN, etc ......

17


The present needs an immediate reaction

18

• Nowadays sharing of analytical chemistry data: pictures, pictures, pictures…


NAMES

Chemical names?

Systematic names

IUPAC systematic names

CAS number

Street names, nick name

=> Confusion propagation of errors

Tower of Babel – Source: Brueghel/WIKI

http://en.wikipedia.org/wiki/Image:TowerOfBabel2.jpg

http://en.wikipedia.org/wiki/Image:TowerOfBabel2.jpg



20

• Nowadays sharing of chemical nomenclature: "systematic" names and nick names

• Other "systematic" names found for 4F-PVP:

• 4-fluoro-a-2-(1-pyrrolidinyl)-Valerophenone

• 4-Fluoro-2-pyrrolidinovalerophenone

• 4'-Fluoro-α-pyrrolidinopentiophenone

• 1-(4-Fluorophenyl)-2-pyrrolizinopentane-1-one

• Other nick names found for 4F-PVP:

• 4-F-α-PVP, FPVP, 4-Fluoro-α-PVP, 4-fluoro-PVP, O-2370…



21

• Nowadays sharing of chemical nomenclature: chemoinformatic identifiers:

• SMILES identifiers found for 4F-PVP:

• CCCC(C(=O)c1ccc(F)cc1)N2CCCC2

• CCCC(C(=O)C1=CC=C(C=C1)F)N2CCCC2

• FC1=CC=C(C=C1)C(C(CCC)N2CCCC2)=O

• CCCC(C(=O)c1ccc(F)cc1)N1CCCC1

• C(C(=O)c1ccc(cc1)F)(N1CCCC1)CCC

• Only unique and unambiguous chemical codes in present world are InChI

and shorter InChi Key

• InChI=1S/C15H20FNO/c1-2-5-14(17-10-3-4-11-17)15(18)12-6-8-13(16)9-7-12/h6-

9,14H,2-5,10-11H2,1H3

• BQLSUBYYRRZHRK-UHFFFAOYSA-N

• …and the *.mol information

1rst Customs 2020 meeting of the Project Group on designer drugs and other illicit productsLisbon 5 & 6 February 2015 EMCDDA

22

61 participants:

-delegates from the European Customs

Laboratories (27 participants from 22 Member

States)

-EC DG TAXUD, DG JRC and DG HOME

-EMCDDA

-Portuguese Police Laboratory, Antifraud

department, etc.)

-9 invited experts.


Scientific and technical support by the Joint Research

Centre (JRC) to DG TAXUD and the Customs Laboratories

European Network (CLEN) for fast recognition of New

Psychoactive Substances (NPS) and identification of

unknown chemicals

close collaboration with the CUSTOMS 2020 CLEN Action 5

PG on designer drugs and other illicit substances

Administrative Arrangement DG TAXUD- JRC - 2014/DE/315

initially 18 months now extended until end 2016,

Proposal of extension until end 201823

CLEN2SAND


CLEN2SAND

24

support the CLEN with JRC’s analytical facilities and

scientific expertise

establish harmonised methods for identification of chemical

structures

dissemination of the scientific methods and best practices

test fast screening techniques with handheld devices

set-up of an electronic repository of chemical and spectral

characteristics of NPS


Identification & confirmation of chemical structure ->

“Publication” of spectra – methods - data

25

18-Jun-2013 15:27:18Q-Tof Premier HAB245SAMPLE_0011

m/z55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185

%

0

100

%

0

100

%

0

100

%

0

100

SAMPLE_0011_MS_MS_172_20EV_RANGE 50-300 30 (0.513) Cm (2:57) TOF MSMS 172.07ES+ 2.31e3139.0521

2314

97.01311563

79.0549571

56.0454267

70.0645219

85.0127272

94.0682224

123.03281022

121.0936463

113.0457317

98.0205228 106.0693

225

125.0491229

138.0459164

154.07831978

140.0574227

155.0797245


11857

139.05212755

97.01311602

56.0468493

123.03281515113.0477

764

155.08211488


28026

155.08213697

172.09081216


30079172.0883

24264

155.07973799

173.09163313

FT-IR & RAMAN

GC / LC MS method

ECICS

ILIADe

EMCDDA National Focal Point -REITOX

Molecular Formula: C8H13NOS

Monoisotopic mass: 171.071777 Da

Systematic name: 2-(Methylamino)-1-(2-thienyl)-1-propanol

SMILES: CC(C(c1cccs1)O)NC

InChI=1S/C8H13NOS/c1-6(9-2)8(10)7-4-3-5-11-7/h3-6,8-10H,1-2H3

Std. InChIKey: PQBXAYQNHATKPC-UHFFFAOYSA-N

• GC/MS, FTIR & Raman as screening techniques

• Advanced analytical tools: NMR for structural ID (600 & 400 MHz) and

HRMS (Q-TOF & Orbitrap) for structural confirmation

NPS Identification


10 mg substance directly in the NMR tube

Dilution with 0.5 mL deuterated DMSO solvent

NMR measurement in automation

1H spectrum (2 min.)

C=O Double bonds

A

l

i

p

h

a

t

i

c

13C spectrum (10 min.)

1H NMR mono- and bi-dimensional

(COSY, TOCSY)

- 13C NMR mono-dimensional

- 1H/13C HSQC phase sensitive

- 1H/15N HMBC

Total of 6 experiments,

performed in automation mode

(ICON NMR software)

Total run time 4 hrs

http://upload.wikimedia.org/wikipedia/commons/b/b3/AKB-48_structure.png

http://upload.wikimedia.org/wikipedia/commons/b/b3/AKB-48_structure.png


Sample 11: 1H – 13C correlation spectrum (15 min.) 1H – 15N correlation spectrum (15 min.)


m/z90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 230 235 240 245 250 255 260 265 270 275 280 285 290 295

%

0

100

SAMPLE_0011_MS_RANGE 50-1000 32 (0.550) Cm (2:58) TOF MS ES+ 2.71e4154.0760

27076

139.05211332116.9899

1106

123.0328933

147.00501060

172.08834106

155.07973269

156.07251633

239.25041096


m/z55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185

%

0

100

%

0

100

%

0

100

%

0

100


2314

97.01311563

79.0549571

56.0454267

70.0645219

85.0127272

94.0682224

123.03281022

121.0936463

113.0457317

98.0205228 106.0693

225

125.0491229

138.0459164

154.07831978

140.0574227

155.0797245


11857

139.05212755

97.01311602

56.0468493

123.03281515113.0477

764

155.08211488


28026

155.08213697

172.09081216


30079172.0883

24264

155.07973799

173.09163313

High Resolution FIA-MS (Resolution 16000) MS-MS fragmentation

S

NH

OH

S

NH

OH

m/z 172.08

S

NH

O 2H

m/z 172.08

+H

S

NH

m/z 154.07

rHR

-H2O

Mass Frontier Mass fragmentation

• Belgian Customs seized a parcel containing two plastic bags

labelled as "white pigments" coming from China

One little story ( among many others) :

5F-AMB(already known synthetic cannabinoid)

Sold as …..

Clonazolam(benzodiazepine)

PX3 (new synthetic cannabinoid)

…but it is

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCOP0-d3SsMgCFcRMFAodk0QBaw&url=https://pharma-chem.biz/&psig=AFQjCNFCUktrRiObtk71s64bnrotLSrjcw&ust=1444317093421103

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCOP0-d3SsMgCFcRMFAodk0QBaw&url=https://pharma-chem.biz/&psig=AFQjCNFCUktrRiObtk71s64bnrotLSrjcw&ust=1444317093421103

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCNyh4YLTsMgCFQZaFAodqqoAiQ&url=http://www.rceshop.com/product/5f-amb-2/&psig=AFQjCNFCUktrRiObtk71s64bnrotLSrjcw&ust=1444317093421103

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCNyh4YLTsMgCFQZaFAodqqoAiQ&url=http://www.rceshop.com/product/5f-amb-2/&psig=AFQjCNFCUktrRiObtk71s64bnrotLSrjcw&ust=1444317093421103


unknown from Belgium - end of March

Reported to EMCDDA beginning of April by Belgiumhttp://hengyixin.en.made-in-china.com/product/jXUEbeFlrWkY/China-Px-3-New-Chemical-Similar-with-Ab-Series-for-Research-Only.html

30

“ Blue light " Forum:

thread on Novel cannabinoid PX-

3 which suggests these names:

"So PX-3 could also be called APP-

CHMINACA, I think, as "the acronym

'APP' signifies the 'amino', 'phenyl'

and 'propanone' elements of the

structure".

http://www.bluelight.org/vb/threads/75

1217-Novel-cannabinoid-PX-3

http://www.bluelight.org/vb/threads/751217-Novel-cannabinoid-PX-3


http://dx.doi.org/10.1016/j.forsciint.2016.01.02

4

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http://dx.doi.org/10.1016/j.forsciint.2016.01.024


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33


34


35


36


37


38

19 New NPS identified for the first time

JRC-TAXUD-CLEN scientific publication in progress


39

But also, (diverted) medicines ? Or pharmaceuticals under clinical trial ? e.g. Cabergoline, Ibutamoren , Tezacaftor (VX-661) …


40

others not necessarily NPS

Or precursors, reagents, enhancer of NPS effect ?

Who knows ? E.g.

found first for Belgian Customs within a package containingcathinones, then a few weeks later for French Customs


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Meeting Brussels November 2015


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Cloud spectroscopy

Reference libraries

For high resolution (lab)

And low resolution (handeld)

not only drugs and NPS

Chemicals in general

Parallel Session 2│ Beyond laboratory walls - Knowledge support, detection and analyses in the field - Going mobile


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AMB-CHMICA-on-60MHz –vs- 400MHz


44


CLEN2SAND

45

support the CLEN with JRC’s analytical facilities and

scientific expertise

establish harmonised methods for identification of chemical

structures

dissemination of the scientific methods and best practices

test fast screening techniques with handheld devices

set-up of an electronic repository of chemical and spectral

characteristics of NPS

CLOUD SPECTROSCOPY

46

Sample A"unknown" chemicalseized by customs

Samples CBlood of overdosedperson

Sample B"unknown" chemicalgathered by police

Sample D"unknown" chemicalseized by customs

As soon as the spectra are stored in database every new sample containing the

substance is more easily identified…

InChi Key, *.mol

Database record

Identification!!

NMR, MS, MS/MS, IR

GC-MS

LC-MS/MS

IR spectrum

GC-MS

DB


47

Current DevelopmentOf JRC-ACD Platform

Towards Web access?In the future


SWGDrug Data with spectra importedinto JRC ACD/Lab DB

48

More than 2000

SWGDrug DB spectra

were imported to

ACD together with

their structures…


EMCDDA European Database on New Drugs (EDND) imported into JRC ACD/Lab DB

49

The database was

corrected to be

containing the

chemoinformatic

information for all

samples:

*.mol structures,

SMILES, InChi, InChi

Keys…

BUT NO SPECTRA!

THIS NEEDS TO BE

DONE MANUALLY !


Conclusions

50

progress of work (update June 2016):

- Over 120 CLEN samples

- Over 250 samples (standards and e-shop) purchased by JRC

- On going study on handheld portable devices

-CLEN samples :

Several unknown substances confirmed

or identified as new NPS or new research chemicals,

about 20 new substances were notified to the EMCDDA by NFPs.

-4 analytical methods recorded in ILIADe,

Future: continuation of the analytical work, sharing data of chemical among

several organisations, trainings on new techniques ….

Acknowledgements

EMCDDA

DG TAXUD

DG HOME

JRC

CLEN

ENFSI

RESPONSE

All my colleagues

And you for listening

28 EU Member States,87 Customs Laboratories

www.jrc.ec.europa.eu

Contact: [email protected]

Serving society

Stimulating innovation

Supporting legislation

Joint Research Centre (JRC)

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Cloud spectroscopy for identification and monitoring of ... · Nootropics “cognitive enhancers”...

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