What is a decarbo meth crystal

New Drugs: Legal Highs and Research Chemicals Analytical and Toxicological Aspects

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1 BAGÄP conference in Stuttgart-Hohenheim Training event for doctors and psychologists in the penal system New drugs: Legal highs and research chemicals Analytical and toxicological aspects Prof. Dr. Volker Auwärter Institute for Forensic Medicine, Freiburg University Medical Center

2 Definitions Designer drug - effectiveness as an intoxicant - synthetically produced - obtained by (minor) chemical modification of a lead structure - lead structures: known drug substances - deliberate avoidance of BtM legal regulations chemical designation - mostly available as pure substances in powder form - code designation

3 Legal classification of the BtMG: BtM are only substances that are listed in Annexes I-III. Single substances only! -> Designer drugs AMG: term of drug: 1. application on / in the body 2. intended for treatment / prophylaxis (presentation drug) or pharmacol. Effect / diagnostic agent (functional medicinal product) Differentiation from food, cosmetics, tobacco products, biocidal products and animal feed

4 New drugs: Other (chemicals, plants, medicines) Synthetic cannabinoids Cathinones Piperazines Tryptamines Phenethylamines

5 drug design O O N JWH-018 K i (CB 1): 9.0 nm O N N F AM-2201 K i (CB 1): 1.0 nm O N JWH-122 K i (CB 1): 0.69 nm K i (CB 1)? Moosmann et al. 2012, FSI F

6 Design of new products New trend (synthetic cannabinoids): - Modular principle: Damiana + pure substance - Liquids for e-cigarettes

7 EU project: SPICE and SPICE II Plus product monitoring Prompt identification of new substances Development of analytical methods Creation of toxicological profiles Pharmacological evaluation Epidemiological studies Prevention work, website (online drug advice) Project No. JUST / 2009 / DPIP / AG / 0948 JUST / 2011 / DPIP / AG / 3597

8 Distribution of incense mixtures: Number of year olds in the Frankfurt area who have already consumed SPICE products 7-8% Spice / "Incense mixtures" lifetime prevalence 30-day prevalence

9 Distribution of smoking mixtures: Number of year olds in the Frankfurt area who have already consumed SPICE products 7-8% - 6.25% of randomly selected MPU urines that tested negative for THC-COOH were positive - positive rates in forensic psychiatric institutions: up to> 80% - US Army: SPICE is perceived as a major problem (decomposition of military strength) - In some countries hardly any problems (causes for this?)

10 Online survey: Consumption motivation (%) of experienced users (n = 860) "important / very important" because I had problems because friends also use (cheaper) price Supply bottleneck with other drugs Non-detectability Alternation recovery / relaxation Legal acquisition Curiosity Effect / get high

11 online survey typology of legal high consumers trial consumers (the largest group) substitutes (substitute illegal drugs with legal highs) stoners 2.0 (alternating cannabis and spice + relatively often) specialists (psychonauts, focus on research chemicals) omnivores (taking everything is currently available)

12 Number of positive results from urine analyzes (forensic psychiatric clinics) 2011 n = n = n =, 8% 42.2% 24.1%

13 Number of urine samples> 500 urine samples from MPU abstinence controls Positive Negative

14 Positive rates [%] 6.25% of the clean samples positive for synthetic cannabinoids Mean value (6.25%) 4 2 0

15 Effect of synthetic cannabinoids - Act on the same receptor system as THC and endocannabinoids (-> cannabimimetics), directly or indirectly - Binding mostly with high affinity to the CB 1 receptor (high potency) - Many active ingredients act as full agonists on the CB 1 receptor (strong maximum effect at high dosage) - Decomposition products in the body can also have an effect -> complex pharmacodynamics

16 Acute toxicity of synthetic cannabinoids addiction (3):

17 Acute toxicity of synthetic cannabinoids Symptoms mostly similar to those after cannabis use - Red eye effect - Sedation / slowing down - Panic attacks / psychotic experience - Palpitations - Reduced memory capacity Additional symptoms (high dose) - Generalized seizures - Hypokalaemia - Hypertension - Nausea / violent vomiting - Extreme restlessness, aggressive behavior - Coma - Relatively rapid development of tolerance In vitro at cell level, relatively low toxicity

18 Risks of long-term consumption Chronic toxicity - Previous in vitro data show a carcinogenic potential for some substances - No in vivo data available

19 Risks of constant consumption Potential for dependency - Probably similarly low as with cannabis - Indications of a faster development of tolerance compared to cannabis - Other psychological changes? - Children / adolescents are particularly vulnerable

20 Excursus: Immunoassays Advantages and Disadvantages - Relatively simple handling - Inexpensive - Specificity / sensitivity (binary classification with cut-off = compromise solution) Particularly problematic: - Amphetamines (biogenic amines) - Benzodiazepines (potency, structural diversity, glucuronides) - Synthetic cannabinoids, Bath salts (cathinone derivatives, piperazines)

21 Analysis of synthetic cannabinoids (blood / serum) Gold Standard: LC-MS / MS (MRM) - High sensitivity (LOD <0.10 ng / ml) - Fast adaptation / re-validation possible - Quantification (clinical / forensic issues) Disadvantage: Target analysis GC-MS (/ MS) - Insufficient sensitivity / robustness - More complex sample preparation

22 Analysis of synthetic cannabinoids in biological samples Blood (serum): up to date, quantitative results -> clinical evaluation invasive Hair: retrospective evaluation, contamination (?) Oral fluid: short detection time (smoking), non-invasive

23 Analysis of urine samples: metabolites Metabolites must be analyzed in urine samples -> metabolism? Time-consuming, complex method development But: urine samples are the standard for drug tests

24 JMS (1) 54 65

25 Metabolism peculiarities O OH O N O N JWH-018 JWH-018-COOH - decarboxylation - hydroxylation OH O N HO-JWH-073

26 Metabolism peculiarities F OH O N? O N AM-2201 HO-JWH-018 After consuming products containing AM-2201, JWH-018 metabolites are also regularly detected!

27 Special chemical features O N T O N UR-144 Is currently. as the main component, biologically active?

28 Interpretation of findings Renewed consumption? - Change in substance profile - Concentration jumps in passive uptake? - Concentration level - comparison with using colleagues Which substance was consumed? JWH-018 -> HO-JWH-073 AM> HO-JWH-018 Always consider the individual case!

29 Detection window Serum day Serum conc. JWH-081 [ng / ml] 0 50 Assumed abstinence start 12 1.0 18 0.30 Serum kinetics Pseudo-1. Order 32 0.08 After a single dose of 100 mg smoke (ingredient JWH-018): Serum still positive for JWH-018 even after 24 h Detection in serum after a single dose up to a few days, after continued consumption several weeks to months

30 days after the last consumption Detection window urine 120 YWH YWH JWH

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32 designer stimulants have not yet played a major role in Germany, in some cases massive problems in other countries (e.g. UK mephedrone, Norway PMMA, Finland α-pvp) methylphenidate / ethylphenidate Popular representatives from the cathinone group: Mephedrone MDPV methylone (4- MMC) O (β-keto-mdma) O NH but e.g. also: Bupropion, Amfepramon O O N O O O NH

33 Effect of stimulants - Lead directly and / or indirectly to an increase in the neurotransmitters noradrenaline, serotonin and / or dopamine in the synaptic gap - Depending on the severity, effects similar to amphetamine, ecstasy or strong hallucinogens - In some cases extremely high potency (MDPV, N-BOMe s) or delayed onset of action / urge to refill

34 Acute toxicity stimulants Symptoms mostly similar to those after amphetamine or MDMA consumption - tachycardia, palpitations, hypertension, hyperthermia - dizziness, headache - restlessness, urge to talk - greatly enlarged pupils - aggressive behavior - anxiety states / psychoses - insomnia - seizures Additional symptoms - nausea / Vomiting (Piperazine) - Increased rate of psychiatric complications (?)

35 Risks of continuous consumption Chronic toxicity - Some representatives are potentially neurotoxic (damage to the nerve cells in the brain) Dependency potential - Low for hallucinogens and entactogens, for pure stimulants with strong dopaminergic components and short duration of action, e.g. Partly very high (see methamphetamine)

36 Detection of stimulants - LC-MS / MS - Urine examination matrix well suited (serum for clinical questions) - Constant updating required (high dynamic) - Problematic immunoassays (structural diversity)

37 designer benzodiazepines

38 designer benzodiazepines

39 designer benzodiazepines

40 Risks of benzodiazepines - Acute toxicity without consumption of other centrally depressant substances (opiates / opioids!) Relatively low - Long duration of action (road traffic) - Danger of accumulation (metabolism, slow elimination) - High potential for dependence -> Analytically via immunoassay possibly positive, but negative opioids for target analysis also available (O-Desmethyltramadol, AH-7921)

41 Conclusions - Synthetic cannabinoids are often used as an undetectable, apparently legal alternative to cannabis (rapid tests unsuitable, high availability) - SC are more dangerous than cannabis (first-time users, high-dose users) High market dynamics - New stimulants so far rather rare in Germany, but on the rise - The use of analytical methods has a preventive effect, but they must be up to date - Systematic market monitoring and rapid adaptation of the methods is essential but very time-consuming - Interpretation of findings can be difficult (low concentrations, redistribution, metabolism) - Immunochemical tests so far unsuitable for reliable detection / Exclusion of a consumption