Drugs in traffic: Forensic analytical aspects Kristian Linnet Section of Forensic Chemistry Dept. of Forensic Medicine University of Copenhagen 2015 From FDM s member journal Motor, 1971 Early study on cannabis and driving performance a Danish input Narkometret KØBENHAVNS skræmmer UNIVERSITET kunderne væk RETSMEDICINSK fra Christiania INSTITUT RETSKEMISK AFDELING 30. Dec. 2012 kl. 08:10 Jyllandsposten Narkometret skræmmer kunderne væk fra Christiania Rafaelsen OJ et al. Cannabis and alcohol: effects on simulated car driving. Science 1973; 179: 920-3. Car simulator study with comparison of effects of cannabis and alcohol Impairment effects in both cases: increased time to brake and start. Dose effect of cannabis (oral doses 8, 12 and 16 mg THC). Alcohol increased while cannabis decreased the number of gear changes Siden slutningen af september og frem til den 10. december har Færdselspolitiet sigtet 15 for at køre, mens de var påvirket af stoffer, mens Task Force Pusherstreet har sigtet 166 på og omkring Christiania. Billedet her er fra en tidligere razzia. 181 bilister er siden Københavns Politi tog to narkometre i brug i slutningen af september og frem til den 10. december 2012 blevet sigtet for at køre påvirket. Police criteria for deciding on taking a blood sample Dräger narcometer : Immunochemistry rapid test system for saliva samples tentative screening for most frequent drug types (cannabis, benzodiazepines, amfetamines, cocaine, opiates, methadone) Traffic case circumstances Inspection of the eyes: Pupilassessment Rapid tests on saliva ( narcometer ) 40 positive by Draeger 39 exceeded Danish legal limit (+50% = 1.5 ng/g) 1
Case flow in traffic case Screening, or single compound investigation (THC) Quantification Over/under fixed limit+50% Chain of custody for analysis of blood samples Reception, bar code labeling Laboratory Information System (LIMS) system with online attached sample-handling robots and analytical instruments Duplicate analyses Accreditation (ISO 17025) Forensic report Identificering og kvantificering ved væskekromatografi-tandem-massespektrometri (LC-MS/MS) Automated sample preparation Forbehandling af prøven Separation på analysekolonne Renset ekstrakt Eksempel på generel screeningsmetode: UHPLC-TOF- MS UHPLC: Ultra-high pressure liquid chromatography (ultra-højtryksvæskekromatografi) UHPLC-TOF-MS Stoffer separeres på analysekolonne TOF: Time- of flight (tid om at flyve) MS: Massespektrometri TOFmassedetektor enhed 2
Forensic analysis Are compounds identified with certainty? A mass spectrum is popularily expressed as a fingerprint of a compound Are compounds measured precisely? All measurements are subject to measurement uncertainty Eksempel på massespektrum: ecstasy (MDMA: 3,4- methylendioxymethamphetamine) 13 Measurement uncertainty Common measurement uncertainty corresponds to relative standard deviation (CV%) of 5-15% (single) or 3.5 10% (duplicate) 50% addition to fixed limit corresponds typically to 4-5 times standard deviation and so negligible probability of measurement exceeding the limit given a true value below the limit Legal approaches to curb drugged driving Assessment of degree of impairment by psychomotor tests (police or medical doctor) and drug measurement Fixed concentration limit in blood for psychoactive compounds ( bagatelgrænse ) After revision of traffic legislation pr. 1/7-2007 Fixed limit ( Bagatelgrænse )-principle ($54 stk. 1): Forbidden to have psychoactive compounds in blood over a fixed limit The legislation comprises all compounds according to Doc. 749 (euphoriant drugs) in the Danish law (with some exceptions) Still legal to have prescribed drugs, in which case a clinical evaluation and drug measurement are performed and evaluation by Retslægerådet ($54 stk. 2) Fixed limits Principle of estimation in DK Limits which typically indicate actual (within hours) use (and impairment) and which distinguish from trace amounts from earlier intake In practice limits set to lower limits of published therapeutic interval limits for psychoactive effect when defined or limits of measurable pharmacological effect Limits set by the Ministry of Justice 3
Euphoriant compounds in DK Examples of limits for drugs of abuse in blood in DK (Bek 901, 2011) (50% added to bagatelgrænse for allowance of analytical variation) Several hundreds explicitly named compounds (illegal and medicinal) Additionally, a general ban against 4 chemical drug groups: Cannabinoids (7 subgroups) Cathinones Tryptamines Phenetylamines Any new derivative within these groups is automatically forbidden Compound acc. to bekendtgørelse nr. 749 about euforiserende stoffer (list A, B, D og E; C exceptet) Active component Liste A Bagatelgrænse (mg. pr. kg. blod) Cannabis THC 0,001 Diacetylmorphin (heroin) Morphin 0,010 Lysergid (LSD) 0,0005 Præpareret opium Morphin 0,010 Planten Papaver somnifer L. Morphin 0,010 Liste B Amfetamin 0,020 Cocain 0,020 Dextromoramid 0,075 Dextropropoxyphen 0,050 Fentanyl 0,001 Hydrocodon 0,010 Hydromorphon 0,010 Ketobemidon 0,025 Kokablad Cocain 0,020 MBDB 0,020 MDMA 0,020 Metamfetamin 0,020 Methadon 0,050 Methylphenidat 0,010 Morphin 0,010 Opium Morphin 0,010 Oxycodon 0,010 Oxymorphon 0,010 Pethidin 0,10 PMA 0,020 PMMA 0,020 Tetrahydrocannabinol (THC) 0,001 Liste C Codein, dextromethorphan, ethylmorphin, pholcodin, dihydrocodein: not included (tramadol not on the list so it is also exceptet) Liste D Buprenorphin 0,0005 Flunitrazepam 0,005 Pentazocin 0,010 Pentobarbital 1,0 Liste E Alprazolam 0,005 Amfepramon 0,003 Barbital 5,0 Bromazepam 0,050 Brotizolam 0,002 Chlordiazepoxid 0,40 Clobazam 0,10 Clonazepam 0,005 Diazepam 0,020 Estazolam 0,050 Lorazepam 0,020 Lormetazepam 0,005 Meprobamat 5,0 Midazolam 0,050 Nitrazepam 0,020 Nordazepam 0,020 Oxazepam 0,20 Phenobarbital 10 Phentermin 0,030 Temazepam 0,020 Triazolam 0,002 Zolpidem 0,080 Zopiclon 0,010 New drugs 3 i Bekendtgørelse 655, 19. juni, 2007: en ubetydelig restmængde 4
Kokainbrug stigende seneste år Flere unge tager hestebedøvelse 18. nov. 2010 17.50 Indland En ud af ti unge natklubgæster og hver tredje af kokainbrugere har taget stoffet, ketamin, som benyttes til at bedøve heste. Det viser en undersøgelse, som Rockwoolfonden står bag. - Det var ret overraskende. Vi havde slet ikke regnet med, at det var så udbredt, siger Jacob Demand, der er en af forskerne bag undersøgelsen. Designer Drugs Derivater af Phenethylamin Bromo-dragonFLY Seneste: Frimærke drugs NBOMe stoffer 3/10-15: Elektronisk fest i København (Elements)endte galt: Ni ambulancer kørte gæster på hospitalet efter overdoser (GHB, ketamin) MDMA (Ecstasy) Methylenedioxymethamphethamin 2C-I Methylon Cathinon (Khat) Påvirkning af Serotonin (5-HT), dopamin og Norepinephrine receptor systemerne. Hallucinogen effekt ved agonisering af 5-HT 2A og 5-HT 2C receptor subunits. Example of new drug group: synthetic cannabis ( Spice products ) Series of compounds stimulating cannabis-receptors (CB1 og CB2) Often potent and may lead to intoxications treated in emergency departments Example of concentration curve for a drug of abuse (cocaine) Annihilation 27 Plasma concentrations of cocaine. (Drummer OH. The forensic pharmacology of drugs of abuse, Arnold, 2001, p. 67). (B/P ratio 1) Fixed legal limit: 10 ng/g Example of concentration curve for a drug of abuse (cannabis, THC) Cannabis (THC) cut-off (bagatelgrænse) Limits in European countries: 0.0003 mg/kg (or L): Sweden, Slovenia Plasma* (ng/ml) 0.001 mg/kg: Germany *, Denmark**, Belgium, Norway 0.0015 mg/kg: Switzerland 0.002 mg/kg: UK 0.003 mg/kg: Portugal, Holland Typical relation after smoking of 15 mg cannabis cigarette (Drummer OH. The forensic pharmacology of drugs of abuse, Arnold, 2001, p. 184). (* B/P-konc = 0.5) Fixed legal limit: 1 ng/g in blood Relation between concentrations and effects of cannabis after smoking (from Drummer) * 0.001 mg/kg plasma = 0.0005 mg/kg blood; ** +50% (0.001 mg/kg = 1 ng/g = 1 x 10-9 g/g) 5
Special problems concerning THC Chronic, heavy use may in some cases be associated with prolonged presence of THC in blood at low concentrations Passive smoking problem? (Röhrich J et al. J Analyt Toxicol 2010; 34: 196-203) Traffic-drug cases other than alcohol in Denmark 1995-2003 2007 2008 2009 2011 2012 New legislation: Fixed limits Traffic cases 221-236 1150 ca 2000 2500 ca 3300 investigated for other drugs than alcohol Positive 80% - 90% ca 75% Cannabis (THC), benzodiazepines, amphetamine and cocaine most frequently detected above limit 2014-15 East-DK: 2529 cases, 1916 (75%) at least one result exceeding the legal limit +50% THC blood concentration distribution 2014-2015 THC 1407/1673 (84%) Cocaine 309/397 (78%) Benzodiazepines 193/350 (55%) Amphetamine 188/228 (82%) Morphine (heroin) 62/88 (70%) GHB (liquid ecstasy) 71/82 (87%) Ecstasy 55/63 (87%) 95% of cases are male drivers mg/kg Distribution of THC results in cases with THC suspected driving (1187 cases with values exceeding zero out of 1315 cases; 1029 (78%) exceeding the fixed limit 0.0015). Median value 0.0051 mg/kg Traffic accidents In EU-area: 35 000 killed each year and several times more seriously injured Among young people the most important cause of death In Denmark a little over 200 killed each year Alcohol regarded as responsible for about 10 000 deaths in EU Drugs? Consequences of drugged driving Epidemiological surveys Aims at quantifying relative risk of accidents in drugged state by comparison of frequencies of drugged driving in accidents and under ordinary driving Experimental studies Real driving or simulated driving experiments under increasing drug doses 5/10-15 Sag i Jylland: 32-årig skal to et halvt år i fængsel for trafikdrab Familiefar mistede livet sidste år, da en mand under påvirkning af amfetamin tørnede ind i ham med en varebil. 6
Drugged driving how frequent? At unselected roadside-screens 1-5% of drivers are positive for psychoactive drugs/compounds Danish study of 1000 drivers: 1,3% positive for illegal compound (cannabis most frequent) and 0.7% positive for benzodiazepines Of 7.5-25% of accidents requiring hospitalisation the drivers are positive for psychoactive drugs/compounds, many in combination with alcohol Danish study: 8% 37 Alkohol > 0.8 prom. + stoffer Alkohol < 0.8 prom. + stoffer 7 Benzodiazepiner + morfin Morfin Benzodiazepiner Alkohol > 1.3 prom. Alkohol 0.8-1.3 prom. Alkohol 0.5 0.8 prom. Gruppe 9 8 6 5 4 3 2 1 0 Relative risik of traffic accident for drivers under influence of alcohol, drugs or a combination of both 0 20 40 60 80 100 120 140 160 180 200 Odds ratio Assum T et al. The prevalence of drug driving and relative risk estimations. Immortal report D-R4.2, 2005. (EU-study) 38 EU-traffic projects Several projects undertaken over the years Latest project: 2006-2012: DRUID project concerning road side saliva testing etc. in cooperation with the Institute of Transport Research, DTU 3000 saliva samples and 1000 blood samples analysed in Denmark Relative risk estimates derived Results of recent EU-project: Driving under the influence of drugs, alcohol and medicines (DRUID) Based on about 20 000 control samples and 3500 case samples Hels T et al. (2012): Risk of injury by driving with alcohol and other drugs. DRUID 6th framework programme deliverable D2.3.5 39 Picture: DTU Danish results in Druid study 3000 oral fluid cases: 0.5% positive for ethanol (>0.5 g/kg), medicinal drugs over fixed limit 0.4% and 0.3% illicit drugs, total 0.7% using DRUID conversion factors for OF/B. Simonsen et al. Presence of psychoactive substances in oral fluid from randomly selected drivers in Denmark. Forensic Sci Int 2012; 221:33-38 840 seriously injured drivers (blood): 24% with alcohol and/or drugs exceeding the legal limits: 18% positive for ethanol, medicinal drugs 6.8% and illicit drugs 4.9%, Simonsen et al. Psychoactive substances in seriously injured drivers in Denmark. Forensic Sci Int 2013; 222:44-50. Experimental traffic studies Dose dependent influence on vigilance, reaction time, ability to drive straight etc for drugs with sedative effects, e.g. benzodiazepines, strong analgesics and some psychotropic drugs Dose dependent effects of illegal drugs such as THC Less clearcut effects of stimulant drugs as amphetamine, cocaine etc. (actually, amphetamine has been used to prevent sleepiness of drivers and pilots in the US air force) 7
Future development Number of new drugs ever increasing Increasing recreative use of drugs Jyllandsposten, 2007 Politiken, 2010 8