**11. Discussion**

370 Pharmacology

30 Yes bl + alcohol BZP TFMPP paracetamol citalopram

Third drug present

Fourth drug present

Fifth drug present

Sixth drug present

Second drug present

26 Yes ur + alcohol pyrovalerone BZP FTMPP

31 Yes bl + alcohol paracetamol citalopram zopiclone

alcohol benzocaine

alcohol benzocaine

metabolites

mine

alcohol venlafaxine quetiapine halperidol lorazepam

alcohol MDPV cocaine levamisole quinine

cocaine & metabolites methadon e

gabapentin oxycodone

33 Yes bl 0.08ug/ml methylone MDPV GBL 34 Yes bl + methadone alcohol cocaine

mine

metabolites

46 Yes bl 1.7mg/l BZP TFMPP codeine diazepam

43 Yes bl + alcohol cannabis diazepam 44 Yes bl 0.05mg/l GHB alcohol ampheta-

Case No.

Mephedrone present

24 Yes bl

23 Yes AM serum

Mephedrone levels

0.042mg/l, ur +

12.15mg/l, ur +

25 Yes ur + cocaine methylone

28 Yes bl trace morphine quetiapine

22 No - morphine

27 Yes bl 0.31ug/ml cannabis

29 Yes bl 0.07mg/l alcohol

use

use

37 Yes bl 0.03ug/ml cannabis 38 Yes bl + ur + diazepam

40 Yes bl + ampheta-

42 Yes bl 6.2mg/l diazepam &

0.033ug/ml, bile 0.05ug/ml, ur 0.24ug/ml

ur 11.67mg/l

39 Yes bl low level diazepam cannabis

41 Yes ur + alcohol cocaine &

32 Yes AM bl +

35 Yes bl + recent

36 Yes bl + recent

45 Yes bl

47 Yes bl <0.05mg/l,

49 Yes bl <0.3125,

48 Yes bl 0.51mg/l alcohol

ur +

The existence of the Special Mortality Register maintained by the National Programme on Substance Abuse Deaths fulfills several major roles: it provides a unique UK-wide historic repository of unparalleled detailed information on drug-related deaths and deaths of drug addicts since 1997; the provision of a nation-wide surveillance capability for monitoring substance-related deaths; and the provision of information on the epidemiology of such events.

This paper contributes to the knowledge-base on mephedrone by providing supplementary/complementary information on the epidemiology of its use in the UK through the provision of centralised collation of post mortem toxicological results. Furthermore, this report has provided an analysis of the only UK-wide, mephedronespecific mortality dataset. Although not all cases have yet been fully investigated, to the best of our knowledge this is the most comprehensive and detailed study of deaths associated with mephedrone in the literature.

#### **11.1 User profile**

One in five of 'mephedrone fatalities' turned out here not to be actually related to mephedrone, since the drug was actually not identified at post mortem. This might be understood in the context of the high levels of both media attention and public concerns surrounding the unprecedented rapidity of the appearance of mephedrone in the UK recreational drug market (Davey et al., 2010). However, some of these cases turned out to involve other methcathinones such as MDPV.

Typical mephedrone victims in this study were young (78% under 35 years of age); male (75%); White (96% where ethnicity was known); either in full time employment,

Mephedrone-Related Fatalities in the United Kingdom: Contextual, Clinical and Practical Issues 373

regarding the acute toxicity potential of the drug itself (James et al., 2011; Maskell et al., 2011; Schifano et al., 2011; Torrance & Cooper, 2010; Wood et al., 2010; Regan et al., 2010). It could be argued that the fact there are such a relatively large number of deaths in a comparatively short period (two years) underlines the need to inform consumers of its

Conversely, most mephedrone victims died of polydrug, and especially alcohol, consumption. Anecdotally, it appears that alcohol is taken in association with stimulants to get a stronger/better 'high'. Similarly, other stimulants such as MDMA/ecstasy, whilst in the presence of alcohol, show more significant physiopathological effects (Pacifici et al., 2002; Schifano et al., 2003a). In 15 cases mephedrone was ingested with stimulants. Cocaine, amphetamines, other methcathinones and/or ecstasy tablets may be taken to maintain arousal and a state of alertness, since the stimulant desired effects of mephedrone fade away in a few hours (Schifano et al., 2011). However, co-ingestion of two stimulants could increase, in a synergic way, both the dopaminergic and serotonergic stimulation, and this is likely to increase mephedrone toxicity effects and harm potential (Schifano et al., 2011). In other cases, arguably to modulate its stimulant effects, mephedrone was associated in this study with opiates (12 cases) and/or diazepam (13 cases). This is likely to be consistent with the observation made here that, where known, about 3 out of 4 victims had a history of drug misuse. It is noteworthy that other newly emerging psychoactive substances (including: GBL/GHB, ketamine, piperazines, as well as other methcathinones) were also found in several cases in conjunction with mephedrone; this is in line with the literature (Deluca et al., 2009; Schifano et al., 2011). In all of these polydrug abuse cases, the precise role of mephedrone in causing fatality was due to simultaneous drug use and remains unclear. Conversely, the use of stimulants might afford some protective effects to those who

The patterns of drug use evidenced by post mortem toxicology results are similar to those reported by surveys and online users' fora; polysubstance use is common, especially the coingestion of alcohol, stimulants and other 'legal highs'. The pathologies (including psychopathologies) exhibited in many of these cases exhibit close similarities to those previous noted for amphetamine, cocaine, MDMA and khat. The implication of these findings is that similar advice to that already given for adverse events caused by other stimulants should be provided to clinicians, the emergency services and first-aiders. It is suggested that the treatment for more life-threatening conditions might be broadly similar to that for amphetamine poisoning. Individuals with less severe symptoms should be assessed and managed as for any psychoactive drug user; they may simply need reassurance, support and observation. People with underlying cardiac, neurological and psychiatric conditions, especially those on medication, are likely to be at greatest risk of

Although our knowledge of mephedrone's potential neurotoxicity or long-term consequences of its use is still very limited, it is sensible to offer the following advice: avoiding regular use to avoid developing tolerance; not using the drug in combination with other stimulants or large amounts of alcohol and other depressants; not injecting the drug; remaining well hydrated when using the drug; and avoiding becoming overheated. Brief

potential to cause death on its own.

overdosed with sedatives.

**11.3 Treatment and prevention of fatalities** 

serious adverse events (Winstock et al., 2010).

unemployed or students; and with a previous history of drug misuse (73% where known). With an average age of 29 years and nearly four-fifths under the age of 35, the age profile of this dataset is much younger than cases typically reported to np-SAD (Ghodse et al., 2010).

Mephedrone misuse in the UK is likely to have started as early as 2007 (Davey et al., 2010), and the first mephedrone-related fatality recorded on the np-SAD database occurred in September 2009. Although further studies are needed to confirm present observations, it seems from the information presented here that reports of mephedrone fatalities dropped in the months following the announcement by the Home Office on 30 March 2010 that the chemical, together with other related substances, was going to become a Controlled Drug. However, there was a further peak in July 2010, as well as additional deaths occurring in February, April and May 2011. This suggests that mephedrone, as well as other illegal methcathinones, are still being consumed in the UK.

The excess number (doubling) of observed mephedrone-associated fatalities between Saturdays and Tuesdays, compared to other days of the week, might be explained by its more frequent intake over the weekend, confirming once again its recreational drug profile.

An issue of particular concern and, to the best of our knowledge, something previously unreported is that 16 victims (about 1 in 3 cases of the current sample) either hanged themselves (13 cases), or used particularly violent means to terminate their own lives. In 10 cases, the coroner gave a verdict of suicide and in 8 further cases an open verdict was returned. In most of these cases, mephedrone was considered to have played a contributory role. Although a full psychiatric history is not typically made available to np-SAD, it is worth emphasizing that, out of the whole sample, antipsychotics were here identified at post mortem in 2 cases and antidepressants in 5 cases. Therefore, it can be postulated that mephedrone (either on its own, or in a polydrug misuse combination) has the potential to cause and/or exacerbate psychosis and/or depression, thus facilitating the occurrence of bizarre behaviour/self harm with particularly violent means. In one instance, the possibility of Excited Delirium was recorded. Although the present report comments on only 60 cases, the suicide rates in our other UK studies of stimulant-related fatalities were quantitatively less significant, being in the range of 3-6%: amphetamine-type drugs (Schifano et al., 2010); MDMA/ecstasy (Schifano et al., 2010; Schifano et al., 2003b); cocaine (Schifano & Corkery, 2008). The rate for khat-related fatalities was about 31% (sample size = 13) (Corkery et al., 2010).

Contributory clinical (e.g. sepsis; bronchopneumonia; pre-existing atherosclerotic cardiovascular conditions) and environmental (e.g. involvement in traffic accidents, drowning, hypothermia) factors were here identified at post mortem in respectively 5 and 5 mephedrone fatalities. These observations are overall consistent with the existing literature on stimulant misuse and may reflect the sympathomimetic actions of mephedrone and the accident-proneness or risk-taking behaviour of stimulant, including mephedrone, misusers (Schifano et al., 2011).

Mean mephedrone blood levels at post mortem were of either about 1.43mg/l (in polydrug cases) or 2.00mg/l (mono-intoxication fatalities), which is broadly in line with previous, small scale, anecdotal observations (Dickson et al., 2010; Lusthof et al., 2011).

#### **11.2 Mephedrone use with other substances**

Although mephedrone was here identified on its own in the cause of death in only one-third of cases (n = 18, 30%), this finding confirms some of the concerns recently expressed regarding the acute toxicity potential of the drug itself (James et al., 2011; Maskell et al., 2011; Schifano et al., 2011; Torrance & Cooper, 2010; Wood et al., 2010; Regan et al., 2010). It could be argued that the fact there are such a relatively large number of deaths in a comparatively short period (two years) underlines the need to inform consumers of its potential to cause death on its own.

Conversely, most mephedrone victims died of polydrug, and especially alcohol, consumption. Anecdotally, it appears that alcohol is taken in association with stimulants to get a stronger/better 'high'. Similarly, other stimulants such as MDMA/ecstasy, whilst in the presence of alcohol, show more significant physiopathological effects (Pacifici et al., 2002; Schifano et al., 2003a). In 15 cases mephedrone was ingested with stimulants. Cocaine, amphetamines, other methcathinones and/or ecstasy tablets may be taken to maintain arousal and a state of alertness, since the stimulant desired effects of mephedrone fade away in a few hours (Schifano et al., 2011). However, co-ingestion of two stimulants could increase, in a synergic way, both the dopaminergic and serotonergic stimulation, and this is likely to increase mephedrone toxicity effects and harm potential (Schifano et al., 2011). In other cases, arguably to modulate its stimulant effects, mephedrone was associated in this study with opiates (12 cases) and/or diazepam (13 cases). This is likely to be consistent with the observation made here that, where known, about 3 out of 4 victims had a history of drug misuse. It is noteworthy that other newly emerging psychoactive substances (including: GBL/GHB, ketamine, piperazines, as well as other methcathinones) were also found in several cases in conjunction with mephedrone; this is in line with the literature (Deluca et al., 2009; Schifano et al., 2011). In all of these polydrug abuse cases, the precise role of mephedrone in causing fatality was due to simultaneous drug use and remains unclear. Conversely, the use of stimulants might afford some protective effects to those who overdosed with sedatives.

#### **11.3 Treatment and prevention of fatalities**

372 Pharmacology

unemployed or students; and with a previous history of drug misuse (73% where known). With an average age of 29 years and nearly four-fifths under the age of 35, the age profile of this dataset is much younger than cases typically reported to np-SAD (Ghodse et al., 2010). Mephedrone misuse in the UK is likely to have started as early as 2007 (Davey et al., 2010), and the first mephedrone-related fatality recorded on the np-SAD database occurred in September 2009. Although further studies are needed to confirm present observations, it seems from the information presented here that reports of mephedrone fatalities dropped in the months following the announcement by the Home Office on 30 March 2010 that the chemical, together with other related substances, was going to become a Controlled Drug. However, there was a further peak in July 2010, as well as additional deaths occurring in February, April and May 2011. This suggests that mephedrone, as well as other illegal

The excess number (doubling) of observed mephedrone-associated fatalities between Saturdays and Tuesdays, compared to other days of the week, might be explained by its more frequent intake over the weekend, confirming once again its recreational drug profile. An issue of particular concern and, to the best of our knowledge, something previously unreported is that 16 victims (about 1 in 3 cases of the current sample) either hanged themselves (13 cases), or used particularly violent means to terminate their own lives. In 10 cases, the coroner gave a verdict of suicide and in 8 further cases an open verdict was returned. In most of these cases, mephedrone was considered to have played a contributory role. Although a full psychiatric history is not typically made available to np-SAD, it is worth emphasizing that, out of the whole sample, antipsychotics were here identified at post mortem in 2 cases and antidepressants in 5 cases. Therefore, it can be postulated that mephedrone (either on its own, or in a polydrug misuse combination) has the potential to cause and/or exacerbate psychosis and/or depression, thus facilitating the occurrence of bizarre behaviour/self harm with particularly violent means. In one instance, the possibility of Excited Delirium was recorded. Although the present report comments on only 60 cases, the suicide rates in our other UK studies of stimulant-related fatalities were quantitatively less significant, being in the range of 3-6%: amphetamine-type drugs (Schifano et al., 2010); MDMA/ecstasy (Schifano et al., 2010; Schifano et al., 2003b); cocaine (Schifano & Corkery, 2008). The rate for

khat-related fatalities was about 31% (sample size = 13) (Corkery et al., 2010).

small scale, anecdotal observations (Dickson et al., 2010; Lusthof et al., 2011).

**11.2 Mephedrone use with other substances** 

Contributory clinical (e.g. sepsis; bronchopneumonia; pre-existing atherosclerotic cardiovascular conditions) and environmental (e.g. involvement in traffic accidents, drowning, hypothermia) factors were here identified at post mortem in respectively 5 and 5 mephedrone fatalities. These observations are overall consistent with the existing literature on stimulant misuse and may reflect the sympathomimetic actions of mephedrone and the accident-proneness or risk-taking behaviour of stimulant, including mephedrone, misusers

Mean mephedrone blood levels at post mortem were of either about 1.43mg/l (in polydrug cases) or 2.00mg/l (mono-intoxication fatalities), which is broadly in line with previous,

Although mephedrone was here identified on its own in the cause of death in only one-third of cases (n = 18, 30%), this finding confirms some of the concerns recently expressed

methcathinones, are still being consumed in the UK.

(Schifano et al., 2011).

The patterns of drug use evidenced by post mortem toxicology results are similar to those reported by surveys and online users' fora; polysubstance use is common, especially the coingestion of alcohol, stimulants and other 'legal highs'. The pathologies (including psychopathologies) exhibited in many of these cases exhibit close similarities to those previous noted for amphetamine, cocaine, MDMA and khat. The implication of these findings is that similar advice to that already given for adverse events caused by other stimulants should be provided to clinicians, the emergency services and first-aiders. It is suggested that the treatment for more life-threatening conditions might be broadly similar to that for amphetamine poisoning. Individuals with less severe symptoms should be assessed and managed as for any psychoactive drug user; they may simply need reassurance, support and observation. People with underlying cardiac, neurological and psychiatric conditions, especially those on medication, are likely to be at greatest risk of serious adverse events (Winstock et al., 2010).

Although our knowledge of mephedrone's potential neurotoxicity or long-term consequences of its use is still very limited, it is sensible to offer the following advice: avoiding regular use to avoid developing tolerance; not using the drug in combination with other stimulants or large amounts of alcohol and other depressants; not injecting the drug; remaining well hydrated when using the drug; and avoiding becoming overheated. Brief

purposes.

interventions and treatments.

**13. Acknowledgements** 

Health in the time frame 2004-2010.

Health Programme (2009 12 16).

**14. Conflicts of interest** 

**15. References** 

Mephedrone-Related Fatalities in the United Kingdom: Contextual, Clinical and Practical Issues 375

Further studies of a similar nature should be conducted in other countries, to see if the clinical and toxicity patterns associated with mephedrone use described here are confirmed. Notwithstanding the possible biases outlined above, the number of cases reported here may however suggest a significant level of caution when ingesting mephedrone for recreational

The limited information yet available on mephedrone underlines the need for basic preclinical and in-vitro research (and the necessary funding to carry it out) on the pharmacology, metabolism, etc. of methcathinones so as to provide evidence-based

The authors wish to thank coroners and their staff in England & Wales, Northern Ireland, and the Islands; Procurators Fiscal in Scotland; and the Scottish Crime & Drug Enforcement Agency for their assistance in providing data to the National Programme on Substance Abuse Deaths. Thanks are also due to colleagues in UK forensic toxicology agencies for assistance in identifying and confirming suspected deaths in which mephedrone consumption was positive. The np-SAD regularly received support from the Department of

This publication arises as well from the activities of the ReDNet Research Project, for which FS has received funding from the European Commission, in the framework of the Public

No conflicts of interest are declared here which may have influenced the interpretation of present data. Please note the following: JC has been the UK Focal Point expert on Drug-Related Deaths for the European Monitoring Centre for Drugs and Drugs Addiction since 2000; FS is a full member of the UK Advisory Council on the Misuse of Drugs (ACMD); JC and FS are members of the ACMD Working Group on Novel Psychoactive Substances, the UK Early Warning System. All authors are members of the International Centre for Drug Policy (ICDP). AHG is current President of the International Narcotics Control Board (INCB). The views expressed here reflect only those of authors and not necessarily those of the Department of Health, Home Office, the ACMD, the ICDP, the EMCDDA, or the INCB.

ACMD. (2010). *ACMD letter to Home Secretary - Mephedrone (and related cathinones)*. 13

Archer, R.P. (2009). Fluoromethcathinone, a new substance of abuse, *Forensic Science* 

Camilleri, A., Johnston, M.R., Brennan, M., Davis, S. & Caldicott, D.G. (2010). Chemical

http://www.homeoffice.gov.uk/publications/alcoholdrugs/drugs/acmd1/acmdmephedrone?view=Binary

*International*, Vol.185:10–20.

January. Advisory Council on the Misuse of Drugs, London, Available from:

analysis of four capsules containing the controlled substance analogues 4-

motivational interventions and appropriately adapted psychosocial intervention may be employed to treat mephedrone addiction (Winstock et al., 2010).

#### **11.4 Limitations**

A number of limitations need to be borne in mind in respect of this study: (a) not all suspected cases may have been identified; (b) remaining 'positive' cases are awaiting further inquiries or inquest; (c) the fact that mephedrone may have been involved in death cannot be confirmed until the relevant Coroner or Procurator Fiscal has concluded her/his inquest or other formal inquiry; (d) the presence of mephedrone in post mortem toxicology does not necessarily imply that it caused or contributed to a death; (e) not all completed cases have been formally notified to the Programme for recording. Hence, the number of identified cases reported here is likely to be an underestimation.

It is thought unlikely that the changes in fatality rates over time observed here are related to parallel changes in coroner methods, which would in turn affect surveillance. Data collection methods have remained unchanged. However, greater awareness of the phenomenon, improved case identification methods, and the devopment of new approaches in forensic toxicology and the range of substances now routinely screened for may have led to more potential cases being notified and registered.

Further limitations of the present report may include: lack of analytical attention to the role of the possible triggering environmental factors (i.e. overcrowding; hot settings etc); lack of total geographical coverage of coroner's jurisdictions; possible incomplete information relating to the prescription of psychoactive medications; and lack of information for some fatalities on the concentration of mephedrone detected in body fluids, so that some victims might have had only traces of the substance. Finally, since mortality rates (e.g. number of deaths out of number of mephedrone intake occasions) were not here calculated, it may be difficult to determine the true extent of risks associated with mephedrone consumption. However, in at least one case death occurred on the first use of mephedrone (albeit in combination with amphetamine).

#### **12. Conclusions**

This chapter has highlighted the dangers associated with mephedrone consumption, especially with regard to recreational use. This study represents the most detailed analysis to date of the largest number of mephedrone-related fatalities world-wide. It is hoped that it will thereby make a major contribution to the evidence-base being built up on this drug, and therefore, to reducing drug-related deaths.

Although identified on its own in only a minority of cases, present data confirm concerns regarding the acute toxicity potential of the drug. It is of concern that about 1 in 3 cases of the current sample used particularly violent means to terminate their own lives.

The number of mephedrone intake occasions was not calculated here, and so it may be difficult to determine the true extent of risks associated with mephedrone consumption. It may be possible to compare the lethality of mephedrone with other substances building on methods developed by King and Corkery (2010).

Further studies of a similar nature should be conducted in other countries, to see if the clinical and toxicity patterns associated with mephedrone use described here are confirmed. Notwithstanding the possible biases outlined above, the number of cases reported here may however suggest a significant level of caution when ingesting mephedrone for recreational purposes.

The limited information yet available on mephedrone underlines the need for basic preclinical and in-vitro research (and the necessary funding to carry it out) on the pharmacology, metabolism, etc. of methcathinones so as to provide evidence-based interventions and treatments.
