Accepted Manuscript Title: A 3 year review of new psychoactive substances in casework Author: Simon Elliott Julie Evans PII: DOI: Reference:
S0379-0738(14)00157-1 http://dx.doi.org/doi:10.1016/j.forsciint.2014.04.017 FSI 7576
To appear in:
FSI
Received date: Revised date: Accepted date:
1-11-2013 24-3-2014 9-4-2014
Please cite this article as: S. Elliott, J. Evans, A 3 year review of new psychoactive substances in casework, Forensic Science International (2014), http://dx.doi.org/10.1016/j.forsciint.2014.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
(ROAR) Forensics Ltd Malvern Hills Science Park Geraldine Road Malvern Worcestershire WR14 3SZ U.K.
E-mail:
[email protected]
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Address:
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Simon Elliott*, Julie Evans
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Authors:
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A 3 year review of new psychoactive substances in casework
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(for correspondence*)
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___________________________________________________________________________
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Keywords: New psychoactive substances; designer drugs; cathinones; fatalities
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A 3 year review of new psychoactive substances in casework
Abstract
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Following the initial popularity of mephedrone (4-methylmethcathinone) there has been a stream of new “recreational drugs” entering the global market. The lack of clinical studies on the effects and toxicity of these drugs has made interpretation of
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toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and the fatalities that have been linked to these compounds we
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present our collated findings in post-mortem and criminal casework where these have been detected and/or implicated. Between January 2010 and December 2012
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we have detected new psychoactive substances (NPS) in 203 cases, with 120 cases in 2012 alone. The drugs detected in in life or post-mortem blood and urine are, in order of decreasing frequency; mephedrone, 4-methylethcathinone, BZP, MDPV,
methylone,
PMMA,
naphyrone,
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TFMPP, methoxetamine, 4-fluoromethcathinone, 4-methylamphetamine, PMA, alpha-methyltryptamine,
butylone,
MDAI
desoxypipradrol, D2PM, MPA, synthetic cannabinoids, 2-AI, 5-IAI, 5-MeODALT,
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MDPBP, 5/6-APB, pentedrone and pentylone. Other drugs or alcohol were detected
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in 84% of the cases including other NPS and in fatalities it should be noted that alternative causes of death (including mechanical suicide, accidental death and non-
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psychoactive drug overdose) accounted for the majority. Related to this was that of all fatalities involving cathinones, 41% of these were hangings or other mechanical suicides, this was a higher proportion than seen with other drugs found in such cases. The presence of multiple NPS and/or other stimulants was a particular feature in various cases, however, of the drug deaths only 7% solely involved NPS. Across all case types and including some cases investigated in 2013, NPS concentrations showed a wide range but these and selected cases are presented to assist toxicological interpretation in future cases.
Keywords: New psychoactive substances; designer drugs; cathinones; fatalities
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Introduction Whilst there has been an evolution in drugs of abuse over the last 30 years, of prime toxicological significance has been the more recent phenomenon of new psychoactive substances, also known as so-called “legal highs”, “designer drugs” or
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“bath salts” [1]. This has been a global issue with the continual emergence of new compounds on the recreational and illicit drug market. In many countries, such
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compounds are rarely included in drug control legislation and may even fall outside of generic legislative systems. This is largely due to these drugs being predominantly
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synthetic derivatives and analogues of existing controlled drugs, analogues of pharmaceutical products, previously researched substances or naturally occurring compounds [2]. Arguably the accessibility and information available through the
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Internet has promoted this evolution with various websites marketing these compounds as “research chemicals” or products purported to be “not for human
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consumption”, being sold as “plant food” or “bath salts” [3]. Whilst there are hundreds of drugs based on the primary chemical frameworks of phenethylamine, cathinone, tryptamine, piperazine and aminoindan, there are additional drug families based on
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their action (e.g. synthetic cannabinoids) as well as distinct atypicals (e.g.
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methiopropamine, AH-7921 and aminopropylbenzofurans). The variety and evolution of drug types has resulted in a continual analytical
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challenge for detection, identification and measurement. The challenge has been met in some regards through the complementary use of techniques such as HPLCDAD, GC-MS, LC-MS and LC or GC coupled with accurate mass-spectrometry [4]. Each technique provides a particular advantage with the analytical toxicologist having to take account of the various analytical characteristics and pitfalls (e.g. isobaric nature of drugs including isomerisation) which have been discussed elsewhere [5]. However, the often initial absence of reference materials can hinder identification and measurement and even if available such compounds may be expensive and may not have corresponding deuterated standards for use in quantification by mass-spectrometry [6]. Aside from the analytical challenge, the lack of clinical studies on the effects of these drugs and their toxicity has made interpretation of toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and particularly
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fatalities that have been linked to these compounds, findings during casework have been collated in respect to fatal and non-fatal cases submitted to our laboratory where new psychoactive substances have been detected and/or implicated.
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Experimental Analytical methods
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Routine analysis involved the use of immunoassay, ultra/high performance liquid chromatography coupled with diode array detection (U/HPLC-DAD), liquid
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chromatography with hybrid linear ion trap tandem mass spectrometry (LC-MS/MS) coupled with DAD, and in some cases ultra-high performance liquid chromatography with high mass accuracy quadrupole time-of-flight mass spectrometry (UHPLC-
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QTOF-MS). The methods have been published elsewhere [7-8].
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Casework
Analysis was undertaken as part of routine case investigations on behalf of HM Coroners or Police Forces using in life and/or post-mortem specimens, further details
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of case types are described below. Drug screening involved a non-targetted
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approach for common drugs of abuse (including alcohol) and prescription drugs with more specific analysis where required.
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Results and discussion Drug frequency
Figure 1 shows the frequency of new psychoactive drugs detected in casework between January 2010 and December 2012. Overall such drugs were detected in 203 cases, with 120 of those being solely from Jan-Dec 2012, showing an increase in frequency compared to 2010 and 2011. The drugs found were collated into the following drug classes (in decreasing order of frequency); cathinones, piperazines, “miscellaneous” compounds, tryptamines and aminoindans. Of the specific drugs detected, desoxypipradrol, 5-methoxy-DALT and 5-iodoaminoindan (5-IAI) were only found in 2010 casework, whereas pentylone, MDPBP and 2-aminoindane were only found in casework in 2011. 5- and 6-Aminopropylbenzofuran (5- and 6-APB), methiopropramine
(MPA),
synthetic
cannabinoids,
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pentedrone
and
para-
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methoxymethylamphetamine (PMMA) were first seen in casework in 2012. However, PMMA had been observed in cases in the early 2000s during its previous presence on the UK drugs market. Also, whilst synthetic cannabinoids may have been involved in cases prior to 2012, the methods of detection were not developed prior to this time
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and due to the metabolism, growth in structural analogues and lack of reference material, this remains an analytical challenge. Separate to synthetic cannabinoids, there were some drugs where a distinct increase in frequency was observed from
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2011 to 2012, namely; methoxetamine, MDPV, 4-methylethcathinone (4-MEC), 4methylamphetamine (4-MA), PMA and mephedrone. For mephedrone, there was a
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linear decrease in case frequency following its control under the 1971 Misuse of Drugs Act, resulting in only 2 cases between August 2010 and January 2011. During
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this time period there was a noticeable increase in the prevalence of other cathinones, especially 4-MEC, which had been controlled itself from April 2010 along with other substituted cathinones. Nevertheless, from February 2011, mephedrone
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began to be seen again in casework and even increased in number compared to the time period before its control.
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Other drugs or alcohol were detected in 84% (170) of the 203 cases with the
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presence of multiple new psychoactive substances being a particular feature in various cases. In fact, of the 170 cases where other drugs/alcohol were detected,
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new psychoactive drugs were the sole agent in 19% of all cases but the sole agent in only 7% of the drug deaths sub-set. Across all case types, the other drugs found in decreasing order of frequency (Figure 2) were; alcohol (77 cases), antidepressants (50), cocaine (47), amphetamines (44), opiates/opioids (43), benzodiazepines (38), cannabis (36), cocaine adulterants (35), paracetamol (14), antipsychotics (12), ketamine (11), ibuprofen (9), quinine (6), sildenafil (5), ephedrine (5), antihistamines (4), carbon monoxide (3), anticonvulsants (3), cardiac drugs (3), gastric drugs (3), zopiclone (2), chloroquine (1), GHB (1) and trimethoprim (1). Out of these drugs there was a relatively high frequency of stimulant drugs such as ephedrine, amphetamines (amphetamine, MDMA, methamphetamine) and cocaine. This would likely to be toxicologically significant due to the potential monoaminergic and cardiac effects of the majority of new psychoactive substances. In addition to this the concomitant use of monoaminergic antidepressants (e.g. SSRIs, SNRIs, tricyclics, etc) could also be considered to be of significance.
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Case types and cathinones in suicide New psychoactive substances were found in all forensic and post-mortem case types investigated by the laboratory. Most of the occurrences (58%) presented in this article related to cases of drug death (i.e. deaths where drugs were suspected, or
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contributory/cause, or were present but not contributory). 17% of cases involving new pyschoactives were fatal hangings and 5% involved other manners of
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mechanical suicide (e.g. struck by a train, asphyxia, fatal gunshot wound or jump/fall). 13% of cases were criminal in nature (e.g. homicide victims or suspects,
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assailants etc), 8% were detected in cases of drug facilitated sexual assault (DFSA) and 9% of cases were road traffic deaths (driver or passenger) or suspected driving under the influence of alcohol or drugs (DUI). Of particular note was the proportional
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high prevalence (41%) of cathinone drugs (e.g. mephedrone, MDPV, 4-MEC) in hangings or other mechanical suicides (i.e. not suicide by drug overdose). This was
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a trend that was noticed relatively early by the authors in the “cathinone phenomenon” within drug users [9]. This was compared to other new psychoactives such as piperazines where of all deaths which involved piperazines, only 14% of
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those were such suicides.
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In order to see if the findings were significant, the most prevalent drugs found in hangings and other suspected mechanical suicides were assessed [9]. The most
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prevalent drug was paracetamol (found in 13.4% of these case types), followed by citalopram (12.7%), diazepam (8.4%), mirtazapine (8.0%), zopiclone (6.8%) and cocaine (6.5%). Figure 3 shows the proportion of cases in which each drug was found, expressed as a percentage of the total number of fatalities investigated (% All Deaths). Figure 3 also shows the proportion of those cases positive for each drug that were hangings or mechanical suicides, expressed as a percentage of all the cases positive for that particular drug (% Mechanical Suicide). Specifically, cathinones were only present in less than 0.1% of all fatalities investigated but when detected, over 40% of these cases were hangings or mechanical suicides. As there have been various studies regarding suicidal ideation and SSRIs [10-11], a selection of the most common of these drugs (paroxetine, sertraline and fluoxetine) was also included (although they did not feature in the most prevalent drugs found). It could be considered that if a drug may be linked with suicidal ideation then it may
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be present in a high proportion of such cases. Whereas if it does not (as potentially evidenced by paracetamol and diazepam), it would be present at a proportionately lower frequency. As for cocaine, an intense “high” may be followed by a subsequent “low”, with lethargy and low mood. As the psychological circumstances surrounding
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suicide are complex, the data are merely presented to show that nearly half of all deaths investigated that involved cathinones were hangings or other modes of
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mechanical suicide. Concentrations and toxicological significance
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Due to the very nature of new psychoactive substances, there is often very little if any data available regarding effects, toxicity and pharmacodynamic profile,
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especially when the compounds first appear on the drugs market [12]. When assessing toxicological significance, ideally it is also typical to utilise concentration data from in life or clinical studies as well as post-mortem casework. With various
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drugs of abuse, clinical therapeutic study data are invariably lacking and it is often difficult to assess what a typical “recreational” concentration is. When interpreting post-mortem concentrations, redistribution is an important consideration [13-14] and
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as such it is usual to compare with post-mortem concentrations found in deaths
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where the drug was not the primary cause or not contributory to death (e.g. road traffic death assuming drug toxicity did not cause impairment in the case of
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drivers/riders). A further consideration for drug concentrations is the stability of the drug and whether the measured level equates to the level at the time of sample collection. Also, as described above, poly-drug use is important when assessing possible drug-drug interactions. With new psychoactive substances, depending on how long they have been on the market and the number of times encountered by toxicologists, all such data are sparse or absent. In the cases presented in this 3 year period, it was not possible to measure the concentrations of all drugs in all cases (e.g. due to sample volume, case circumstances, etc). Therefore, in order to assist in presenting as much concentration data as possible, some cases investigated during 2013 are included and show a further increase in certain NPS (particularly 5/6-APB, MPA, PMA and AMT). The data are particularly presented to aid post-mortem interpretation, whereby
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concentrations found in cases of alternative causes of death (i.e. not directly drug related) along with those of sudden death are shown (Table 1). The data in Table 1 show a wide range of concentrations have been found in fatalities, with an overlap in the various case types including drugs driving. This is not
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unexpected and has been the case for a wide variety of drugs due to the differing drug behaviour of users (including frequency and dose) as well as the circumstances
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of the drug taking and outcome. In particular, it is often difficult (even with some well researched drugs like amphetamine and MDMA) to determine “recreational” and
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“excessive” use. This is coupled with the already described common situation of poly drug use, preventing a “toxic” or “fatal” concentration range to be proposed. Apart from mephedrone none of the other NPS were present in sufficient cases to permit
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meaningful comparisons of post-mortem concentrations in cases where there was an alternative cause of death to cases where drugs (not always or necessarily due to
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NPS) were the likely cause of death. Mephedrone exhibited a range of 0.02-2.23 mg/L (median 0.49 mg/L) for cases with an alternative cause of death (mainly hangings or passengers in road traffic collisions), compared to a range of 0.15-3.09
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mg/L (median 1.25 mg/L) in drug related deaths. This reflects similar findings
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reported by other toxicologists [15-16].
In relation to the other factors presented above for concentration interpretation, as
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various researchers have demonstrated instability in the cathinone compounds [1718], it is important to consider this when assessing the concentrations presented, not least the ranges mentioned above for mephedrone. However, recent work has shown that many of the other new psychoactive drug types encountered are stable [8].
Nevertheless,
the
overriding
consideration
when
assessing
the
drug
concentrations presented is the predominant feature of poly drug use in the cases presented. As mentioned above, this does not just involve concomitant prescription drug use but also combined use of new psychoactive drugs in isolation. This results in a comparatively “low” concentration of one or a number of drugs being found with or without a comparatively “higher” concentration of another new psychoactive. This is very common with the stimulant drugs resulting in a likely toxicological significance of monoaminergic effects (e.g. serotonin syndrome) and associated symptoms (e.g. seizures, increased body temperature) and/or acute cardiotoxicity [19-24]. Some particularly serious combinations found in the cases included AMT and drugs such Page 8
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as APB and MDPV, whereby AMT has monoamine oxidase activity, thus producing an elevation of serotonin, dopamine or noradrenaline. Exemplifying poly-drug use, one particular case within the 3 year period involved the ingestion of “Legal Highs” purchased from the Internet such as, “Mad Cat III”, “Super MDAI”, AMT,
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phenazepam, 5-IAI and methoxetamine. In the decomposed post-mortem heart blood, MDMA, MDPV, 4-FMC, methylone, MDAI, AMT, methoxetamine and 5-IAI
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were found (the state and nature of the blood prevented measurement). Selected post mortem cases
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In 3 previously reported cases where, in the absence of an alternative explanation for the death, NPS have been assumed to be the cause, concentrations of MDAI -
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26.3 mg/L [25], AMT - 0.89 mg/L [7] and desoxypipradrol - 1.16 mg/L [26] were found. In addition to these, the following cases have been selected where there was seemingly no other cause of death and the new psychoactive drugs found may have
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contributed to death.
Case 1: a 47 year old male with a history of hypertension was found unresponsive
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and was pronounced dead upon arrival at hospital. A post-mortem femoral blood
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BZP concentration of 20.4 mg/L was found, with no alcohol or other drugs. Case 2: a 20 year old female became ill and started hallucinating after taking 3
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“Ecstasy” tablets. She was taken to hospital but died the following morning. A PMA concentration of 1.61 mg/L was found in an ante mortem blood sample obtained around the time of admission. No alcohol or other drugs were detected. Case 3: a 31 year old male suffered a cardiac arrest and died having taken “MCAT”. Apart from cannabinoids and a low level of ibuprofen, a post-mortem femoral blood 4-FMC concentration of 4.42 mg/L was found. Case 4: a 25 year old female was found dead following a party. Apart from cannabinoids, low levels of cocaine, quinine, hydroxyzine (both likely as cocaine adulterants) and 4-FMC, post-mortem femoral blood concentrations of methylone (4.31 mg/L) and 4-MEC (5.83 mg/L) were found along with a blood ethanol level of 45 mg/dL.
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Case 5: a 43 year old male was found collapsed on his bedroom floor having taken a product named “China White”. Apart from a low level of phenytoin (although there was no history of epilepsy), only MPA (3.2 mg/L) and methoxetamine (1.1 mg/L) were
found
in
a
fluoride-preserved
post-mortem
femoral
blood
sample.
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Corresponding MPA and methoxetamine concentrations in the unpreserved blood were 2.8 mg/L and 0.89 mg/L. This suggested possible instability of the drugs but as
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mentioned this was not observed in a recent study of these and other NPS [8].
Case 6: a 51 year old male was found dead at home. In addition to a trace amount of
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MPA, AMT (0.19 mg/L), 5-APB (0.15 mg/L) and 5-MAPB (1.94 mg/L) were found in the post-mortem femoral blood. No alcohol or other drugs were detected.
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Case 7: a 22 year old female was found dead in bed. Apart from a low concentration of ethanol (19 mg/dL), a 4-methylamphetamine concentration of 5.8 mg/L was found in the post-mortem femoral blood. Although amphetamine and ketamine use prior to
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death was suspected, these nor any other drugs were detected. Subsequent to these cases, in 2013 there have been some additional fatalities
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involving existing and newly emerging drugs. Specifically, the opioid AH-7921 has
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been encountered on 3 occasions (0.58 mg/L, 0.05 mg/L and 4.46 mg/L in post – mortem femoral blood). Atypical benzodiazepines (e.g. phenazepam, etizolam,
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pyrazolam and flubromazepam) have also been encountered in casework but along with other drugs. However, some cases have involved existing and newly emerging drugs as a potential major contributor to death (i.e. camfetamine, APB, EAPB, methylone, AMT, 5-MeO-DALT, 4-methylamphetamine, 25B-NBOMe, 25C-NBOMe and PMA). These findings will be published in due course.
Conclusions
The frequency of new psychoactive drugs in casework has increased, particularly in recent years. Over the 3 year data collated, the majority of cases involved alcohol and/or other drugs with the high frequency of other stimulants (notably cocaine and amphetamines) being a constant feature. Nevertheless, new psychoactive substances were the sole agent in 19% of all cases and the sole agent in 7% of drug deaths. One particular observation of fatalities involving cathinones showed that a high proportion of cases were linked to suspected suicides. A review of
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concentrations showed a wide range of values across the varying case types and especially within the drug related deaths. This is likely to be due to the contribution of other drugs including other NPS and prescription drugs or drugs of abuse. Already in 2013 there has been the emergence of other new psychoactive
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substances in casework (e.g. etizolam, flubromazepam, ethylphenidate, etaqualone, AH-7921, MAPB, EAPB, 25B-NBOMe, 25C-NBOMe and 25I-NBOMe) in addition to
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further cases involving those NPS detailed here. Further work will continue to monitor and report these data and where possible assess trends or links within case
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Acknowledgements The authors thankfully acknowledge HM Coroners and the assistance and support of Dr Simon Brandt, Liverpool John Moore’s University.
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Figure 1
Figure 1 – The frequency of new psychoactive substances in cases between 20102012 (203 cases)
5/6-APB MPA Synthetic cann Methoxetamine Desoxypipradrol D2PM AMT 5-MeO-DALT Pentylone Naphyrone Methylone Pentedrone Mephedrone MDPV MDPBP Butylone 4-FMC 4-Methylethcathinone TFMPP BZP PMMA PMA 4-Methylamphetamine MDAI 5-IAI 2-AI
1 2 2 11 2 2 4
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1 1 4
cr
7 1
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20
106
1 3
an
10
28 16 21
M
6 9 10
20
ce pt
0
ed
3
1 1
Miscellaneous
60
Cathinones
80
100
120
Piperazines
Aminoindans
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Phenethylamines
Tryptamine
40
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Figure 2
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Figure 2 – The frequency of other drugs found in cases with new psychoactive substances between 2010-2012
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Amphetamine Methamphetamine MDMA
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ce pt
ed
M
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Hydroxyzine Lignocaine Levamisole Benzocaine
Buprenorphine Methadone Tramadol Heroin/Morphine
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Figure 3 revised
Figure 3 – Drugs detected as % in All Deaths and % of those that were Mechanical Suicide
50.0 45.0 40.0
30.0
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25.0 20.0
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15.0 10.0
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5.0
Mechanical Suicides
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ed
M
All Deaths
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0.0
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% Cases
35.0
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Table 1
Alternative Cause of Death
concentration/range mg/L
(median) if applicable
5/6-APB
0.48, 0.29, 0.89, 1.00, 0.75AM, 0.32, 0.16, 0.19, 1.3 (0.48)
N/A
0.34
N/A
0.10, 4.31, 11.0
N/A
0.02-2.23 (0.49 n=24)
0.15, 0.21, 0.36, 0.50, 0.68, 1.20AM, 1.30, 1.31, 1.51, 2.09, 2.17, 3.06 (1.25)
0.12,
S0379-0738(14)00157-1 http://dx.doi.org/doi:10.1016/j.forsciint.2014.04.017 FSI 7576
To appear in:
FSI
Received date: Revised date: Accepted date:
1-11-2013 24-3-2014 9-4-2014
Please cite this article as: S. Elliott, J. Evans, A 3 year review of new psychoactive substances in casework, Forensic Science International (2014), http://dx.doi.org/10.1016/j.forsciint.2014.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
(ROAR) Forensics Ltd Malvern Hills Science Park Geraldine Road Malvern Worcestershire WR14 3SZ U.K.
E-mail:
[email protected]
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Address:
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Simon Elliott*, Julie Evans
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Authors:
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A 3 year review of new psychoactive substances in casework
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(for correspondence*)
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___________________________________________________________________________
Ac ce p
Keywords: New psychoactive substances; designer drugs; cathinones; fatalities
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A 3 year review of new psychoactive substances in casework
Abstract
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Following the initial popularity of mephedrone (4-methylmethcathinone) there has been a stream of new “recreational drugs” entering the global market. The lack of clinical studies on the effects and toxicity of these drugs has made interpretation of
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toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and the fatalities that have been linked to these compounds we
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present our collated findings in post-mortem and criminal casework where these have been detected and/or implicated. Between January 2010 and December 2012
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we have detected new psychoactive substances (NPS) in 203 cases, with 120 cases in 2012 alone. The drugs detected in in life or post-mortem blood and urine are, in order of decreasing frequency; mephedrone, 4-methylethcathinone, BZP, MDPV,
methylone,
PMMA,
naphyrone,
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TFMPP, methoxetamine, 4-fluoromethcathinone, 4-methylamphetamine, PMA, alpha-methyltryptamine,
butylone,
MDAI
desoxypipradrol, D2PM, MPA, synthetic cannabinoids, 2-AI, 5-IAI, 5-MeODALT,
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MDPBP, 5/6-APB, pentedrone and pentylone. Other drugs or alcohol were detected
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in 84% of the cases including other NPS and in fatalities it should be noted that alternative causes of death (including mechanical suicide, accidental death and non-
Ac ce p
psychoactive drug overdose) accounted for the majority. Related to this was that of all fatalities involving cathinones, 41% of these were hangings or other mechanical suicides, this was a higher proportion than seen with other drugs found in such cases. The presence of multiple NPS and/or other stimulants was a particular feature in various cases, however, of the drug deaths only 7% solely involved NPS. Across all case types and including some cases investigated in 2013, NPS concentrations showed a wide range but these and selected cases are presented to assist toxicological interpretation in future cases.
Keywords: New psychoactive substances; designer drugs; cathinones; fatalities
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Introduction Whilst there has been an evolution in drugs of abuse over the last 30 years, of prime toxicological significance has been the more recent phenomenon of new psychoactive substances, also known as so-called “legal highs”, “designer drugs” or
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“bath salts” [1]. This has been a global issue with the continual emergence of new compounds on the recreational and illicit drug market. In many countries, such
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compounds are rarely included in drug control legislation and may even fall outside of generic legislative systems. This is largely due to these drugs being predominantly
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synthetic derivatives and analogues of existing controlled drugs, analogues of pharmaceutical products, previously researched substances or naturally occurring compounds [2]. Arguably the accessibility and information available through the
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Internet has promoted this evolution with various websites marketing these compounds as “research chemicals” or products purported to be “not for human
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consumption”, being sold as “plant food” or “bath salts” [3]. Whilst there are hundreds of drugs based on the primary chemical frameworks of phenethylamine, cathinone, tryptamine, piperazine and aminoindan, there are additional drug families based on
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their action (e.g. synthetic cannabinoids) as well as distinct atypicals (e.g.
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methiopropamine, AH-7921 and aminopropylbenzofurans). The variety and evolution of drug types has resulted in a continual analytical
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challenge for detection, identification and measurement. The challenge has been met in some regards through the complementary use of techniques such as HPLCDAD, GC-MS, LC-MS and LC or GC coupled with accurate mass-spectrometry [4]. Each technique provides a particular advantage with the analytical toxicologist having to take account of the various analytical characteristics and pitfalls (e.g. isobaric nature of drugs including isomerisation) which have been discussed elsewhere [5]. However, the often initial absence of reference materials can hinder identification and measurement and even if available such compounds may be expensive and may not have corresponding deuterated standards for use in quantification by mass-spectrometry [6]. Aside from the analytical challenge, the lack of clinical studies on the effects of these drugs and their toxicity has made interpretation of toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and particularly
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fatalities that have been linked to these compounds, findings during casework have been collated in respect to fatal and non-fatal cases submitted to our laboratory where new psychoactive substances have been detected and/or implicated.
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Experimental Analytical methods
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Routine analysis involved the use of immunoassay, ultra/high performance liquid chromatography coupled with diode array detection (U/HPLC-DAD), liquid
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chromatography with hybrid linear ion trap tandem mass spectrometry (LC-MS/MS) coupled with DAD, and in some cases ultra-high performance liquid chromatography with high mass accuracy quadrupole time-of-flight mass spectrometry (UHPLC-
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QTOF-MS). The methods have been published elsewhere [7-8].
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Casework
Analysis was undertaken as part of routine case investigations on behalf of HM Coroners or Police Forces using in life and/or post-mortem specimens, further details
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of case types are described below. Drug screening involved a non-targetted
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approach for common drugs of abuse (including alcohol) and prescription drugs with more specific analysis where required.
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Results and discussion Drug frequency
Figure 1 shows the frequency of new psychoactive drugs detected in casework between January 2010 and December 2012. Overall such drugs were detected in 203 cases, with 120 of those being solely from Jan-Dec 2012, showing an increase in frequency compared to 2010 and 2011. The drugs found were collated into the following drug classes (in decreasing order of frequency); cathinones, piperazines, “miscellaneous” compounds, tryptamines and aminoindans. Of the specific drugs detected, desoxypipradrol, 5-methoxy-DALT and 5-iodoaminoindan (5-IAI) were only found in 2010 casework, whereas pentylone, MDPBP and 2-aminoindane were only found in casework in 2011. 5- and 6-Aminopropylbenzofuran (5- and 6-APB), methiopropramine
(MPA),
synthetic
cannabinoids,
Page 4
pentedrone
and
para-
Page 4 of 19
methoxymethylamphetamine (PMMA) were first seen in casework in 2012. However, PMMA had been observed in cases in the early 2000s during its previous presence on the UK drugs market. Also, whilst synthetic cannabinoids may have been involved in cases prior to 2012, the methods of detection were not developed prior to this time
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and due to the metabolism, growth in structural analogues and lack of reference material, this remains an analytical challenge. Separate to synthetic cannabinoids, there were some drugs where a distinct increase in frequency was observed from
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2011 to 2012, namely; methoxetamine, MDPV, 4-methylethcathinone (4-MEC), 4methylamphetamine (4-MA), PMA and mephedrone. For mephedrone, there was a
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linear decrease in case frequency following its control under the 1971 Misuse of Drugs Act, resulting in only 2 cases between August 2010 and January 2011. During
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this time period there was a noticeable increase in the prevalence of other cathinones, especially 4-MEC, which had been controlled itself from April 2010 along with other substituted cathinones. Nevertheless, from February 2011, mephedrone
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began to be seen again in casework and even increased in number compared to the time period before its control.
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Other drugs or alcohol were detected in 84% (170) of the 203 cases with the
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presence of multiple new psychoactive substances being a particular feature in various cases. In fact, of the 170 cases where other drugs/alcohol were detected,
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new psychoactive drugs were the sole agent in 19% of all cases but the sole agent in only 7% of the drug deaths sub-set. Across all case types, the other drugs found in decreasing order of frequency (Figure 2) were; alcohol (77 cases), antidepressants (50), cocaine (47), amphetamines (44), opiates/opioids (43), benzodiazepines (38), cannabis (36), cocaine adulterants (35), paracetamol (14), antipsychotics (12), ketamine (11), ibuprofen (9), quinine (6), sildenafil (5), ephedrine (5), antihistamines (4), carbon monoxide (3), anticonvulsants (3), cardiac drugs (3), gastric drugs (3), zopiclone (2), chloroquine (1), GHB (1) and trimethoprim (1). Out of these drugs there was a relatively high frequency of stimulant drugs such as ephedrine, amphetamines (amphetamine, MDMA, methamphetamine) and cocaine. This would likely to be toxicologically significant due to the potential monoaminergic and cardiac effects of the majority of new psychoactive substances. In addition to this the concomitant use of monoaminergic antidepressants (e.g. SSRIs, SNRIs, tricyclics, etc) could also be considered to be of significance.
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Case types and cathinones in suicide New psychoactive substances were found in all forensic and post-mortem case types investigated by the laboratory. Most of the occurrences (58%) presented in this article related to cases of drug death (i.e. deaths where drugs were suspected, or
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contributory/cause, or were present but not contributory). 17% of cases involving new pyschoactives were fatal hangings and 5% involved other manners of
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mechanical suicide (e.g. struck by a train, asphyxia, fatal gunshot wound or jump/fall). 13% of cases were criminal in nature (e.g. homicide victims or suspects,
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assailants etc), 8% were detected in cases of drug facilitated sexual assault (DFSA) and 9% of cases were road traffic deaths (driver or passenger) or suspected driving under the influence of alcohol or drugs (DUI). Of particular note was the proportional
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high prevalence (41%) of cathinone drugs (e.g. mephedrone, MDPV, 4-MEC) in hangings or other mechanical suicides (i.e. not suicide by drug overdose). This was
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a trend that was noticed relatively early by the authors in the “cathinone phenomenon” within drug users [9]. This was compared to other new psychoactives such as piperazines where of all deaths which involved piperazines, only 14% of
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those were such suicides.
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In order to see if the findings were significant, the most prevalent drugs found in hangings and other suspected mechanical suicides were assessed [9]. The most
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prevalent drug was paracetamol (found in 13.4% of these case types), followed by citalopram (12.7%), diazepam (8.4%), mirtazapine (8.0%), zopiclone (6.8%) and cocaine (6.5%). Figure 3 shows the proportion of cases in which each drug was found, expressed as a percentage of the total number of fatalities investigated (% All Deaths). Figure 3 also shows the proportion of those cases positive for each drug that were hangings or mechanical suicides, expressed as a percentage of all the cases positive for that particular drug (% Mechanical Suicide). Specifically, cathinones were only present in less than 0.1% of all fatalities investigated but when detected, over 40% of these cases were hangings or mechanical suicides. As there have been various studies regarding suicidal ideation and SSRIs [10-11], a selection of the most common of these drugs (paroxetine, sertraline and fluoxetine) was also included (although they did not feature in the most prevalent drugs found). It could be considered that if a drug may be linked with suicidal ideation then it may
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be present in a high proportion of such cases. Whereas if it does not (as potentially evidenced by paracetamol and diazepam), it would be present at a proportionately lower frequency. As for cocaine, an intense “high” may be followed by a subsequent “low”, with lethargy and low mood. As the psychological circumstances surrounding
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suicide are complex, the data are merely presented to show that nearly half of all deaths investigated that involved cathinones were hangings or other modes of
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mechanical suicide. Concentrations and toxicological significance
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Due to the very nature of new psychoactive substances, there is often very little if any data available regarding effects, toxicity and pharmacodynamic profile,
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especially when the compounds first appear on the drugs market [12]. When assessing toxicological significance, ideally it is also typical to utilise concentration data from in life or clinical studies as well as post-mortem casework. With various
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drugs of abuse, clinical therapeutic study data are invariably lacking and it is often difficult to assess what a typical “recreational” concentration is. When interpreting post-mortem concentrations, redistribution is an important consideration [13-14] and
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as such it is usual to compare with post-mortem concentrations found in deaths
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where the drug was not the primary cause or not contributory to death (e.g. road traffic death assuming drug toxicity did not cause impairment in the case of
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drivers/riders). A further consideration for drug concentrations is the stability of the drug and whether the measured level equates to the level at the time of sample collection. Also, as described above, poly-drug use is important when assessing possible drug-drug interactions. With new psychoactive substances, depending on how long they have been on the market and the number of times encountered by toxicologists, all such data are sparse or absent. In the cases presented in this 3 year period, it was not possible to measure the concentrations of all drugs in all cases (e.g. due to sample volume, case circumstances, etc). Therefore, in order to assist in presenting as much concentration data as possible, some cases investigated during 2013 are included and show a further increase in certain NPS (particularly 5/6-APB, MPA, PMA and AMT). The data are particularly presented to aid post-mortem interpretation, whereby
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concentrations found in cases of alternative causes of death (i.e. not directly drug related) along with those of sudden death are shown (Table 1). The data in Table 1 show a wide range of concentrations have been found in fatalities, with an overlap in the various case types including drugs driving. This is not
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unexpected and has been the case for a wide variety of drugs due to the differing drug behaviour of users (including frequency and dose) as well as the circumstances
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of the drug taking and outcome. In particular, it is often difficult (even with some well researched drugs like amphetamine and MDMA) to determine “recreational” and
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“excessive” use. This is coupled with the already described common situation of poly drug use, preventing a “toxic” or “fatal” concentration range to be proposed. Apart from mephedrone none of the other NPS were present in sufficient cases to permit
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meaningful comparisons of post-mortem concentrations in cases where there was an alternative cause of death to cases where drugs (not always or necessarily due to
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NPS) were the likely cause of death. Mephedrone exhibited a range of 0.02-2.23 mg/L (median 0.49 mg/L) for cases with an alternative cause of death (mainly hangings or passengers in road traffic collisions), compared to a range of 0.15-3.09
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mg/L (median 1.25 mg/L) in drug related deaths. This reflects similar findings
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reported by other toxicologists [15-16].
In relation to the other factors presented above for concentration interpretation, as
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various researchers have demonstrated instability in the cathinone compounds [1718], it is important to consider this when assessing the concentrations presented, not least the ranges mentioned above for mephedrone. However, recent work has shown that many of the other new psychoactive drug types encountered are stable [8].
Nevertheless,
the
overriding
consideration
when
assessing
the
drug
concentrations presented is the predominant feature of poly drug use in the cases presented. As mentioned above, this does not just involve concomitant prescription drug use but also combined use of new psychoactive drugs in isolation. This results in a comparatively “low” concentration of one or a number of drugs being found with or without a comparatively “higher” concentration of another new psychoactive. This is very common with the stimulant drugs resulting in a likely toxicological significance of monoaminergic effects (e.g. serotonin syndrome) and associated symptoms (e.g. seizures, increased body temperature) and/or acute cardiotoxicity [19-24]. Some particularly serious combinations found in the cases included AMT and drugs such Page 8
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as APB and MDPV, whereby AMT has monoamine oxidase activity, thus producing an elevation of serotonin, dopamine or noradrenaline. Exemplifying poly-drug use, one particular case within the 3 year period involved the ingestion of “Legal Highs” purchased from the Internet such as, “Mad Cat III”, “Super MDAI”, AMT,
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phenazepam, 5-IAI and methoxetamine. In the decomposed post-mortem heart blood, MDMA, MDPV, 4-FMC, methylone, MDAI, AMT, methoxetamine and 5-IAI
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were found (the state and nature of the blood prevented measurement). Selected post mortem cases
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In 3 previously reported cases where, in the absence of an alternative explanation for the death, NPS have been assumed to be the cause, concentrations of MDAI -
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26.3 mg/L [25], AMT - 0.89 mg/L [7] and desoxypipradrol - 1.16 mg/L [26] were found. In addition to these, the following cases have been selected where there was seemingly no other cause of death and the new psychoactive drugs found may have
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contributed to death.
Case 1: a 47 year old male with a history of hypertension was found unresponsive
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and was pronounced dead upon arrival at hospital. A post-mortem femoral blood
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BZP concentration of 20.4 mg/L was found, with no alcohol or other drugs. Case 2: a 20 year old female became ill and started hallucinating after taking 3
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“Ecstasy” tablets. She was taken to hospital but died the following morning. A PMA concentration of 1.61 mg/L was found in an ante mortem blood sample obtained around the time of admission. No alcohol or other drugs were detected. Case 3: a 31 year old male suffered a cardiac arrest and died having taken “MCAT”. Apart from cannabinoids and a low level of ibuprofen, a post-mortem femoral blood 4-FMC concentration of 4.42 mg/L was found. Case 4: a 25 year old female was found dead following a party. Apart from cannabinoids, low levels of cocaine, quinine, hydroxyzine (both likely as cocaine adulterants) and 4-FMC, post-mortem femoral blood concentrations of methylone (4.31 mg/L) and 4-MEC (5.83 mg/L) were found along with a blood ethanol level of 45 mg/dL.
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Case 5: a 43 year old male was found collapsed on his bedroom floor having taken a product named “China White”. Apart from a low level of phenytoin (although there was no history of epilepsy), only MPA (3.2 mg/L) and methoxetamine (1.1 mg/L) were
found
in
a
fluoride-preserved
post-mortem
femoral
blood
sample.
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Corresponding MPA and methoxetamine concentrations in the unpreserved blood were 2.8 mg/L and 0.89 mg/L. This suggested possible instability of the drugs but as
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mentioned this was not observed in a recent study of these and other NPS [8].
Case 6: a 51 year old male was found dead at home. In addition to a trace amount of
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MPA, AMT (0.19 mg/L), 5-APB (0.15 mg/L) and 5-MAPB (1.94 mg/L) were found in the post-mortem femoral blood. No alcohol or other drugs were detected.
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Case 7: a 22 year old female was found dead in bed. Apart from a low concentration of ethanol (19 mg/dL), a 4-methylamphetamine concentration of 5.8 mg/L was found in the post-mortem femoral blood. Although amphetamine and ketamine use prior to
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death was suspected, these nor any other drugs were detected. Subsequent to these cases, in 2013 there have been some additional fatalities
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involving existing and newly emerging drugs. Specifically, the opioid AH-7921 has
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been encountered on 3 occasions (0.58 mg/L, 0.05 mg/L and 4.46 mg/L in post – mortem femoral blood). Atypical benzodiazepines (e.g. phenazepam, etizolam,
Ac ce p
pyrazolam and flubromazepam) have also been encountered in casework but along with other drugs. However, some cases have involved existing and newly emerging drugs as a potential major contributor to death (i.e. camfetamine, APB, EAPB, methylone, AMT, 5-MeO-DALT, 4-methylamphetamine, 25B-NBOMe, 25C-NBOMe and PMA). These findings will be published in due course.
Conclusions
The frequency of new psychoactive drugs in casework has increased, particularly in recent years. Over the 3 year data collated, the majority of cases involved alcohol and/or other drugs with the high frequency of other stimulants (notably cocaine and amphetamines) being a constant feature. Nevertheless, new psychoactive substances were the sole agent in 19% of all cases and the sole agent in 7% of drug deaths. One particular observation of fatalities involving cathinones showed that a high proportion of cases were linked to suspected suicides. A review of
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concentrations showed a wide range of values across the varying case types and especially within the drug related deaths. This is likely to be due to the contribution of other drugs including other NPS and prescription drugs or drugs of abuse. Already in 2013 there has been the emergence of other new psychoactive
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substances in casework (e.g. etizolam, flubromazepam, ethylphenidate, etaqualone, AH-7921, MAPB, EAPB, 25B-NBOMe, 25C-NBOMe and 25I-NBOMe) in addition to
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further cases involving those NPS detailed here. Further work will continue to monitor and report these data and where possible assess trends or links within case
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types.
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Acknowledgements The authors thankfully acknowledge HM Coroners and the assistance and support of Dr Simon Brandt, Liverpool John Moore’s University.
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Figure 1
Figure 1 – The frequency of new psychoactive substances in cases between 20102012 (203 cases)
5/6-APB MPA Synthetic cann Methoxetamine Desoxypipradrol D2PM AMT 5-MeO-DALT Pentylone Naphyrone Methylone Pentedrone Mephedrone MDPV MDPBP Butylone 4-FMC 4-Methylethcathinone TFMPP BZP PMMA PMA 4-Methylamphetamine MDAI 5-IAI 2-AI
1 2 2 11 2 2 4
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1 1 4
cr
7 1
us
20
106
1 3
an
10
28 16 21
M
6 9 10
20
ce pt
0
ed
3
1 1
Miscellaneous
60
Cathinones
80
100
120
Piperazines
Aminoindans
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Phenethylamines
Tryptamine
40
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Figure 2
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Figure 2 – The frequency of other drugs found in cases with new psychoactive substances between 2010-2012
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Amphetamine Methamphetamine MDMA
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ce pt
ed
M
an
Hydroxyzine Lignocaine Levamisole Benzocaine
Buprenorphine Methadone Tramadol Heroin/Morphine
Page 17 of 19
Figure 3 revised
Figure 3 – Drugs detected as % in All Deaths and % of those that were Mechanical Suicide
50.0 45.0 40.0
30.0
ip t
25.0 20.0
cr
15.0 10.0
us
5.0
Mechanical Suicides
ce pt
ed
M
All Deaths
an
0.0
Ac
% Cases
35.0
Page 18 of 19
ip t
Table 1
Alternative Cause of Death
concentration/range mg/L
(median) if applicable
5/6-APB
0.48, 0.29, 0.89, 1.00, 0.75AM, 0.32, 0.16, 0.19, 1.3 (0.48)
N/A
0.34
N/A
0.10, 4.31, 11.0
N/A
0.02-2.23 (0.49 n=24)
0.15, 0.21, 0.36, 0.50, 0.68, 1.20AM, 1.30, 1.31, 1.51, 2.09, 2.17, 3.06 (1.25)
0.12,
