Dear Dr Brittain,

I am writing in response to the Regulation 28 Report to prevent future deaths received on 15th May 2017. I understand that Mr BARR (aka JEFFERS) died on 23rd February 2016 having been behaving bizarrely the previous day. He was found collapsed and in cardiac arrest at 5:36 pm on 23rd February and was pronounced dead at 6:46 pm. It is understood that on searching the ward a substance labelled as “Kronic” was found which was reported to contain the synthetic cannabinoid 5F-CUMYL-PINACA. Toxicological analysis was undertaken (including specific analysis for this substance) and according to the toxicology report of Imperial College London, only modafinil and olanzapine were detected (no 5F- CUMYL-PINACA or other drugs within the range of screening performed). At the inquest on 5th May 2017, the Court heard evidence that the nature of NPS (New Psychoactive Substances) is such that analysis of these compounds is difficult owing to frequent changes in their components and structure. There was a concern that the deceased may have used NPS during his admission to hospital which may have caused or contributed to death but this could not be substantiated by the available evidence. You were concerned that there was no specific evidence adduced which assured you that steps are being taken to address the risk that future deaths may occur unless NPS can be more accurately analysed and detected by toxicological testing.

Whilst we were not directly involved in the case, I welcome the Coroner contacting me and also identifying us as a prominent toxicology provider. I believe I may be able to assist HM Coroner with the issues involved and the concerns. In order to do this, I will address the case of Mr BARR specifically as well as the wider issue of NPS and toxicology.

The death of Mr BARR (aka JEFFERS)

The toxicology report indicates that screening for drugs in blood was performed utilising a “general screening” approach which is appropriate, although the database upon which detection/identification is based on may be limited as although “new psychoactive substances” was cited, the actual NPS included was not stated. Nevertheless, the key feature of this case was the seizure and analysis of the suspected drug product used “Kronic Black Label”. This is especially important nowadays in NPS testing as often they may only be unlabelled white powders, tablets, liquids, herbal plant material or branded products, the latter having no consistent relation to the brand and the contents. Dr R. Brittain HM Assistant Coroner Inner London North St Pancras Coroner's Court Camley Street London N1C4PP

FORM Letter 0034.05
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Subsequent analysis of the “Kronic” product identified 5F-CUMYL-PINACA which is a synthetic cannabinoid first seen in the UK in late 2014. It appears analysis of the blood for this compound as well as 3 other synthetic cannabinoids detected no compounds. It is unclear if this analysis was performed by Imperial College or not but as stated in the report, there are hundreds of potential compounds so it is unclear why only 3 additional substances were analysed for. Nevertheless, focusing on the suspected drug in question was entirely appropriate. The reason for its apparent absence in the blood could be due to it being present at a concentration below the limit of detection (thought to be 0.25 ng/mL for the additional 3 and not sure if this also applied to 5F-CUMYL-PINACA). As there are no published concentrations in post-mortem blood for 5F-CUMYL-PINACA it is not known if this limit of detection was sufficient or not but on the whole such a limit should suffice. Another reason is that the substance may have metabolised and been eliminated from the blood during the time elapsed between using the substance and death. In this case this may have been many hours and although no specific data exist for the expected time window of detection, current information suggests rapid metabolism/elimination of synthetic cannabinoids so it is possible that disappearance from the blood may have occurred. A third reason may be that synthetic cannabinoids are known to be unstable, although 5F-CUMYL- PINACA does not possess the chemical components found in current synthetic cannabinoids that are highly prone to instability in blood. A final reason for its apparent absence may be that Mr BARR had not used the product or had used a different product (if at all) recently prior to death. I am not aware if these scenarios were discussed during the inquest.

If it assists HM Coroner, our approach would have also been to undertake a general drug screen but in both blood and urine which would have included a significant number of known (over 1000) and unknown compounds - including many NPS. A list is available if required. In such a case, along with analysis of the “Kronic” product, we would have also applied advanced techniques to analyse for latent drug metabolites in the urine especially for synthetic cannabinoids as due to their purported rapid metabolism/elimination, they are often present as metabolites only. Regardless we would have described the various scenarios that may have occurred and provided extended interpretation in the report. This is no criticism of the approach by Imperial College but merely provides HM Coroner with some form of comparative approach to inform my next point.

New Psychoactive Substances

Clearly the inquest heard evidence of the challenging nature of NPS and their analysis. This is due to a number of things but is largely in part due to the changing chemistries, sometimes potent nature leading to very low concentrations, lack of reference material to enable “pro- active” method optimisation and potential instability of such substances in biological fluid – especially post-mortem samples. This is not helped by the variable analytical methods employed by toxicology organisations as there is no one “gold standard” technique or instrument as a multi-technique approach is the best option and this requires time and investment, that is not possible for all or many organisations or palatable in the current climate of lower costs and quicker turnaround time for analysis. So you raise an appropriate concern in that how is this being addressed by the toxicological community. The short answer is that it is but also it isn’t or has not been sufficient across the board. You will have seen in this single case, a slightly different approach outlined by two long-standing and experienced organisations, therefore concern is warranted if this is extrapolated to the wider laboratory marketplace.

FORM Letter 0034.05
22.08.2016 | SE LGM Forensics Ltd, company no. 06167670. VAT registered no. 926 4130 39. Also trading as Alere Forensics (Previously ROAR Forensics). Additional office: Windsor House, Ackhurst Business Park, Chorley PR7 1NY

The toxicology community is aware of the challenges and problems involved in NPS and there is a concerted effort to first ensure they are aware of the various drugs of concern, whether this is through awareness of the scientific literature and/or attendance at scientific meetings (both national and international) where NPS are invariably discussed, not least at the UK & Ireland Association of Forensic Toxicologists (UKIAFT) where Dr Paterson and myself are Chair and Vice-Chair, respectively. Within these meetings (especially internationally) analytical methodologies are presented and published but of course it is the duty of the toxicologists and organisations to assess whether they have the necessary opportunity to replicate such work.

For our organisation in particular, we regularly attend and present at such meetings as well publishing on the topic of NPS (see list of publications on our website) and importantly are also actively engaged in the UK and European Early Warning Systems for NPS. I am also personally a Member of the Expert Committee for Drugs and Drug Dependence (ECDD) at the World Health Organisation that prioritises NPS for assessment for international drug control as well as working directly with the United Nations Office on Drugs and Crime (UNODC) that monitor the situation worldwide. This has resulted from my many years involvement in the investigation and identification of NPS (sometimes for the first time in the UK, Europe and the world) which has resulted from a significant time investment and determined effort in such investigations on the back of clinical and post-mortem toxicology casework. We also work with Liverpool John Moore’s University to obtain synthesised or characterised reference material of NPS that are newly on the market or have yet to become fully commercialised. This is subsequently coupled with publications to allow other laboratories to detect and identify such substances. This particular approach has been very successful in many cases on behalf of HM Coroners and the Police, with us being able to pre-emptively identify NPS that have had a positive impact on the investigation; including cause of death and driving under the influence in particular. We also provide training for stakeholders (HM Coroners, Coroners’ Officers, Pathologists and APTs) in relation to current drugs and toxicology. Even for ourselves there are still challenges such as ensuring methodologies are kept up-to-date and potential substance instability is researched and understood; to this end we regularly accommodate university MSc studentships (including King’s College London and the University of Birmingham) for short-term projects to do this.

In conclusion, I hope some of these comments address some of your entirely valid concerns but there is also a recognition that it requires investment and effort of all parties, not least toxicology providers, to move forward with this. Despite variations in legislation, NPS continue to be a challenge to all those concerned and you rightly highlight that improvements should be made to prevent future deaths. If it assists, I would be happy to discuss any of these aspects with yourself and HM Senior Coroner further, as well as providing any analytical support for the District.

Dear Dr Brittain,

Thank you for your Regulation 28 Report to prevent future deaths, dated 15th May 2017, bringing to my attention the Coroner’s concerns arising from the inquest into the death of Nature Barr. The members of the Psychopharmacology, Drug Misuse and Novel Psychoactive Substance Research Unit at the University of Hertfordshire have given careful consideration to the concerns outlined. I set out the actions we have taken and plan to take in response to the concerns below.

(1) “… [the] risk that future deaths may occur unless NPS can be more accurately analysed and detected by toxicological testing.”

Novel Psychoactive Substances (NPS) is the scientific name of mind-altering substances also misleadingly known as “legal highs”. The phenomenon of NPS began, among a small group of individuals, about a decade ago but in the last few years it has grown exponentially and represent now a major treat in terms of public health.

There is a growing evidence of negative effects secondary to the use of NPS. This evidence was at first anecdotal (e.g. media coverage), but recently the scientific community has focused its interest on NPS and therefore there is now a growing number of scientific studies and related publications. The Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit at the University of Hertfordshire is actively engaged in research to facilitate the accurate identification of NPS from “seized” samples, and to provide clinicians with updated guidelines to help them better manage patients presenting with toxicities associated with abuse of NPS. The head of the unit, Professor Fabrizio Schifano, is a full member of the Advisory Council on the Misuse of Drugs (ACMD). Both he and another member of the unit, Mr John Corkery, are members of the ACMD's Technical and NPS Committees. In addition, Prof. Schifano has recently been appointed chair of the ACMD's new committee on Performance and Image-Enhancing Drugs.

Overall, unprecedented knowledge has been provided by our research group on the epidemiological, psychopathological and overdose issues related to the misuse of NPS. To this respect, Professor Schifano has been the Principal Investigator of 6 consecutive EU Commission-funded, multi-centre (i.e. 12 EU countries), Novel Psychoactive Substance-based, research

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programmes (since 2002). These have included the following: ‘Psychonaut 2002’ (2002-2004); ‘Psychonaut Web Mapping system’ (2008-2009); ‘EU-ReDNet/Recreational Drug Network’ (2010-
2012); EU-MADNESS (2014-2016); and EPS/NPS (2015-2016) projects. In particular, the University of Hertfordshire and St George's University of London co-led the EU-funded EU-MADNESS project “EUropean-wide, Monitoring, Analysis and knowledge Dissemination on Novel/Emerging pSychoactiveS”. The objective was to develop integrated monitoring and profiling of Novel Psychoactive Substances (NPS) in Europe in order to prevent health harms and update relevant professionals. The project aimed: to monitor, test, profile, and feed back into education and prevention knowledge relating to the types of NPS emerging, their associated characteristics and potential harms.

Specific actions taken to address the concern: Very little is known of the effect of NPS in individuals with mental health conditions. Our University of Hertfordshire (UH)-based NPS Unit has started to collect data on the effect of the NPS in individuals admitted in the Highgate Mental Health Centre.

This particular project is being carried out in collaboration with two Highgate Mental Health Centre psychiatrists who have also enrolled for a PhD with our University (supervisor: Dr Ornella Corazza). The aim of their study is to gather new information on the effect of the NPS among vulnerable individuals, but also to develop evidence-based policies that will help to control and reduce the damage caused by these compounds.

In 1997 whilst working at the Home Office, John Corkery helped to set up the National Programme on Substance Abuse Deaths (NPSAD), which is based at St George's University of London. He also served on the Council's reconvened Drug-Related Deaths Working Group, having worked as a Home Office Official on the original Working Group in 1999-2000. Professor Fabrizio Schifano joined the NPSAD in 2000. Although their formal association with NPSAD has ended, they both continue to work together on research projects and publish together.

Our efforts are also focused to improve in-field methods of NPS identification in products using analytical approaches (led by Dr Jacqueline Stair). The main approach we are currently researching in handheld Raman spectroscopy which allows the identification of key molecular scaffolds via the scattering of light. This tool is to enable the quick identification of NPS at borders, from seizures, or from individuals. Due to the > 650 NPS that exists, Raman spectroscopy can differentiate between closely related NPS analogues which can vastly reduce the number of substances sent to forensic labs for full analytical testing, which can be costly and time-consuming. A particular challenge is that NPS products are often available as complicated mixtures of NPS, adulterants, and cutting agents. To this end, we are focused on examining sophisticated mixture algorithms for their effectiveness of NPS identification in product mixtures often found with ‘street’ samples. As only a sample of suspected products can usually be send for full analytical testing/ NPS subsequently identified, this technology can improve presumptive analysis throughput for identification of more NPS products arriving in the EU and UK. The idea is to greatly reduce the NPS making it to the UK market for human consumption via improved identification.

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As an extension of this work, Dr Amira Guirguis recently completed a PhD (supervised by Dr Jacqueline Stair, Dr Stewart Kirton and Dr Suzanne Fergus) on the ‘identification of NPS using spectroscopic and chemometric approaches’. Her work examined the issues surrounding the appropriate selection of analytical conditions and instrumentation for the detection of NPS; a scientifically-robust approach to construct compound libraries that have relevance to ‘in-field’ analysis and data analytical science that examined approaches that can be employed to develop accurate NPS identification algorithms from spectroscopic information for use by non-experts. This work aimed at providing advice and support in the following areas: General education on NPS for pharmacists, common cutting agents and adulterants in NPS samples, what they are, how to identify and classify them, health harms posed by NPS and harm reduction techniques. Additionally, research was carried out with respect to education on the strengths and limitations of in-field techniques used for the identification of NPS, education on using handheld Raman techniques in the field and advice on improving the signals obtained and hence increasing the chances of detecting NPS. The technical aspects of these studies to aid accurate identification of NPS in “street” samples included:  Strategies to reduce fluorescence and enhance signal to noise in field Raman measurements.  Approaches to validate and use spectral libraries that can identify and categorise chemical species present in complex mixtures of poorly-defined provenance.  Signal processing approaches that can be employed to introduce greater discrimination for adulterants that often contribute to the noise in Raman spectra, which pose a barrier to identification of unknown constituents in typical mixtures.  Development of chemometric approaches to build a spectral library that provides appropriate cover of the entire chemical space underlying known NPS.  Incorporation of common adulterants and cutting agents into high resolution spectral databases in order to develop categorisation approaches using an expanded ‘importable’ library and subsequent attempts to deploy that strategy for hand-held device, remote analysis.

Dr Guirguis is also leading on potential collaborations with the Royal Pharmaceutical Society (RPS), consultant psychiatrists, addiction specialists, general community pharmacists, mental health pharmacists and mental health nurses in the UK to assess the baseline knowledge on NPS and the design of education and training courses on NPS targeting healthcare professionals. Future work over the next year will include collaborations with French psychiatrists and addiction specialists to design a tool that clinicians can use for the efficient identification of NPS. She is also leading on a two-fold study: 1) to train and educate police officers on the use of handheld Raman instruments which could be employed on road-sides as well as in prisons for the identification of solid samples confiscated from prisoners and 2) to train and educate police officers and healthcare professionals who work in prisons on NPS and their categorization, which may potentially enhance the management of NPS use and assist in treatment decision-making. Her work is currently exploring developing undergraduate pharmacy curricula on NPS, which can be piloted nationally.

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In order to compliment and extend the work carried out to systematically classify existing NPS, Dr Stewart Kirton, Dr Jacqueline Stair and Dr Suzanne Fergus are leading research into predicting the next generation of chemical scaffolds that could be exploited by those who synthesize and distribute NPS. One PhD student (Michelle Botha) has used computers to identify a series of commercially available compounds that have the potential to bind to the CB1 receptor, but crucially are significantly different with respect to their chemical structures from any of the identified synthetic cannabinoids. Currently, biological testing is underway to establish if the activity predicted in silico is apparent in vitro/in vivo. Where biological activity exists, the spectral properties of the active compounds will be fed into the computational models that have previously been described. For the first time, this will provide a technology capable of identifying and classifying molecular scaffolds prior to them appearing on the market. Funding will be sought to extend the scope of this research into other classes of NPS beyond that of the synthetic cannabinoids.

We hope that our response demonstrates the actions that are being taken here in the Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit at the University of Hertfordshire to address the concerns around the real and significant dangers posed by the abuse of NPS. As you can see our approaches to tackling the problem are multi-faceted and extend from physical science and informatics, through medicinal chemistry and biological evaluation to clinical guidance and epidemiology. However, it is important to be clear that at this time we have no plans to develop techniques for the identification of NPS and their metabolites from biological matrices (e.g. blood and urine). The expertise of the members of the group does not extend to this type of biological analysis, and we feel others are better placed to address this issue.

I6 |Ssmv Imperial College 2 6 London Toxicology Unit Imperial College London Charing Cross Campus St Dunstan Road London W6 SRP Tel; 020 8846 7107 Fax: 020 8846 7110 spilletsuk qinperalac uk HWW Imperial_aC uk/medicine/toxicology Dr $ Paterson BSc MSc PhD Head of Toxicology Unit Consultant Forensic Toxicologist Re: Response to Report to Prevent Future Deaths concerning Nature Barr (also known as Howard Jeffers) (deceased) Tox Ref: 0354/16 Qualifications and experience Lhave a BSc degree in Physiology & Biochemistry. an MSc degree in Forensic Science and a PhD degree in Pharmacology: am Head of the Toxicology Unit at Imperial College London; a position [ have held since 1994. have over 30 years' experience of analysing samples from Coroners' post- mortem cases and interpreting the results_ Ireceived a Report to Prevent Future Deaths concerning Nature Barr (also known as Howard Jeffers) from R Brittan, Assistant Coroner for Inner London North dated 15 May 2017. Coroner' $ concerns Evidence was heard stating that the analysis of NPSs is difficult owing to frequent changes in their components and structure. The concern was that Mr Barr may have used NPSs during his admission to hospital which may have caused or contributed to his death. However; this could nol be substantiated in the available evidence. The concern is that there is a risk that future deaths may occur unless NPS can be more accurately analysed and detected by toxicological testing: The concern is that at the inquest in to Mr Barr there was no specific evidence adduced which reassured that steps are taken to address the risk of death from NPSs_ NPSs The major classes of NPS available for purchase on the streets or via the internet include B- phenethylamines, cathinones and piperazines, which were the first NPSs t0 make an appearance in the early 2000s. ~Spice" 0r synthetic cannabinoids started to appear around the same time and the first one was identified in 2008. Within the last year another group of compounds have started to appear, synthetic fentanyls. For each ofthese classes of NPSs a starter compound has been identified, phenylethylamine (CxHnN) for phenylethylamines; cathinone CoHnNO) for cathinones, piperazine (C4HmoNz) for piperazines. tetrahydrocannaibinol (C2H302) for synthetic cannabinoids and fentanyl (Cz2HzsNzo) for synthetic fentanyls. These starter compounds are then structurally modified eg a hydroxyl group is removed, a oth/ RECEIVED JUN 2017 being

Mhethyl group added etc to produce absetaPhenylethylamineso odiconcomaodndiowhich mimic the effects of the subslieuamine; synthetic cannabinoodss and piperazines give effects common of substitutes heroin_ similar to cannabis; broadly similar to parentheses) shows that the et the empirical fommula for the synthetic fentanyls can be estimated that the number of possible synthetic starter compounds (shown in over 100 synthetic cannabinoids Coblpounds is massive. For examplevnt is available. Mstrumentation for Analysis of the NPS can be detected instrument of choice is one thatest in post-mortem blood if advanced presumptive identification capable of giving the accurate masscef is used. The all for ithout a standard These instrumenes compound and therefore case in many coroners work should be carried out cost in excess of_
000. Ideally laboratories; This maybe of the such instrumentation but this is noe he which is paid by cost of the instrumentation, Highly trained staff are also authorities been severely cut for necessary if such instrumentationes back in recent years used. of NPSs Some of have 10,000 rOmnouode.are extremely potent for example even with the shepotency of morphine. This makexdheF one fentanyl is estimated to consistent with inost advanced as "desctibedheborlysie techcically very challengiagand ingestion of a fatal would be below the concentration present in blood the limit of detection; Standards In order to positively identify required, For most and to measure the amount manufacture them . NPSs no standard is available; it present, a standard of that is It is possible to make is not cost effective presumptive identification anyone to only without a standard of NPS types The NPSs available on the market possibly standard becomee avaikblerherontinually changing Once one been the compound and produce then the suppliers of these identified and a new modified compound compounds tweak the structure of Interpretation Nailabae abae Tocoloeical clinical trials etc; have been sale on the streetlinternet Even if the performed on the novel compounds pharmacological effects the will have. NPS is identified it is difficult to predictiae measured interpretation is not possible even if a standard is available and the concentcatioe because no reference ranges for these are available_ Conclusion Analysis of NPSs is limited and challenging because of the number of potency; lack of lack of standards and lack of compounds available, their proposed pharmacological data. Therefore no action is Sikatess Dr Sue Paterson 22nd June 2017 Consultant Forensic Toxicologist drugs very for smoking Looking are Many technology screening 'E250,( using because Coroners toxicology local Funding has Potency these times analogue technology dose Drug drug drug drug for drug Availability has testing; drug " Also drugs funding;