The changing pattern of synthetic cannabinoid use within England,April 2014 to March 2018

Abstract

Introduction

Synthetic cannabinoids (SC), designed to mimic delta-9-tetrahydrocannabinol, the natural component of cannabis, have seen a rapid increase in popularity since 2008. Nearly 200 SC have been detected to date. However, there are limited data available reporting the changing trend in their use. Here, we report the temporal changes in SC use, as well as the demographic profile of users.

Method

In this retrospective study, case background and toxicology findings were collected from forensic toxicology reports dated between 1 April 2014 and 31 March 2018 that included a positive result for the presence of one or more SC and/or metabolites.

Results

A total of 113 cases were positive for SC; 103 (91.2%) of the individuals were male, with a median age of 40 years (range 15–80 years). Over the four-year time period, a total of 12 different SC were detected; seven of these SC were detected in more than six cases each. The most commonly detected SC had a lifetime of one to two years before being replaced.

Discussion and conclusion: Our data show that SC were being used for approximately one to two years before they were superseded by newer structures. It is therefore extremely difficult to predict future patterns of SC use and is consequently not advisable to offer limited screening.

Keywords

High-resolution accurate tandem mass spectrometry NPS synthetic cannabinoids

Introduction

Since the early 2000s, there has been seen a steady rise in the use of so-called legal highs, or new psychoactive substances, of which synthetic cannabinoids (SC) comprise the largest group.¹ SC were first developed in the 1960s to investigate the therapeutic potential of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, as well as investigate its endogenous receptors.² However, they eventually emerged onto the illegal drug scene where they quickly became popular due to their potent affect, undetectable nature in routine screening and undetermined legal status, the latter of which made them both cheap and easily accessible.^3,4

THC and SC exhibit their effect through the endocannabinoid system, which is comprised of the two cannabinoid receptors type 1 (CB₁) and type 2 (CB₂).⁵ CB₁ are located within the central nervous system (CNS) and the periphery, and are responsible for the psychotropic effects of cannabinoids.^2,6 CB₂ are mainly found on immune and haematopoietic cells (although they have been detected in small quantities in the CNS⁷ where they are thought to play a role in immune modulation.^2,6 The exact relationship between the two receptors is poorly understood.

Despite working through a common receptor system, very few SC share any structural similarities with THC.⁸ To date, >179 SC have been detected, which are classified into 14 distinct groups depending on their structures, with new SC emerging every year.¹ The large scale and variability of this group of substances means very little is known about the pharmacodynamics of each individual SC. THC is known to be a partial agonist of cannabinoid receptors. However, SC may be full, partial, neutral or even inverse agonists.^9,10 As well as this, many SC also have increased binding affinities,¹¹ longer half-lives and can result in the production of multiple active metabolites.^12,13 These differences can all account for the unpredictable and often serious adverse effects seen following ingestion of SC compared to THC.

SC are synthesised as powders, which are then dissolved in acetone and sprayed onto dried plants and herbs to be sold under names such as ‘Spice’ or ‘Black Mamba’. This allows the products to be smoked in a manner similar to cannabis.¹⁴ As there is little standardisation in the production of SC, there can be significant batch-to-batch variation.^4,5 This means users are often unaware of how much they are taking, making overdose a serious risk. The majority of the current knowledge on the effects of SC is anecdotal, coming from self-report surveys,^10,15,16 records of self-referral to emergency departments¹⁷ and case reports.^14,18,19 Only a small amount of data has been provided by controlled administration studies.^20–24

Until December 2009, SC were legal in the UK and were sold freely over the Internet and on the high street.⁹ As the popularity of SC increased, so did the associated problems. To overcome this, the Misuse of Drugs Act 1971 was updated to include five SC, listed by name, and their overall sale was banned.²⁵ However, this resulted in the synthesis of newer and stronger SC that differed in structure and were therefore not covered by the updated law.²⁶ Eventually, in May 2016, the Psychoactive Substances Act 2016 came into force, imposing a blanket ban on substances that stimulate or depress the CNS, or affect mental function or emotional state (with the exception of alcohol, nicotine, caffeine, food, drink and medicinal products).²⁷

One long-standing issue with SC has been their detectability in urine and blood tests. Due to the structural differences between SC and THC, most SC are not picked up by standard drug screening.^5,28 This issue has recently been overcome by the use of high-resolution accurate mass (HRAM) spectrometry combined with information and intelligence from drug seizures, forensic networks and the European Monitoring Centre for Drugs and Drug Addiction.^29,30 Despite these advances, SC screens are performed off-site, so results are not instantly accessible. Therefore, the screens are of limited use when determining a management plan in the case of intoxication.

To date, there are minimal data describing the trends in SC use over time. Knowing this information could help direct SC research, such as formulating antidotes to acute intoxication and facilitating the design of rapid in-house drug screening. Since 2014, all post-mortem toxicological investigations at the University of Leicester NHS Trust into deaths that have occurred in prison or where there has been a history consistent with drug use have been referred for a SC screen when standard screens have no provided a reasonable cause of death. Here, we report the general epidemiology and temporal changes in SC detected in post-mortem cases across England between April 2014 and March 2018.

Methods

Study population and data collection

Key inclusion criteria were the detection of one or more SC, or metabolites, in biological samples through toxicology testing. Samples came from North West England, North East England, Yorkshire and the Humber, East Midlands, East Anglia and South West England. Data were collected retrospectively from toxicology reports produced between 1 April 2014 and 31 March 2018. Data collected included case background (age, sex, date of death, region, medical history, psychiatric history, forensic history and drug use history) and toxicology findings.

Statistical analysis

Data are expressed as median and range or number and percentage (%) as appropriate. All data are presented to one decimal place.

Results

Demographics

During the period 1 April 2014 to 31 March 2018, 11,460 cases were received by the East Midlands Forensic Toxicology service, of which 473 were sent for SC analysis. Of these, 113 cases were positive for SC. Most (103; 91.2%) of the individuals were male, with a median age of 40 years (range 15–80 years). Age was not available in two cases. The majority of cases were from the East Midlands (73 cases; 64.6%) and Yorkshire and the Humber (25 cases; 22.1%). Over the time period analysed, four cases were detected between April 2014 and March 2015, 36 cases between April 2015 and March 2016, 35 cases between April 2016 and March 2017 and 38 cases between April 2017 and March 2018.

SC

Twelve different SC were detected (Table 1). The number of SC detected was variable for each case, with 60 cases being positive for one SC, 42 cases positive for two SC, 10 cases positive for three SC and one case positive for four SC. The most commonly detected SC were 5F-ADB (55 cases; 48.7%), AB-FUBINACA (38 cases; 33.6%), MDMB-CHMICA (34 cases; 30.1%), 5F AKB-48 (25 cases; 22.1%), 5F PB-22 (8 cases; 7.1%), AMB-CHMICA (6 cases; 5.3%) and AB-CHMINACA (6 cases; 5.3%; Table 1).

Table 1.

Synthetic cannabinoids detected.

Synthetic cannabinoid	Cases detected	%
5F-ADB	55	48.7
AB-FUBINACA	38	33.6
MDMB-CHMICA	34	30.1
5F AKB-48	25	22.1
5F PB-22	8	7.1
AMB-CHMICA	6	5.3
AB-CHMINACA	6	5.3
AMB-FUBINACA	2	1.7
ADB-CHMINACA	1	0.9
5F-AMB	1	0.9
THJ-2201	1	0.9
ADB-FUBINACA	1	0.9

Incidence of individual SC

Over the given time period, there was a distinct variation in the incidence of SC detection: 5F AKB-48, 25 cases detected from May 2014 to April 2016; 5F PB-22, seven cases detected from December 2014 to September 2015, with one further case detected in December 2017; MDMB-CHMICA, 34 cases detected from April 2015 to September 2017; THJ-2201, one case detected in May 2015; AMB-CHMICA, six cases detected from August 2015 to September 2016; AB-CHMINACA, six cases from November 2015 to January 2017; 5F-AMB, one case detected in November 2015; 5F-ADB, 55 cases detected from January 2016 to March 2018; AB-FUBINACA, 38 cases detected from January 2016 to February 2018; AMB-FUBINACA, two cases detected in March 2016 and December 2016; ADB-FUBINACA, one case detected in May 2016; and ADB-CHINACA, one case detected in May 2016. Figure 1 shows the incidence of the seven most commonly detected SC.

Figure 1.

Incidence of the seven most commonly detected synthetic cannabinoids.

Case background

Eight (7.1%) individuals had a medical history of myocardial infarction/cardiac arrest, 10 (8.8%) had diagnoses of asthma/COPD and six (5.3%) were hepatitis B/C positive.

Thirty-two (28.3%) individuals had a known psychiatric history. The most commonly reported conditions were depression (15 cases; 13.2%), and anxiety (6 cases; 5.3%). Sixteen (14.2%) individuals had committed suicide. However, only three of these cases had a documented history of self-harm or previous suicide attempt (out of nine [8.0%] cases in total).

Thirty (26.5%) individuals had a forensic history, defined as having spent time in prison. Twenty-six (23.0%) died whilst incarcerated, of whom 14 (12.4%) had committed suicide.

Additional toxicology findings

Eighty-three (73.5%) individuals were known to be drug users and/or alcohol dependent. Of the 113 SC-positive cases, drugs were detected in 87 (77.0%). Some of the most commonly detected drugs (positive in 10+ cases) included illicit/controlled drugs – cannabis (18 cases; 15.9%), cocaine (27 cases; 23.9%), morphine/6-MAM (30 cases; 26.5%), methadone (16 cases; 14.2%) and diazepam (29 cases; 25.7%) – and prescription/over-the-counter drugs – pregabalin (18 cases; 15.9%), mirtazapine (21 cases; 18.6%), amitriptyline (10 cases; 8.8%), codeine (20 cases; 17.7%) and paracetamol (28 cases; 24.7%). Alcohol was detected in a total of 40 (35.4%) cases. Of the remaining 26 (23.0%) cases, seven (6.2%) were positive for SC and alcohol, whereas 19 (16.8%) were positive for SC alone. Table 2 summarises the most commonly detected drugs.

Table 2.

Drugs detected along with synthetic cannabinoids.

Drug	Cases detected	%
Morphine/6-MAM	30	26.5
Diazepam	29	25.7
Paracetamol	28	24.7
Cocaine	27	23.9
Mirtazapine	21	18.6
Codeine	20	17.7
Cannabis	18	16.8
Pregabalin	18	16.8
Amitriptyline	10	8.8

Discussion

This study is the largest post-mortem analysis of SC use to be performed in the UK. In keeping with the findings from previous literature, we found that the majority of SC users were male.^10,15–17 Interestingly, compared to previous self-surveys on SC use, we actually found the proportion of male-to-female users to be higher by about 10–20% (70.7–79.6% vs. 91.2%).^10,15,16 Additionally, we also found that users in our study had an increased median age (23–27 years vs. 40 years).^10,15,16 Our data are more in keeping with that of Sud et al.¹⁷ who found that in a sample of patients presenting with SC intoxication, approximately 98% of users were male with a median age of 35 years. However, our data set looks at a very specific group of users and therefore is not easily comparable to other studies. One explanation for the difference in age could be accounted for by the fact that older users of SC are more likely to have other significant co-morbidities. Unfortunately, the amount of detail provided for the past medical history varies significantly between each case. So, we cannot definitively comment on the role co-morbidities may have played. For this reason, we also cannot comment on the high proportion of individuals who had a reported psychiatric history.

Over the four-year period, there was a distinct variation in the incidence of each SC detected. It has previously been noted that SC have a life cycle of about one to two years,²⁵ which is similar to what we have observed. JWH-018 was the first SC to be detected in 2009, and in 2010 was found in the majority of ‘Spice’ products analysed.^4,17,31 However, by 2012, following a wave of modifications throughout Europe and the USA to the legal status of JWH-018, it had all but disappeared from the market and had instead been replaced by XLR-11.¹⁷ This trend has been seen to continue, and in keeping with our findings, the most commonly detected SC in the UK in 2015 were 5F AKB-48 and 5F-PB22,³² but by 2016 this included MDMB-CHMICA and AB-CHMINACA.¹ It is only two years since the Psychoactive Substances Act 2016 came into force in the UK, which means it is difficult to analyse fully the impact this change in law will have on the future trends of SC use. However, our data are suggestive of a change in the previously seen pattern, as the current two most common SC – 5F-ADB and AB-FUBINACA – have already been detected in post-mortem samples for more than two years, with their rate of detection increasing in recent months.

Nearly a quarter of the individuals in our study died whilst incarcerated. The use of drugs in prison is a well-known occurrence. However, SC have quickly become the main drug of choice. This is reflected in the number of seizures of SC from prisons in England and Wales, which rose from 15 in 2010 to 430 in the first half of 2014.³² This increase in SC consumption in prisons has been directly linked to an increase in serious assault and violence against staff, as well as self-harm and suicide.^33,34 These observations have been reflected in our study, as more than half of our cases who died in prison had in fact committed suicide.

Other drugs (including alcohol), aside from SC, were detected in the majority of our post-mortem cases. This agrees with data from self-surveys, where most users of SC report polydrug use.^10,15,35 Interestingly, 19 of the cases reported here were positive for SC only. The direct role of SC in contributing or causing death is still undetermined, as data on the relationship between blood SC concentrations and their effects are scant. However, some deaths are being associated with SC consumption in the absence of any other more plausible cause of death.³⁶ Two of the SC detected in our 19 cases were MDMB-CHMICA and 5F-ADB. Both have previously appeared in the literature as leading to fatal intoxication due to the lack of detection of significant quantities of other drugs.^14,37 Unfortunately, the concentration of each SC present in our cases was not available and neither was the pathologist’s final report. Therefore, we cannot fully determine the role SC may have played, but it is possible, and in some cases likely, that they were directly attributed to death.

A major limitation to this study is that the rapid turnover of SC makes it difficult to detect newly emerging structures. All samples in this report were analysed by LGC Sport Specialised Analytical Services (Fordham, UK) and compared to an in-house database that is updated on a regular basis. Therefore, over the four-year period, the scope of SC testing changed. It is believed that the databases were current and up to date. However, it is possible that some SC could have been missed early on in their use. Additionally, some cases where SC could have been present may not have been referred for SC screening due to an alternative cause of death having already been determined. This means we could be underestimating the incidence of SC in post-mortem cases.

Conclusions

Our data show that SC were available for about one to two years. Their rapid turnover means it is difficult to predict future patterns of SC use, and therefore it would be advisable to offer specific screening to detect SC in biological samples wherever possible. These data only cover up to March 2018. There may be future changes in SC receptor agonists that will require continued intelligence and updating of analytical databases to ensure the trends and hence detection of SC receptor agonists remains fit for purpose.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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