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Investigating drugs of abuse at autopsy
MINI-SYMPOSIUM: AUTOPSY PATHOLOGY
Investigating drugs of abuse at autopsy
Amphetamines Amphetamine itself and related compounds are part of the phenethylamine class of compounds. This class also includes methamphetamine, MDMA and some “designer drugs” such as PMMA (para-methoxymethylamphetamine) and PMA (paramethoxyamphetamine) amongst many others. Amphetamine and methamphetamine in particular are potent central nervous system stimulant drugs which are widely abused for their euphoric effects and psychoactive properties.2 Concentrations of amphetamines in post-mortem blood can be difficult to interpret, particularly due to the overlap (largely through tolerance and differential abuse situations) between those found in non-fatal cases and those found in cases where the drug may be implicated.3 Death from amphetamine toxicity following an acute excessive dose may not occur immediately but after several hours during which time the individual may experience tachycardia, hypertension, hyperthermia, convulsions, unconsciousness and respiratory and cardiac failure.3 In this situation, the blood concentration at the time of death may have decreased significantly. Myocardial infarction and cerebral haemorrhage have also occurred in some abusers. Findings at the post-mortem examination may include organ congestion and haemorrhaging. MDMA (3,4-methylenedioxymethylamphetamine), also known by the street names ‘Ecstasy’, ‘E’ and ‘XTC’) and its metabolite, 3,4-methylenedioxyamphetamine (MDA) are amphetamine-derived compounds. MDA is a metabolite of MDMA, but may also be present in “Ecstasy” tablets itself. Adverse effects from MDMA can include various clinical symptoms such as visual hallucinations, confusion, agitation, sweating, coma and cardiotoxic effects such as tachycardia, hypotension, myocardial infarctions and in some cases arterial spasm.4 Other common toxic symptoms include hyponatraemia (usually due to excessive water intake) and/or hyperpyrexia; leading to secondary features such as cerebral oedema, seizures, organ damage and ultimately death. Of some note and consideration for amphetamines, is that methamphetamine is a known metabolite of the anti-parkinson’s drug selegiline, therefore the prescription history of the deceased is important. Also some amphetamines (e.g. PMA, PMMA and 4methylthioamphetamine) have a pronounced delayed effect which can result in unintended excessive ingestion.3 Finally, it should be noted that phenyl-2-ethylamine is a common putrefactive compound that is also obviously a phenethylamine, which can create potential “false positive” situations with laboratory presumptive immunoassays for amphetamine(s) that may cross-react with its presence, requiring confirmation using more specific techniques.
Simon Elliott
Abstract Post-mortem toxicology is an important diagnostic part of the investigative process, not least when drugs of abuse are suspected, some of which require special attention. This review summarises key information regarding current common drugs of abuse, including amphetamines, benzodiazepines, cannabis, cocaine, ketamine, pregabalin as well as new psychoactive substances (NPS). The importance of sufficient and appropriate information (such as case circumstances and drug history) in addition to scene evidence and other considerations (including analytical and sampling factors) are presented that are relevant to the interpretation of results and the pathological process.
Keywords amphetamines; autopsy; benzodiazepines; cannabis; cocaine; ketamine; NPS; opiates; pregabalin; toxicology
Introduction There are two primary issues relating to the investigation of drugs of abuse at autopsy. Firstly, as with any drug, evidence of drug use may not be immediately apparent aside from any needle marks from intravenous administration or presence of tablets/ material in the stomach. Secondly, the nature of drugs of abuse is continually changing and does not necessarily constitute “classical” drugs of abuse such as heroin, cocaine, MDMA and other amphetamines.1 In the last decade or so, whether it be the increased use of gamma-hydroxybutyrate (GHB) followed by socalled “legal highs”, there have been many hundreds of new compounds that have been abused, also notwithstanding increases in the abuse of some prescription drugs (e.g. pregabalin, gabapentin and opioids such as oxycodone and fentanyl). Of particular note are the so-called “legal highs” (as were) which have invariably been synthesised to mimic the effects of controlled drugs but following legislative changes these are either controlled under the Misuse of Drugs Act 1971 or the more controversial Psychoactive Substances Act 2016. As such, in the UK and around the world these compounds are referred to as “novel or new psychoactive substances” (NPS). Having first entered drug markets via accessible websites, “head shops” in the street or some market stalls, access is now more restricted to less accessible websites (e.g. the so-called “dark web”) or other purveyors of illicit drugs. This article will describe the necessary considerations for “classical” drugs of abuse as well as more recent NPS and other drug oddities that may be encountered at autopsy.
Cocaine Cocaine is a drug abused primarily for its central nervous system stimulant effects. These effects include increased energy and alertness, excitement, euphoria, increased confidence and increased talkativeness. In addition, the use of cocaine may be associated with increased risk taking behaviour and aggression. In high doses, the effects of cocaine use may also include paranoia, bizarre and violent behaviour, hyperactivity and restlessness. Once the stimulant effects of cocaine subside, the user may experience “come-down” effects such as low mood, depression,
Simon Elliott PhD BSc, Consultant Forensic Toxicologist, Alere Forensics, Malvern Hills Science Park, Malvern, UK. Conflicts of interest: none declared.
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Elliott S, Investigating drugs of abuse at autopsy, Diagnostic Histopathology (2018), https://doi.org/10.1016/ j.mpdhp.2018.08.001
MINI-SYMPOSIUM: AUTOPSY PATHOLOGY
diamorphine), however it is not possible to completely exclude additional morphine use. As codeine is metabolised to morphine, it is also important to monitor the relative concentration of codeine versus morphine. Additional analytical merit can be the relative concentration ratios of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).11 Nevertheless, as in all cases involving opiate/opioid drugs, the toxicological significance of any morphine concentration will depend upon the degree of tolerance possessed by the deceased. Therefore, knowledge of an individual’s drug history regarding opiate and opioid drugs is very important. It is important to note that tolerance can be gained within a few days of repeated use, conversely, infrequent use or periods of abstinence can result in loss of tolerance with a naı¨ve user having little to no tolerance. The major risk to life from opiates and opioids is their depressant effect on the central nervous system (CNS), notably causing respiratory depression. The use of other CNS depressant drugs (e.g. benzodiazepines, barbiturates, etc) or alcohol that may exacerbate the CNS effects will reduce the threshold to which an individual would succumb to fatal toxicity so concomitant drug use should be a consideration in such cases, as well as positional asphyxiation in appropriate circumstances. Of some note and consideration for opioids, is the recent phenomenon of fentanyl and fentanyl analogue abuse as well as other synthetic opioids (e.g. AH-7921 and U-47700) within the wider “new psychoactive substance” phenomenon. In the last few years in the UK (and particularly Canada and the USA), use of fentanils has increased significantly and pose a particular danger to users due to their high potency, even when compared to morphine and heroin.12 Although fentanyl and its derivatives/ analogues (fentanils) have been controlled in the UK for over 30 years, they emerged on the NPS market over the last 5 years or so, typically available as white or coloured powders. More recently, there have been reports and instances of their presence in illicit heroin in particular as an adulterant or replacement as well as in fake medicines. These modes of use present both intended and unintended user consumption and exposure. Care should be taken if any suspected powders are submitted or found with decedents.
anxiety and irritability. A relatively small number of deaths due to acute cocaine toxicity are seen considering its wide use; however cardiotoxicity has been implicated as a major contributory factor in cocaine induced deaths resulting in symptoms including myocardial infarction, ventricular tachycardia and fibrillation, cerebrovascular accident and pulmonary dysfunction.5 There is also evidence that cocaine use accelerates atherosclerosis and other vascular disease issues.6 Convulsions have also been reported when the drug is used excessively. If cocaine is taken whilst there is ethanol in the bloodstream, an interaction takes place to form cocaethylene.7 Therefore, the presence of cocaethylene may be evident in post-mortem blood and/or urine and can demonstrate that the deceased had used cocaine whilst there was ethanol in the blood stream. Cocaethylene can prolong the stimulant effects of cocaine and eases its comedown effects. Of some note and consideration for cocaine, is that cocaine is quickly metabolised and being unstable also breaks down to form benzoylecgonine (BZE) and ecgonine methylester (EME). Therefore, cocaine concentrations in post-mortem blood may not reflect those at the time of death. An additional consideration for cocaine investigations is that as the illicit drug product is often adulterated with other drugs that may or may not present additional toxicity. Typical adulterants include levamisole, lignocaine, benzocaine and phenacetin.
Opiates/opioids An opiate can be described as a compound found naturally in the opium poppy (e.g. morphine, noscapine, thebaine, papaverine, codeine) whereas an opioid is a synthetic compound, synthesised to provide opiate-like effects (e.g. heroin, dihydrocodeine, methadone, oxycodone, tramadol, fentanyl). Methadone is an opioid drug which can be used for pain relief in some circumstances but is more commonly used as replacement therapy for heroin addiction/withdrawal. Opiates and other opioids are predominantly prescribed for pain relief (usually moderate to severe), both in the short-term and long-term. The concentrations of opiates and opioids found in blood during therapy are very variable and there is a significant overlap between concentrations found in acute fatal poisonings and concentrations obtained therapeutically. Therefore, the toxicological significance of a measured post-mortem blood concentration will depend upon the degree of tolerance possessed by the deceased.8 The majority of opioids are also prone to post-mortem redistribution and therefore may be artificially elevated after death depending on the site and manner of blood sampling as well as the length of the post-mortem interval. Fentanyl is highly prone to this and particular attention should be placed on the presence, site and number of any fentanyl patches on a body (especially in comparison to any prescribed dose regimen).9 It should also be noted that fentanyl release/delivery from transdermal patches can accelerate with heat and patients are warned of this, with some case evidence of this even occurring after a prolonged hot bath.10 For heroin (diacetylmorphine), the presence of 6monoacetylmorphine (6-MAM, a specific diacetylmorphine metabolite) as well as codeine, noscapine and papaverine will provide analytical evidence of heroin use (rather than medical
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Ketamine Ketamine is a dissociative anaesthetic drug used in human and veterinary medicine. However, due to the production of hallucinogenic effects, ketamine has also gained popularity as a drug of abuse. The toxicity of ketamine is known to be dosedependent with deaths resulting from direct acute ketamine ingestion being very rare with a significant overlap between the therapeutic or recreational concentrations and those detected in fatalities.13 Low doses of ketamine can produce drowsiness and perceptual distortions, whereas higher doses can produce euphoria, hallucinations and feelings of alternate consciousness. Adverse effects of ketamine may include anxiety, tachycardia, cardiac arrhythmia, dizziness, vomiting, seizures, delirium, paranoia and potentially respiratory depression.13 In recent years, there has been an observation of increased bladder problems with ketamine users, especially chronic high dose users.14 This can result in reduction in bladder size, development of
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Please cite this article in press as: Elliott S, Investigating drugs of abuse at autopsy, Diagnostic Histopathology (2018), https://doi.org/10.1016/ j.mpdhp.2018.08.001
MINI-SYMPOSIUM: AUTOPSY PATHOLOGY
metabolite. Following the use of cannabis, THC and its active metabolite 11-OH-THC are rapidly eliminated from the blood and may only be detectable for a few hours following occasional use. However, cannabinoids are distributed into the fatty tissues of the body and slowly released over time and in regular and/or heavy users of cannabis it may be possible to detect cannabinoids in the blood for days or possibly even weeks following its last use.17 The effects of cannabis are variable but include euphoria, relaxation, laughter, talkativeness, distortion in the perception of space and time, slowed reaction times, reduced coordination and drowsiness. Some studies have suggested that long-term heavy cannabis use can increase the risk of developing psychosis, particularly in those with a predisposition to or history of mental health problems.18 There are also some concerns over the potential cardiotoxicity of the drug, especially from chronic use but this is a controversial aspect of the scientific literature relating to cannabis although the evidence base is growing, especially in relation to more recent high purity THC cannabis extracts/concentrates (e.g. “Butane Hash Oil”).19
fibrosis, ulcers on the urothelium’s surface and inner layers, and obstruction of the ureter. Of some note and consideration for ketamine is its use in human medicine, especially in emergency situations such as road traffic incidents for stabilising patients prior to hospital transport or in situ treatment. Consequently, the circumstances of death is important in determining the provenance and significance of any ketamine if detected in post-mortem situations.
Benzodiazepines Benzodiazepines have been used for anxiety, insomnia and sedation for decades and can also be prescribed in the treatment of drug and alcohol withdrawal. They have equally been subject to abuse. They can cause light-headedness, drowsiness and reduced co-ordination and can produce or contribute to CNS depression. Whilst it is likely that persons taking a benzodiazepine regularly will develop some tolerance to the effects of the drug, concomitant use of other CNS depressant drugs and especially alcohol can increase the risk and severity of sedation and potential respiratory depression. A current particular issue is the adulteration of illicit heroin with potent benzodiazepines (such as alprazolam) which have also appeared in fake benzodiazepine tablets.15 Benzodiazepines are typically eliminated from the body over an extended period of time and due to this and the potential significant tolerance that can be acquired, post-mortem blood concentrations need to be interpreted in the context of other drugs being used and the drug/prescription history of the deceased. Of some note and consideration for benzodiazepines is that some benzodiazepines (designed or otherwise) have appeared in the NPS market and pose risks to the user in terms of not knowing the drug being ingested as well as the dose and potency.15
New psychoactive substances (NPS) Whilst there is no definitive definition, an NPS could be considered to be a recently encountered psychoactive substance that often mimics the effects of a substance that is under drug control (international or otherwise) but could have been developed many years previously. Because of this, NPS can encompass many drugs that produce effects similar to “classical” drugs of abuse and around 800 NPS have been recorded as of 2018.20,21 They are invariably made available or sold via the Internet or previously in so-called ‘Head Shops’ using product terms such as “research chemicals”, “bath salts”, “plant food” or “herbal incense”. They exist as powders, pellets, tablets, liquids or herbal material and may be labelled as “Not For Human Consumption” and with potential branding that should not be relied upon to be consistent or relatable to the exact constituents (especially geographically or with time). Despite the wide range of compound types, they are generally stimulant, sedating/CNS depressant or hallucinatory in nature producing cardiotoxicity, respiratory depression or accidental injury, respectively as their major risks.22 However, specific dangers associated with their use include; (i) the constituent compound may not be correct or known to the user, (ii) unknown dosage and (iii) production of bizarre behaviour and aggression that affects the wider public and users driving under the influence of NPS. Currently, the three most common types of NPS are cathinones, synthetic cannabinoids and benzodiazepines but the synthetic opioids are of particular concern due to their nature and potency.23 If there is no scene evidence, no specific drug history or no obvious indication of new psychoactive drug use, it is important to be aware of the possible signs and symptoms, particularly in relation to available case circumstances. Within the case history or any documented clinical presentation there may be euphoria (stimulants), confusion (hallucinogens, sedatives), disinhibition (stimulants, sedatives), hallucinations (stimulants, hallucinogens), unsteadiness (hallucinogens, sedatives), hyperthermia (stimulants), vomiting (stimulants, hallucinogens, sedatives), cardiac effects (stimulants, hallucinogens), drowsiness (sedatives), odd behaviour (stimulants, hallucinogens), coma
Pregabalin Pregabalin is typically used in the treatment of epilepsy, pain and generalised anxiety disorder but is also abused at high doses for its euphoric effects, often along with opiates and opioids. Although pregabalin is not considered to be an especially toxic drug, somnolence, tachycardia and hypertonicity are effects that have been reported in instances of overdose. Due to its chemical similarity to GABA, pregabalin may exacerbate the effects of alcohol and other drugs such as benzodiazepines and opiates/ opioids. Furthermore, due to the presence of other drugs (especially opiates/opioids) in pregabalin cases it is often difficult to determine the significance of pregabalin as a causal factor, however, fatalities have been reported and studies have indicated that post-mortem blood concentrations greater than 25 mg/ L may be toxicologically significant.16
Cannabis Cannabis contains a number of cannabinoids (naturally occurring compounds in the plant). The main pharmacologically active cannabinoid of cannabis is delta-9-tetrahydrocannabinol (THC). THC is metabolised rapidly to form 11-hydroxy-THC (11-OH-THC), which is an active metabolite, and subsequently THC-carboxylic acid (THC-COOH), which is an inactive
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Please cite this article in press as: Elliott S, Investigating drugs of abuse at autopsy, Diagnostic Histopathology (2018), https://doi.org/10.1016/ j.mpdhp.2018.08.001
MINI-SYMPOSIUM: AUTOPSY PATHOLOGY
(sedatives) and respiratory depression (sedatives).22 In determining the potential significance of NPS in a death, it is necessary to consider; a) the presence, concentration and nature of the NPS, b) the presence, concentration and nature of other drugs present (including alcohol), c) the circumstances of death and d) other pathological findings.24 Due to the wide range of NPS that exist, sufficient scientific literature may not be available, especially in relation to the complete pharmacological actions as well as pharmacokinetics (metabolism and detection windows in particular). In relation to analytical detectability, reference materials are not always available for NPS or their metabolites and some NPS (e.g. cathinones and synthetic cannabinoids) have been found to be unstable (especially in blood). Whilst scene evidence and seized items are beneficial in determining the potential use of NPS, as stated above, care must be taken when handling such products, especially if as a powder as it may be a potent synthetic cannabinoid or opioid.
obtained from a “peripheral” site such as the femoral vein using an appropriate method of sampling. Blood and urine should be obtained and placed in a fluoride-preserved and non-fluoride (i.e. “plain/unpreserved) container. The former is beneficial in reducing any post-mortem production of e.g. alcohol, whilst potentially assisting in reducing the impact of any drug instability that may be associated with some drugs of abuse (e.g. cocaine, heroin) and NPS (e.g. cathinones).27e29 The investigation of drugs of abuse (as well as other suspected or possible drugs) relies on a strong collaboration between pathological and toxicological practices that hopefully this review has highlighted.A
Practice points C
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Other considerations for the pathologist As with any investigation, the investigative strategy (including analytical toxicology) and interpretation of results and findings is reliant on appropriate and sufficient information to allow an assessment to be made within the context of the case. This includes full knowledge of the case circumstances, drug/prescription history (not just of the deceased but potentially of the wider household or acquaintances to determine accessibility to drugs) and any scene evidence that may indicate use of drugs (including description of the product(s) and if NPS, the physical nature of the substance and any labelling or packaging identification). As there is not one method or technique that can enable the toxicology laboratory to analyse for all drugs and poisons, this information can assist in forming an appropriate analytical strategy, especially as certain substances may not feature in typical standard/routine testing protocols. Such non-standard substances that may need to be highlighted to the laboratory in advance (e.g. if use is known/suspected) include GHB (“Liquid Ecstasy”), some anti-epileptics (e.g. valproate, pregabalin and gabapentin), metals (arsenic, lead, mercury), herbicides/pesticides, volatiles (butane, propane, dichloromethane), cyanide and ethylene glycol (anti-freeze). Unfortunately, the trend in more recent years to limit the scope of testing with the intention of being more cost effective, has particular consequences when in relation to NPS. Due to the large variety and chemical diversity of these substances, even if use is suspected, they pose significant challenges to analytical toxicology (and not least interpretative toxicology) and often require a combination of non-targeted (general) and targeted (specific) toxicological analyses. The former is required to ensure an appropriate coverage of potential NPS, the latter is required in order to achieve the necessary specificity and sensitivity for the detection and potential measurement of compounds present at exceptionally low concentrations in the body (blood in particular), for example, synthetic cannabinoids and fentanils.25,26 Somewhat related to this is the subsequent requirement for any toxicological request to be allowed its greatest chance of success by being provided with appropriate and sufficient specimens for analysis. In the vast majority of cases (aside from volatile substances where brain and/or lung is preferred) this is predominantly urine and blood
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evidence of drug use may not be immediately apparent or known, obtain information regarding drug history and any scene evidence the nature of drugs of abuse is continually changing and does not necessarily constitute “classical” drugs of abuse but now incorporates an evolving variety of new psychoactive substances (NPS) that could be considered to be stimulant, sedating or hallucinogenic in nature phenyl-2-ethylamine is a common putrefactive compound that can create potential “false positive” situations with laboratory presumptive immunoassays for amphetamine(s) cocaine toxicity potentially contributing to death can result from acute and chronic use the possibility of intentional or unintentional use of opioids (e.g. fentanyl and analogues) and/or benzodiazepines (e.g. alprazolam) should be considered where heroin and cocaine use may be suspected, in addition to “fake” medication products be mindful of potentially potent fentanils and other opioids constituting white powder or other seized material; take associated health and safety precautions be aware of new high purity THC extracts of cannabis (e.g. “Butane Hash Oil”) and associated potential toxicity to the user appropriate toxicological analysis requires targeted and nontargeted approaches to enable detection of a wide range of drugs, not least new psychoactive substances but some drugs require notification of suspected use to assist analytical strategies (e.g. GHB, some anticonvulsants, metals and volatile substances) post-mortem blood should be obtained from a suitably isolated peripheral anatomical site (e.g. femoral vein) and provided (along with urine) in unpreserved and fluoride-preserved sample containers
REFERENCES 1 Davies Johnston, Holt, eds. Forensic toxicology: drug use and misuse. UK: Royal Society of Chemistry, 2016. 2 Paratz ED, Cunningham NJ, MacIsaac AI. The cardiac complications of methamphetamines. Heart Lung Circ 2016; 25: 325e32. 3 De Letter EA, Piette MH, Lambert WE, Cordonnier JA. Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976-2004. Med Sci Law 2006; 46: 37e65.
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4 Michael White C. How MDMA’s pharmacology and pharmacokinetics drive desired effects and harms. J Clin Pharmacol 2014; 54: 245e52. 5 Turillazzi E, Bello S, Neri M, Pomara C, Riezzo I, Fineschi V. Cardiovascular effects of cocaine: cellular, ionic and molecular mechanisms. Curr Med Chem 2012; 19: 5664e76. 6 Bachi K, Mani V, Jeyachandran D, Fayad ZA, Goldstein RZ, AliaKlein N. Vascular disease in cocaine addiction. Atherosclerosis 2017; 262: 154e62. 7 Andrews P. Cocaethylene toxicity. J Addict Dis 1997; 16: 75e84. 8 Jones AW, Holmgren A, Ahlner J. Concentrations of freemorphine in peripheral blood after recent use of heroin in overdose deaths and in apprehended drivers. Forensic Sci Int 2012; 215: 18e24. 9 Gill JR, Lin PT, Nelson L. Reliability of postmortem fentanyl concentrations in determining the cause of death. J Med Toxicol 2013; 9: 34e41. 10 Prodduturi S, Sadrieh N, Wokovich AM, Doub WH, Westenberger BJ, Buhse L. Transdermal delivery of fentanyl from matrix and reservoir systems: effect of heat and compromised skin. J Pharm Sci 2010; 99: 2357e66. 11 Taylor K, Elliott S. A validated hybrid quadrupole linear ion-trap LC-MS method for the analysis of morphine and morphine glucuronides applied to opiate deaths. Forensic Sci Int 2009; 187: 34e41. FP. Acute 12 Pichini S, Solimini R, Berretta P, Pacifici R, Busardo intoxications and fatalities from illicit fentanyl and analogues: an update. Ther Drug Monit 2018; 40: 38e51. 13 Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract 2014; 27: 582e6. 14 Myers FA, Bluth MH, Cheung WW. Ketamine: a cause of urinary tract dysfunction. Clin Lab Med 2016; 36: 721e44. 15 United Nations Office on Drugs and Crime (UNODC). Non-medical use of benzodiazepines: a growing threat to public health? https:// www.unodc.org/documents/scientific/Global_SMART_Update_ 2017_Vol_18.pdf (accessed August 2018). 16 Elliott SP, Burke T, Smith C. Determining the toxicological significance of pregabalin in fatalities. J Forensic Sci 2017; 62: 169e73.
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17 Karschner EL, Swortwood MJ, Hirvonen J, et al. Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance. Drug Test Anal 2016; 8: 682e9. A, Ferna ndez-Expo sito M, Berge D, et al. Relationship be18 Mane tween cannabis and psychosis: reasons for use and associated clinical variables. Psychiatry Res 2015; 229: 70e4. 19 Alzghari SK, Fung V, Rickner SS, Chacko L, Fleming SW. To dab or not to dab: rising concerns regarding the toxicity of cannabis concentrates. Cureus 2017; 9: e1676. 20 UNODC. https://www.unodc.org/LSS/Announcement/Details/ 2935a8a7-434b-4abf-baa3-e1481ca5e209 (accessed August 2018). 21 UNODC. https://www.unodc.org/LSS/Attachment/Download/ 39fbc807-03c0-4e24-a208-b9d3ba8695d9 (accessed August 2018). 22 Elliott S. In: Johnston Davies, Holt, eds. “Mephedrone and New Psychoactive Substances” in forensic toxicology: drug use and misuse. UK: Royal Society of Chemistry, 2016; 94e126. 23 European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European drug report. 2018. EMCDDA, http://www. emcdda.europa.eu/edr2018_en. (accessed August 2018). 24 Elliott S, Sedefov R, Evans-Brown M. Assessing the toxicological significance of new psychoactive substances in fatalities. Drug Test Anal 2018; 10: 120e6. 25 Presley BC, Gurney SM, Scott KS, Kacinko SL, Logan BK. Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues. Forensic Sci Rev 2016; 28: 103e69. 26 Gerace E, Salomone A, Vincenti M. Analytical approaches in fatal intoxication cases involving new synthetic opioids. Curr Pharm Biotechnol 2018; 19: 113e23. 27 Giorgi SN, Meeker JE. A 5-year stability study of common illicit drugs in blood. J Anal Toxicol 1995; 19: 392e8. 28 Papoutsis I, Nikolaou P, Pistos C, et al. Stability of morphine, codeine, and 6-acetylmorphine in blood at different sampling and storage conditions. J Forensic Sci 2014; 59: 550e4. FP, Kyriakou C, Tittarelli R, et al. Assessment of the 29 Busardo stability of mephedrone in ante-mortem and post-mortem blood specimens. Forensic Sci Int 2015; 256: 28e37.
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Investigating drugs of abuse at autopsy
Amphetamines Amphetamine itself and related compounds are part of the phenethylamine class of compounds. This class also includes methamphetamine, MDMA and some “designer drugs” such as PMMA (para-methoxymethylamphetamine) and PMA (paramethoxyamphetamine) amongst many others. Amphetamine and methamphetamine in particular are potent central nervous system stimulant drugs which are widely abused for their euphoric effects and psychoactive properties.2 Concentrations of amphetamines in post-mortem blood can be difficult to interpret, particularly due to the overlap (largely through tolerance and differential abuse situations) between those found in non-fatal cases and those found in cases where the drug may be implicated.3 Death from amphetamine toxicity following an acute excessive dose may not occur immediately but after several hours during which time the individual may experience tachycardia, hypertension, hyperthermia, convulsions, unconsciousness and respiratory and cardiac failure.3 In this situation, the blood concentration at the time of death may have decreased significantly. Myocardial infarction and cerebral haemorrhage have also occurred in some abusers. Findings at the post-mortem examination may include organ congestion and haemorrhaging. MDMA (3,4-methylenedioxymethylamphetamine), also known by the street names ‘Ecstasy’, ‘E’ and ‘XTC’) and its metabolite, 3,4-methylenedioxyamphetamine (MDA) are amphetamine-derived compounds. MDA is a metabolite of MDMA, but may also be present in “Ecstasy” tablets itself. Adverse effects from MDMA can include various clinical symptoms such as visual hallucinations, confusion, agitation, sweating, coma and cardiotoxic effects such as tachycardia, hypotension, myocardial infarctions and in some cases arterial spasm.4 Other common toxic symptoms include hyponatraemia (usually due to excessive water intake) and/or hyperpyrexia; leading to secondary features such as cerebral oedema, seizures, organ damage and ultimately death. Of some note and consideration for amphetamines, is that methamphetamine is a known metabolite of the anti-parkinson’s drug selegiline, therefore the prescription history of the deceased is important. Also some amphetamines (e.g. PMA, PMMA and 4methylthioamphetamine) have a pronounced delayed effect which can result in unintended excessive ingestion.3 Finally, it should be noted that phenyl-2-ethylamine is a common putrefactive compound that is also obviously a phenethylamine, which can create potential “false positive” situations with laboratory presumptive immunoassays for amphetamine(s) that may cross-react with its presence, requiring confirmation using more specific techniques.
Simon Elliott
Abstract Post-mortem toxicology is an important diagnostic part of the investigative process, not least when drugs of abuse are suspected, some of which require special attention. This review summarises key information regarding current common drugs of abuse, including amphetamines, benzodiazepines, cannabis, cocaine, ketamine, pregabalin as well as new psychoactive substances (NPS). The importance of sufficient and appropriate information (such as case circumstances and drug history) in addition to scene evidence and other considerations (including analytical and sampling factors) are presented that are relevant to the interpretation of results and the pathological process.
Keywords amphetamines; autopsy; benzodiazepines; cannabis; cocaine; ketamine; NPS; opiates; pregabalin; toxicology
Introduction There are two primary issues relating to the investigation of drugs of abuse at autopsy. Firstly, as with any drug, evidence of drug use may not be immediately apparent aside from any needle marks from intravenous administration or presence of tablets/ material in the stomach. Secondly, the nature of drugs of abuse is continually changing and does not necessarily constitute “classical” drugs of abuse such as heroin, cocaine, MDMA and other amphetamines.1 In the last decade or so, whether it be the increased use of gamma-hydroxybutyrate (GHB) followed by socalled “legal highs”, there have been many hundreds of new compounds that have been abused, also notwithstanding increases in the abuse of some prescription drugs (e.g. pregabalin, gabapentin and opioids such as oxycodone and fentanyl). Of particular note are the so-called “legal highs” (as were) which have invariably been synthesised to mimic the effects of controlled drugs but following legislative changes these are either controlled under the Misuse of Drugs Act 1971 or the more controversial Psychoactive Substances Act 2016. As such, in the UK and around the world these compounds are referred to as “novel or new psychoactive substances” (NPS). Having first entered drug markets via accessible websites, “head shops” in the street or some market stalls, access is now more restricted to less accessible websites (e.g. the so-called “dark web”) or other purveyors of illicit drugs. This article will describe the necessary considerations for “classical” drugs of abuse as well as more recent NPS and other drug oddities that may be encountered at autopsy.
Cocaine Cocaine is a drug abused primarily for its central nervous system stimulant effects. These effects include increased energy and alertness, excitement, euphoria, increased confidence and increased talkativeness. In addition, the use of cocaine may be associated with increased risk taking behaviour and aggression. In high doses, the effects of cocaine use may also include paranoia, bizarre and violent behaviour, hyperactivity and restlessness. Once the stimulant effects of cocaine subside, the user may experience “come-down” effects such as low mood, depression,
Simon Elliott PhD BSc, Consultant Forensic Toxicologist, Alere Forensics, Malvern Hills Science Park, Malvern, UK. Conflicts of interest: none declared.
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diamorphine), however it is not possible to completely exclude additional morphine use. As codeine is metabolised to morphine, it is also important to monitor the relative concentration of codeine versus morphine. Additional analytical merit can be the relative concentration ratios of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).11 Nevertheless, as in all cases involving opiate/opioid drugs, the toxicological significance of any morphine concentration will depend upon the degree of tolerance possessed by the deceased. Therefore, knowledge of an individual’s drug history regarding opiate and opioid drugs is very important. It is important to note that tolerance can be gained within a few days of repeated use, conversely, infrequent use or periods of abstinence can result in loss of tolerance with a naı¨ve user having little to no tolerance. The major risk to life from opiates and opioids is their depressant effect on the central nervous system (CNS), notably causing respiratory depression. The use of other CNS depressant drugs (e.g. benzodiazepines, barbiturates, etc) or alcohol that may exacerbate the CNS effects will reduce the threshold to which an individual would succumb to fatal toxicity so concomitant drug use should be a consideration in such cases, as well as positional asphyxiation in appropriate circumstances. Of some note and consideration for opioids, is the recent phenomenon of fentanyl and fentanyl analogue abuse as well as other synthetic opioids (e.g. AH-7921 and U-47700) within the wider “new psychoactive substance” phenomenon. In the last few years in the UK (and particularly Canada and the USA), use of fentanils has increased significantly and pose a particular danger to users due to their high potency, even when compared to morphine and heroin.12 Although fentanyl and its derivatives/ analogues (fentanils) have been controlled in the UK for over 30 years, they emerged on the NPS market over the last 5 years or so, typically available as white or coloured powders. More recently, there have been reports and instances of their presence in illicit heroin in particular as an adulterant or replacement as well as in fake medicines. These modes of use present both intended and unintended user consumption and exposure. Care should be taken if any suspected powders are submitted or found with decedents.
anxiety and irritability. A relatively small number of deaths due to acute cocaine toxicity are seen considering its wide use; however cardiotoxicity has been implicated as a major contributory factor in cocaine induced deaths resulting in symptoms including myocardial infarction, ventricular tachycardia and fibrillation, cerebrovascular accident and pulmonary dysfunction.5 There is also evidence that cocaine use accelerates atherosclerosis and other vascular disease issues.6 Convulsions have also been reported when the drug is used excessively. If cocaine is taken whilst there is ethanol in the bloodstream, an interaction takes place to form cocaethylene.7 Therefore, the presence of cocaethylene may be evident in post-mortem blood and/or urine and can demonstrate that the deceased had used cocaine whilst there was ethanol in the blood stream. Cocaethylene can prolong the stimulant effects of cocaine and eases its comedown effects. Of some note and consideration for cocaine, is that cocaine is quickly metabolised and being unstable also breaks down to form benzoylecgonine (BZE) and ecgonine methylester (EME). Therefore, cocaine concentrations in post-mortem blood may not reflect those at the time of death. An additional consideration for cocaine investigations is that as the illicit drug product is often adulterated with other drugs that may or may not present additional toxicity. Typical adulterants include levamisole, lignocaine, benzocaine and phenacetin.
Opiates/opioids An opiate can be described as a compound found naturally in the opium poppy (e.g. morphine, noscapine, thebaine, papaverine, codeine) whereas an opioid is a synthetic compound, synthesised to provide opiate-like effects (e.g. heroin, dihydrocodeine, methadone, oxycodone, tramadol, fentanyl). Methadone is an opioid drug which can be used for pain relief in some circumstances but is more commonly used as replacement therapy for heroin addiction/withdrawal. Opiates and other opioids are predominantly prescribed for pain relief (usually moderate to severe), both in the short-term and long-term. The concentrations of opiates and opioids found in blood during therapy are very variable and there is a significant overlap between concentrations found in acute fatal poisonings and concentrations obtained therapeutically. Therefore, the toxicological significance of a measured post-mortem blood concentration will depend upon the degree of tolerance possessed by the deceased.8 The majority of opioids are also prone to post-mortem redistribution and therefore may be artificially elevated after death depending on the site and manner of blood sampling as well as the length of the post-mortem interval. Fentanyl is highly prone to this and particular attention should be placed on the presence, site and number of any fentanyl patches on a body (especially in comparison to any prescribed dose regimen).9 It should also be noted that fentanyl release/delivery from transdermal patches can accelerate with heat and patients are warned of this, with some case evidence of this even occurring after a prolonged hot bath.10 For heroin (diacetylmorphine), the presence of 6monoacetylmorphine (6-MAM, a specific diacetylmorphine metabolite) as well as codeine, noscapine and papaverine will provide analytical evidence of heroin use (rather than medical
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Ketamine Ketamine is a dissociative anaesthetic drug used in human and veterinary medicine. However, due to the production of hallucinogenic effects, ketamine has also gained popularity as a drug of abuse. The toxicity of ketamine is known to be dosedependent with deaths resulting from direct acute ketamine ingestion being very rare with a significant overlap between the therapeutic or recreational concentrations and those detected in fatalities.13 Low doses of ketamine can produce drowsiness and perceptual distortions, whereas higher doses can produce euphoria, hallucinations and feelings of alternate consciousness. Adverse effects of ketamine may include anxiety, tachycardia, cardiac arrhythmia, dizziness, vomiting, seizures, delirium, paranoia and potentially respiratory depression.13 In recent years, there has been an observation of increased bladder problems with ketamine users, especially chronic high dose users.14 This can result in reduction in bladder size, development of
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metabolite. Following the use of cannabis, THC and its active metabolite 11-OH-THC are rapidly eliminated from the blood and may only be detectable for a few hours following occasional use. However, cannabinoids are distributed into the fatty tissues of the body and slowly released over time and in regular and/or heavy users of cannabis it may be possible to detect cannabinoids in the blood for days or possibly even weeks following its last use.17 The effects of cannabis are variable but include euphoria, relaxation, laughter, talkativeness, distortion in the perception of space and time, slowed reaction times, reduced coordination and drowsiness. Some studies have suggested that long-term heavy cannabis use can increase the risk of developing psychosis, particularly in those with a predisposition to or history of mental health problems.18 There are also some concerns over the potential cardiotoxicity of the drug, especially from chronic use but this is a controversial aspect of the scientific literature relating to cannabis although the evidence base is growing, especially in relation to more recent high purity THC cannabis extracts/concentrates (e.g. “Butane Hash Oil”).19
fibrosis, ulcers on the urothelium’s surface and inner layers, and obstruction of the ureter. Of some note and consideration for ketamine is its use in human medicine, especially in emergency situations such as road traffic incidents for stabilising patients prior to hospital transport or in situ treatment. Consequently, the circumstances of death is important in determining the provenance and significance of any ketamine if detected in post-mortem situations.
Benzodiazepines Benzodiazepines have been used for anxiety, insomnia and sedation for decades and can also be prescribed in the treatment of drug and alcohol withdrawal. They have equally been subject to abuse. They can cause light-headedness, drowsiness and reduced co-ordination and can produce or contribute to CNS depression. Whilst it is likely that persons taking a benzodiazepine regularly will develop some tolerance to the effects of the drug, concomitant use of other CNS depressant drugs and especially alcohol can increase the risk and severity of sedation and potential respiratory depression. A current particular issue is the adulteration of illicit heroin with potent benzodiazepines (such as alprazolam) which have also appeared in fake benzodiazepine tablets.15 Benzodiazepines are typically eliminated from the body over an extended period of time and due to this and the potential significant tolerance that can be acquired, post-mortem blood concentrations need to be interpreted in the context of other drugs being used and the drug/prescription history of the deceased. Of some note and consideration for benzodiazepines is that some benzodiazepines (designed or otherwise) have appeared in the NPS market and pose risks to the user in terms of not knowing the drug being ingested as well as the dose and potency.15
New psychoactive substances (NPS) Whilst there is no definitive definition, an NPS could be considered to be a recently encountered psychoactive substance that often mimics the effects of a substance that is under drug control (international or otherwise) but could have been developed many years previously. Because of this, NPS can encompass many drugs that produce effects similar to “classical” drugs of abuse and around 800 NPS have been recorded as of 2018.20,21 They are invariably made available or sold via the Internet or previously in so-called ‘Head Shops’ using product terms such as “research chemicals”, “bath salts”, “plant food” or “herbal incense”. They exist as powders, pellets, tablets, liquids or herbal material and may be labelled as “Not For Human Consumption” and with potential branding that should not be relied upon to be consistent or relatable to the exact constituents (especially geographically or with time). Despite the wide range of compound types, they are generally stimulant, sedating/CNS depressant or hallucinatory in nature producing cardiotoxicity, respiratory depression or accidental injury, respectively as their major risks.22 However, specific dangers associated with their use include; (i) the constituent compound may not be correct or known to the user, (ii) unknown dosage and (iii) production of bizarre behaviour and aggression that affects the wider public and users driving under the influence of NPS. Currently, the three most common types of NPS are cathinones, synthetic cannabinoids and benzodiazepines but the synthetic opioids are of particular concern due to their nature and potency.23 If there is no scene evidence, no specific drug history or no obvious indication of new psychoactive drug use, it is important to be aware of the possible signs and symptoms, particularly in relation to available case circumstances. Within the case history or any documented clinical presentation there may be euphoria (stimulants), confusion (hallucinogens, sedatives), disinhibition (stimulants, sedatives), hallucinations (stimulants, hallucinogens), unsteadiness (hallucinogens, sedatives), hyperthermia (stimulants), vomiting (stimulants, hallucinogens, sedatives), cardiac effects (stimulants, hallucinogens), drowsiness (sedatives), odd behaviour (stimulants, hallucinogens), coma
Pregabalin Pregabalin is typically used in the treatment of epilepsy, pain and generalised anxiety disorder but is also abused at high doses for its euphoric effects, often along with opiates and opioids. Although pregabalin is not considered to be an especially toxic drug, somnolence, tachycardia and hypertonicity are effects that have been reported in instances of overdose. Due to its chemical similarity to GABA, pregabalin may exacerbate the effects of alcohol and other drugs such as benzodiazepines and opiates/ opioids. Furthermore, due to the presence of other drugs (especially opiates/opioids) in pregabalin cases it is often difficult to determine the significance of pregabalin as a causal factor, however, fatalities have been reported and studies have indicated that post-mortem blood concentrations greater than 25 mg/ L may be toxicologically significant.16
Cannabis Cannabis contains a number of cannabinoids (naturally occurring compounds in the plant). The main pharmacologically active cannabinoid of cannabis is delta-9-tetrahydrocannabinol (THC). THC is metabolised rapidly to form 11-hydroxy-THC (11-OH-THC), which is an active metabolite, and subsequently THC-carboxylic acid (THC-COOH), which is an inactive
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(sedatives) and respiratory depression (sedatives).22 In determining the potential significance of NPS in a death, it is necessary to consider; a) the presence, concentration and nature of the NPS, b) the presence, concentration and nature of other drugs present (including alcohol), c) the circumstances of death and d) other pathological findings.24 Due to the wide range of NPS that exist, sufficient scientific literature may not be available, especially in relation to the complete pharmacological actions as well as pharmacokinetics (metabolism and detection windows in particular). In relation to analytical detectability, reference materials are not always available for NPS or their metabolites and some NPS (e.g. cathinones and synthetic cannabinoids) have been found to be unstable (especially in blood). Whilst scene evidence and seized items are beneficial in determining the potential use of NPS, as stated above, care must be taken when handling such products, especially if as a powder as it may be a potent synthetic cannabinoid or opioid.
obtained from a “peripheral” site such as the femoral vein using an appropriate method of sampling. Blood and urine should be obtained and placed in a fluoride-preserved and non-fluoride (i.e. “plain/unpreserved) container. The former is beneficial in reducing any post-mortem production of e.g. alcohol, whilst potentially assisting in reducing the impact of any drug instability that may be associated with some drugs of abuse (e.g. cocaine, heroin) and NPS (e.g. cathinones).27e29 The investigation of drugs of abuse (as well as other suspected or possible drugs) relies on a strong collaboration between pathological and toxicological practices that hopefully this review has highlighted.A
Practice points C
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Other considerations for the pathologist As with any investigation, the investigative strategy (including analytical toxicology) and interpretation of results and findings is reliant on appropriate and sufficient information to allow an assessment to be made within the context of the case. This includes full knowledge of the case circumstances, drug/prescription history (not just of the deceased but potentially of the wider household or acquaintances to determine accessibility to drugs) and any scene evidence that may indicate use of drugs (including description of the product(s) and if NPS, the physical nature of the substance and any labelling or packaging identification). As there is not one method or technique that can enable the toxicology laboratory to analyse for all drugs and poisons, this information can assist in forming an appropriate analytical strategy, especially as certain substances may not feature in typical standard/routine testing protocols. Such non-standard substances that may need to be highlighted to the laboratory in advance (e.g. if use is known/suspected) include GHB (“Liquid Ecstasy”), some anti-epileptics (e.g. valproate, pregabalin and gabapentin), metals (arsenic, lead, mercury), herbicides/pesticides, volatiles (butane, propane, dichloromethane), cyanide and ethylene glycol (anti-freeze). Unfortunately, the trend in more recent years to limit the scope of testing with the intention of being more cost effective, has particular consequences when in relation to NPS. Due to the large variety and chemical diversity of these substances, even if use is suspected, they pose significant challenges to analytical toxicology (and not least interpretative toxicology) and often require a combination of non-targeted (general) and targeted (specific) toxicological analyses. The former is required to ensure an appropriate coverage of potential NPS, the latter is required in order to achieve the necessary specificity and sensitivity for the detection and potential measurement of compounds present at exceptionally low concentrations in the body (blood in particular), for example, synthetic cannabinoids and fentanils.25,26 Somewhat related to this is the subsequent requirement for any toxicological request to be allowed its greatest chance of success by being provided with appropriate and sufficient specimens for analysis. In the vast majority of cases (aside from volatile substances where brain and/or lung is preferred) this is predominantly urine and blood
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evidence of drug use may not be immediately apparent or known, obtain information regarding drug history and any scene evidence the nature of drugs of abuse is continually changing and does not necessarily constitute “classical” drugs of abuse but now incorporates an evolving variety of new psychoactive substances (NPS) that could be considered to be stimulant, sedating or hallucinogenic in nature phenyl-2-ethylamine is a common putrefactive compound that can create potential “false positive” situations with laboratory presumptive immunoassays for amphetamine(s) cocaine toxicity potentially contributing to death can result from acute and chronic use the possibility of intentional or unintentional use of opioids (e.g. fentanyl and analogues) and/or benzodiazepines (e.g. alprazolam) should be considered where heroin and cocaine use may be suspected, in addition to “fake” medication products be mindful of potentially potent fentanils and other opioids constituting white powder or other seized material; take associated health and safety precautions be aware of new high purity THC extracts of cannabis (e.g. “Butane Hash Oil”) and associated potential toxicity to the user appropriate toxicological analysis requires targeted and nontargeted approaches to enable detection of a wide range of drugs, not least new psychoactive substances but some drugs require notification of suspected use to assist analytical strategies (e.g. GHB, some anticonvulsants, metals and volatile substances) post-mortem blood should be obtained from a suitably isolated peripheral anatomical site (e.g. femoral vein) and provided (along with urine) in unpreserved and fluoride-preserved sample containers
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