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||Analytical Strategy, HS 2019
Legal Highs
Structure and Action – Legal Situation – Detection and Analytics
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Legal Highs / Novel Psychoactive Substances
Cedric Wüthrich, Konrad Münch 08.10.2018Cedric Wüthrich, Konrad Münch 1
||Analytical Strategy, HS 2019
Legal Highs
From Pharmaceutical Research to Legal Highs
https://www.mcmp.purdue.edu/faculty/nicholsd; Nature 469 (2011), 7
David E. Nichols
▪ Professor Emeritus of Pharmacology, Purdue University
▪ Research on Neurotransmitters (e.g. Dopamine, Serotonin), their
receptors and treatment of Parkinson’s disease
▪ Development of new antipsychotic drugs
▪ Used as reference for the development of legal highs
▪ “I was stunned I had published information that ultimately led to
human death”
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Legal Highs
▪ “A substance with stimulant or mood-altering properties whose sale or use is not
banned by current legislation regarding the misuse of drugs.”
Legal Highs (Oxford English Dictionary)
https://www.lexico.com/en/definition/legal_high
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Legal Highs
…“Bath salts”, “Pond cleaners”, “Glass cleaners”, “Plant Food”…
Available as…
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Legal Highs
…“Research chemicals”, but also “Nasal Decongestant”, plants…
Available as…
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Legal Highs
▪ GABA immitates
Legal Highs – Examples (1)
Open Access Emergency Medicine (2018), 10, 9–23, Clinical Toxicology (2012), 50
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Legal Highs
▪ Phenylethylamine and derivatives
Legal Highs – Examples (2)
Open Access Emergency Medicine (2018), 10, 9–23, Clinical Toxicology (2012), 50
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Legal Highs
▪ Tryptamines and derivatives
Legal Highs – Examples (3)
Open Access Emergency Medicine (2018), 10, 9–23, Clinical Toxicology (2012), 50
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Legal Highs
▪ Ketamines
▪ Cocaine Derivatives
Legal Highs – Examples (4)
Open Access Emergency Medicine (2018), 10, 9–23, Clinical Toxicology (2012), 50
▪ Methylphenidate derivatives
▪ Synthetic Cannabinoids
▪ …
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Legal Highs
Can be
▪ Novel psychoactive compounds, “Designer Drugs”
▪ Over-the-counter medications (e.g. nasal decongestant)
▪ Household culinary spice and plant products (e.g. nutmeg, fly agaric mushroom)
▪ Hallucinogenic, Euphoria, Dissociative Behaviour
▪ Toxidromes like tachycardia, mydriasis, urinary retention, dry mucosal
membranes, hypoactive bowel sound, hypothermia, organ complications
▪ Often similarities with neurotransmitters
▪ Small structural changes to circumvent drug legislation
Legal Highs
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Open Access Emergency Medicine (2018), 10, 9–23, Clinical Toxicology (2012), 50, The American Journal of Drug and Alcohol Abuse (2012), 38, 176–180
||Analytical Strategy, HS 2019
Legal Highs
Legal Situation in Switzerland: Betäubungsmittelgesetz, BetmG
https://www.admin.ch/opc/de/classified-compilation/20101220/index.html, https://www.admin.ch/opc/de/classified-compilation/19981989/index.html, https://www.bag.admin.ch/bag/de/home/gesetze-und-
bewilligungen/gesetzgebung/gesetzgebung-mensch-gesundheit/gesetzgebung-betaeubungsmittel.html
▪ Principle: “Prevention, Therapy, Damage
Reduction, Repression”
▪ List of illegal drugs (synthetic or natural) and
controlled substances, including
▪ Auxiliary Chemicals for production (Solvents, Acids, …)
▪ Precursors, Stereoisomers, Salts, Esters, Substitutes
(presumed similar effects)
||Analytical Strategy, HS 2019
Legal Highs
▪ Drug regulation is individual in every country
▪ Fast adoption of novel substances in member state legislation
European Monitoring Centre for Drugs and Drug Addiction
▪ Research, Data Acquisition
▪ Early warning system
▪ Fast response to novel substances
Legal Situation in EU
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http://www.emcdda.europa.eu, http://www.europarl.europa.eu/news/de/press-room/20171020IPR86547/drogen-schnelles-eu-weites-verbot-von-neuen-gefahrlichen-substanzen
||Analytical Strategy, HS 2019
Legal Highs
▪ “At 1:00 a.m. a 23 year old male patient is admitted to the emergency
department of the University Hospital in Basel. He was very agitated, had a
combative violent behaviour and hallucination. He has been found in his
home standing on his bed complaining of mice everywhere. He was given the
antidote for opiate intoxications without any effect. The classical drugs of
abuse screening tests in the laboratory were negative. The physicians then
suspected the intake of legal highs or research chemicals and sent a urine
and a blood sample to the laboratory.”
Case
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Legal Highs
▪ Symptomatic supportive care
▪ e.g. schizophrenia, paranoia, aggression, hypothermia, …
▪ Intravenous Fluids
▪ Drug Screening:
▪ Interferences with assays for other drugs (false-positive?)
▪ Search for unknown compound?
▪ Degradation?
▪ Probably mixture of different drugs?
Treatment
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The American Journal of Drug and Alcohol Abuse (2012), 38, 176–180
||Analytical Strategy, HS 2019
Legal Highs
Requirements for the Analysis in the Problem Set
• Use of the required techniques can be performed with little
training
• Little manual work, high degree of automatization
• Little to no sample treatment
• Sophisticated instrumentation
• Instruments need to produce fast qualitative results
• Data treatment and interpretation should be performed mostly
automatically
Data
OperatorInstrument
0 1
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Preparing Blood and Urine Samples (1)
Urine and blood mostly contain water
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Legal Highs
Preparing Blood and Urine Samples (2)
Centrifuge for removing large particles
• Precipitate proteins with acetone• Solid-phase extraction• Liquid-liquid extraction
• Solid-phase extraction• Liquid-liquid extraction
S. F. Lo, V. Young, W. J. Rhead, in Clin. Apllications Mass Spectrom. (Eds.: U. Garg, C.A. Hammett-Stabler), Humana Press, Totowa, NJ, 2010, pp. 433–443.T. M. Annesley, Clin. Chem. 2003, 49, 1041–1044.S. Tiziani, A.-H. Emwas, A. Lodi, C. Ludwig, C. M. Bunce, M. R. Viant, U. L. Günther, Anal. Biochem. 2008, 377, 16–23.
Many possibilities for extracting the aqueous layer, some methods utilize buffers
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Gas and Liquid Chromatography
C. F. Poole, Gas Chromatography, Elsevier, 2012.S. Fanali, P. R. Haddad, C. F. Poole, M.-L. Riekkola, Liquid Chromatography, Elsevier, 2017.
Some GC-Detectors:TCD, FID, ECD, NPD, AED, IRD, MSD
Some LC-MS-Detectors:UV/Vis, Conductivity, Refractive Index, MS
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Mass Spectrometer / HR-MS
J. H. Gross, Mass Spectrometry, Springer International Publishing, 2017.
𝑅 =
𝑚𝑧
Δ(𝑚𝑧 )
High resolution approximately achieved at R > 5000
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Ion Source / Electron Ionization
J. H. Gross, Mass Spectrometry, Springer International Publishing, 2017.
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MSn
Selection of precursor ion, collision, analysis of the collision products
J. H. Gross, Mass Spectrometry, Springer International Publishing, 2017.
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Legal Highs
Mass Analyzer / LTQ-Orbitrap
J. H. Gross, Mass Spectrometry, Springer International Publishing, 2017.
Linear Ion Trap:Can store ions over time, select ions, can accumulate ions
C-Trap:Quadrupole, injects the ions into the orbitrap
Orbitrap:Electrostatic spindle with gradient, oscillations of ions are treated with Fourier Transformation
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Legal Highs
Mass Analyzer / FT-ICR-MS
Ions in the magnetic field cause a local magnetic field in the detectors, signal is Fourier transformed
J. H. Gross, Mass Spectrometry, Springer International Publishing, 2017.
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Data Analysis (1)
D. Pasin, A. Cawley, S. Bidny, S. Fu, Anal. Bioanal. Chem. 2017, 409, 5821–5836.
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Legal Highs
Data Analysis (2)
Top-Down
Check the TIC-chromatogram
Get molecular formula
Check database
See if MS/MS-fragments match
product
Bottom-Up
Check extracted-ion chromatogram
for known ions
Put together ions belonging to the
same peak
Generate molecular formula
D. Pasin, A. Cawley, S. Bidny, S. Fu, Anal. Bioanal. Chem. 2017, 409, 5821–5836.
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Conclusion
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▪ Legal Highs comprise a group of psychoactive substances that are not
controlled by current legislation
▪ Treatment: Supportive Symptomatic Care
▪ Legislation was adapted to NPS (Novel Psychoactive Substances)
▪ Analytics: Sophisticated automated instrumentation, Orbitrap?
▪ Data: Target screening faster, less trained operator
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Legal Highs08.10.2018Cedric Wüthrich, Konrad Münch 27