Synthetic cannabinoids

in Europe – a review
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 I Contents
 2
I I Methods and information sources

 4
I Executive summary

 5
I Background

 5

 5 I History of the development of synthetic cannabinoids

Legitimate uses of synthetic cannabinoids

 6 I International control measures

  6 I Synthetic cannabinoids in Europe

  6 I Emergence as new psychoactive substances

  6 I Availability and size of the market

  9 I Response to synthetic cannabinoids

10 I Replacement

10 I Physical, chemical and pharmacological description

10 I Physical and chemical description

12 I Physical and pharmaceutical form

14 I Pharmacology

21 I Health and social risks

21 I Acute toxicity

29 I Chronic toxicity

31 I Psychological and behavioural effects

31 I Dependence and abuse potential

32 I Effects on ability to drive and operate machines

32 I Social risks

32 I Extent and patterns of use, availability and potential for diffusion

32 I Prevalence of use

33 I Patterns of use

34 I Availability, supply and involvement of organised crime

36 I Conclusions

37 I References

51 I Annex 1. Profiles of selected synthetic cannabinoids

61 I Annex 2. Synthetic cannabinoids monitored by the EMCDDA through the EU Early
Warning System on new psychoactive substances (as of 16 April 2021)
Synthetic cannabinoids in Europe – a review

Authors I Methods and information sources

Volker Auwärter (*), Joanna de Morais (**), Ana In the context of this report, ‘synthetic cannabinoids’ are
Gallegos (**), Michael Evans-Brown (**), Rachel defined as new psychoactive substances that mimic the
Christie (**), Rita Jorge (**) and Roumen Sedefov (**) effects of tetrahydrocannabinol, the major psychoactive
(*) Forensic Toxicology Department, Institute of Forensic Medicine,
substance in cannabis. Another common name for this
Medical Center, University of Freiburg, Germany group of substances is ‘synthetic cannabinoid receptor
(**) European Monitoring Centre for Drugs and Drug Addiction
agonists’.
(EMCDDA), Lisbon, Portugal

Funding The terms ‘synthetic cannabinoid receptor agonists’, ‘spice’

and ‘synthetic cannabinoid’ were searched in Medline,
Part of this work was supported by EMCDDA
Google Scholar and PubMed. Literature searches used
contracts CT.18.SAS.0085.1.0 with Dr Volker
both the chemical structure and text queries in online
Auwärter and CT.18.SAS.0089.1.0 with Dr Simon
databases; searches were conducted in August 2019. The
Brandt.
publications retrieved were then reviewed for additional
Acknowledgements relevant references (the snowball technique). Searches
of the websites of selected medical specialty societies
The EMCDDA would like to extend its sincere thanks and international, national and local government agencies
and appreciation to the Early Warning System were conducted to identify position statements and
correspondents of the Reitox national focal points reports. Search strings were introduced in Google and
and experts from their national early warning Google Scholar, and the first 100 hits were screened to
system networks, as well as the Europol national find additional relevant content. Although the systematic
units. The authors would like to thank the Forensic searches were conducted in 2018, information from
Toxicology Department (Institute of Forensic thematic scientific papers and reports published in 2019
Medicine, Medical Center, University of Freiburg, and 2020 was also included in this report.
Germany); the Italian National Institute of Health; the
Forensic Science Centre of Lithuania; and Dr Craig English-language articles were selected from a search of
McKenzie (Leverhulme Research Centre for Forensic PubMed (National Center for Biotechnology Information),
Science, University of Dundee, United Kingdom), Web of Science (Thomson Reuters), Medline and
for the images used in this publication. The authors Google Scholar. The search terms used were ‘synthetic
also thank Arianna Giorgetti, Sebastian Halter, cannabinoid receptor agonists’, ‘spice’ and ‘synthetic
Belal Haschimi, Laura Huppertz and Lukas Mogler cannabinoid’. Textual searches were also conducted in
(Institute of Forensic Medicine, Medical Center, popular English-language drug forums.
University of Freiburg, Germany) for their support; Dr
Simon Brandt (School of Pharmacy and Biomolecular In addition, exact chemical structure-based searches
Sciences, Liverpool John Moores University, United were done in SciFinder (American Chemical Society,
Kingdom) for peer-reviewing this report; and Regina Chemical Abstract Service) and Reaxys (Elsevier). As
Kühnl (IFT Institut für Therapieforschung München, part of the report, the individual profiles of selected
German Monitoring Centre for Drugs and Drug synthetic cannabinoids were developed. The substances
Addiction) for reviewing parts of this report. were identified by the European Monitoring Centre for
Statement on the United Kingdom Drugs and Drug Addiction (EMCDDA) based on reports
of high availability in Europe and/or reports of serious
The United Kingdom left the European Union on adverse events. Google and specific drug user discussion
1 February 2020. For the purpose of this report, the forums and related websites (such as Bluelight, Eve
United Kingdom is not included in the term ‘Member and Rave, and Erowid) were searched for the terms
States’. ‘CUMYL-PeGACLONE’, ‘AMB-FUBINACA’, ‘AB-FUBINACA’,
‘CUMYL-5F-P7AICA’ and ‘5F-MDMB-PICA’, alone or
in combination with ‘buy’, ‘shop’, ‘research chemical’,
‘synthetic cannabinoid’, ‘dosing’, ‘poisoning’, ‘kaufen’,
‘räuchermischung’, ‘powder’ or ‘synthesis’. In addition,
colleagues within the authors’ scientific networks were
contacted to obtain information.

2
 Synthetic cannabinoids in Europe – a review

Searches of open source information, including scientific

articles, official reports, grey literature, internet drug
discussion forums and related websites, were also
included.

Information from the European Union Early Warning

System on NPS (EWS), operated by the EMCDDA, has
been included, as relevant. The EWS is composed of a
multiagency and multidisciplinary network, which includes
the EMCDDA, 29 national early warning systems (27 EU
Member States, Turkey, and Norway), Europol and its law
enforcement networks, the European Medicines Agency
(EMA), the European Commission and other partners.
Information from United Nations agencies (the United
Nations Office on Drugs and Crime and the World Health
Organization) as well as from third countries such as
Canada, Russia, the United Kingdom, and the United
States has also been included, as relevant.

3
Synthetic cannabinoids in Europe – a review

I Executive summary and act as full agonists at the cannabinoid receptors

(THC, in contrast, is a partial agonist). This means that,
Synthetic cannabinoids are functionally similar to Δ9- even at very small doses, synthetic cannabinoids can
tetrahydrocannabinol (Δ9-THC), the major psychoactive activate the cannabinoid receptors much more strongly
substance in cannabis. They bind to the same cannabinoid than THC. Secondly, products containing synthetic
receptors in the brain and other organs as THC. They were cannabinoids often contain high doses of the substances.
originally developed by scientists to study the body’s The combination of these two factors makes it difficult
endocannabinoid system, as well as to provide insights for users to control the dose that they are exposed to.
into disease and to help develop new medicines. Around This can lead them to rapidly administer a toxic dose
the mid-2000s, they began to appear in Europe in products unintentionally. These factors are also responsible for
called ‘Spice’ that were sold as ‘legal’ replacements for the outbreaks of mass poisonings seen with synthetic
cannabis. In these products, synthetic cannabinoids were cannabinoids, which have ranged from a handful of people
mixed with plant material, which could then be smoked to hundreds, some of whom have died. While many of
as cigarettes (‘joints’). In recent years, alongside these the outbreaks reported so far have been in the United
smoking mixtures, new products, including e-liquids for States, they have also occurred in Russia, Canada and
vaping using electronic cigarettes and paper impregnated Europe. Outbreaks due to synthetic cannabinoids being
with synthetic cannabinoids, have been sold on the drug mis-sold or used to adulterate cannabis products, as well
market. Unknown to users, synthetic cannabinoids have as other illicit drugs, such as opioids, are increasingly
also been mis-sold or used to adulterate cannabidiol common. Such outbreaks can rapidly overwhelm
(CBD) and THC e-liquids, as well as other illicit drugs, the capacity of emergency responders and hospital
such as opioids. Another concerning development is the emergency departments, which is of particular concern
recent adulteration of cannabis products with synthetic given the ongoing COVID‑19 pandemic and the additional
cannabinoids in Europe. Typically, these adulterated burden already placed on healthcare systems. There is
products are low-THC herbal material or resins. In terms no approved antidote to poisoning caused by synthetic
of look, smell and flavour, these adulterated products cannabinoids. The effects on health from the chronic
would be very difficult to distinguish from ‘genuine’ illicit use of synthetic cannabinoids are largely unknown;
cannabis products and, as a result, users may be unaware however, regular use has been linked to problems such as
that they are using synthetic cannabinoids. As synthetic dependence and withdrawal symptoms.
cannabinoids are highly potent substances, people who
use these products could be at high risk of poisoning. Synthetic cannabinoids are used by a range of people,
including those who use cannabis, those who are regularly
Synthetic cannabinoids activate the same cannabinoid subjected to drug-testing procedures (such as prisoners)
receptors in the body as THC. The behavioural and and people who experiment with a range of substances
physiological effects that have been reported with (so called ‘psychonauts’). Increasingly, synthetic
synthetic cannabinoids include relaxation, euphoria, cannabinoids are also used by some high-risk drug users
lethargy, depersonalisation, distorted perception of time, and other vulnerable groups (such as prisoners and
impaired motor performance, hallucinations, paranoia, people experiencing homelessness), as they have gained
confusion, fear, anxiety, dry mouth, bloodshot eyes, a reputation for causing profound intoxication, they can be
tachycardia, nausea, and vomiting. cheaper than other drugs and they are easy to smuggle.

Despite similarities, however, synthetic cannabinoids In Europe, synthetic cannabinoids are monitored as
can cause more profound intoxication than cannabis. new psychoactive substances by the European Union
Severe poisonings are also more common, and fatalities Early Warning System. They are the largest group of
linked to the consumption of these substances have substances monitored by the European Monitoring
been recorded. There have been case reports of serious Centre for Drugs and Drug Addiction (EMCDDA), with
cardiovascular toxicity (including sudden death), rapid 209 reported between 1 January 2008 and 31 December
loss of consciousness/coma, respiratory depression, 2020. Since 2015, there has been a decrease in the
seizures and convulsions, hyperemesis, delirium, agitation, number of synthetic cannabinoids appearing for the
psychosis, and aggressive and violent behaviour. It appears first time each year on the drug market and an overall
that, at least in part, these effects are due to the high decrease in seizures of synthetic cannabinoids by law
potency of synthetic cannabinoids and the unintentionally enforcement. In part, these changes appear to be related
high doses that users may be exposed to. Firstly, laboratory to a disruption in the ‘legal high’ trade, which for a period
studies have found that many of the cannabinoids sold saw new psychoactive substances being sold openly
on the drug market are much more potent than THC on the high street in many countries in Europe. More

4
 Synthetic cannabinoids in Europe – a review

generally, broader policy responses designed to restrict This report provides a technical review of the current
the availability of new psychoactive substances are also body of knowledge regarding synthetic cannabinoids
likely to have had an effect. Despite this, the market in that are monitored by the EMCDDA. The aim of this
synthetic cannabinoids, once the epitome of the ‘legal report is to strengthen situational awareness of synthetic
highs’ phenomenon, continues to evolve and pose a cannabinoids in Europe and to help stakeholders prepare
threat to health security. During 2020, signals related for and respond to public health and social threats caused
to two synthetic cannabinoids, MDMB-4en-PINACA and by such substances.
4F-MDMB-BICA, led the EMCDDA to launch initial reports
on the substances because of concerns of potential
public health and social threats to Europe. Both MDMB-
4en-PINACA and 4F-MDMB-BICA were formally risk I Background
assessed by the EMCDDA in December 2020. Based on
the risk assessment reports, in March 2021 the European
Commission proposed that MDMB-4en-PINACA and
4F-MDMB-BICA be controlled in Europe. Since 2016, a
total of seven synthetic cannabinoids have been formally
I History of the development of synthetic
cannabinoids

risk assessed by the EMCDDA (i.e. MDMB-CHMICA (2016), The first synthetic analogues of Δ9-tetrahydrocannabinol
5F-MDMB-PINACA, AB-CHMINACA, ADB-CHMINACA, (Δ9-THC; the major psychoactive substance in cannabis)
CUMYL-4CN-BINACA (2017), 4F-MDMB-BICA and MDMB- were synthesised by Mechoulam (Mechoulam and Carlini,
4en-PINACA (2020)). 1978) shortly after the first total synthesis of Δ9-THC was
published (Mechoulam and Gaoni, 1965). Their chemical
Despite measures intended to reduce the availability structure was similar to the structure of Δ9-THC (e.g.
of synthetic cannabinoids on the drug market, data nabilone and A-41988). After the identification and cloning
reported to the EMCDDA through the EU Early Warning of the CB1 and CB2 cannabinoid receptors (Matsuda et
System show that synthetic cannabinoids continue to be al., 1990; Munro et al., 1993), a variety of chemicals with
widely available across Europe. As noted, the relatively diverse structures were screened for the ability to bind
low cost, easy availability and high potency of synthetic to these receptors. This led to the discovery of several
cannabinoids appear to have resulted in increased use classes of substances that could bind to and activate
among marginalised groups such as people experiencing the cannabinoid receptors (Huffman and Padgett, 2005;
homelessness and prisoners. This development has been Makriyannis and Deng, 2007). Subsequently, a large
associated with an increase in reports of serious harms. body of literature on the subject emerged, focused on the
For example, in prisons, alongside the adverse health development of synthetic cannabinoids as medicines.
effects, the market in and use of synthetic cannabinoids Cannabis was recognised as potentially useful for the
has been linked to an increase in aggression, violence, treatment of conditions such as pain, anorexia, wasting
bullying and debt. In some cases, this has caused a syndrome, muscle spasms and glaucoma (Compton et
serious threat to the overall safety and security of the al.,1992; Melvin et al., 1984), and new drug candidates
prison environment. were developed, focusing on easy to synthesise synthetic
cannabinoids with fewer psychotropic side effects
In the future, it can be expected that synthetic than cannabis. Simultaneously, other groups were also
cannabinoids with high potency and that are easy to investigating the structure–activity relationships of this
synthesise will continue to be introduced into the market. new class of substances (Aung et al., 2000; Huffman et al.,
2005; Melvin et al., 1993; Wiley et al., 2014).
The ongoing COVID‑19 pandemic and the related response
measures may affect the existing synthetic cannabinoid
drug markets in unpredictable ways. Such effects may I Legitimate uses of synthetic cannabinoids
extend to changes in use and patterns of use of synthetic
cannabinoids. Seizures of bulk powders by European Synthetic cannabinoids have been the subject of extensive
national customs agencies during the pandemic suggest pharmacological and toxicological research. Some were
that synthetic cannabinoids continue to be imported into developed as drug candidates. Nabilone (Cesamet), for
and distributed within Europe. It is possible that, in the example, is used as an orally administered medicine
case of a reduced availability of cannabis and other illicit for the treatment of nausea and vomiting induced by
drugs in Europe, criminal groups, as well as drug users, cancer chemotherapy in patients receiving a wide variety
may use a range of replacement substances, including of chemotherapy regimens, or to treat cachexia under
synthetic cannabinoids. HIV treatment for patients who have failed to respond

5
Synthetic cannabinoids in Europe – a review

adequately to conventional antiemetic treatments. Owing synthetic cannabinoids mixed with plant (herbal) material,
to its side effects and potential for abuse, which are very which could then be smoked as cigarettes (‘joints’)
similar to those of THC, nabilone is not a first-choice (Auwärter et al., 2009; EMCDDA, 2009, 2017; Jack, 2009).
therapy. In addition, synthetic cannabinoids are widely Such smoking mixtures have been referred to by a variety
used in scientific research and in analytical reference of names, depending on the country, region, product type,
material in clinical and forensic case work. brand name and user group. Names associated with these
products include ‘smoking mixtures’, ‘herbal smoking
mixtures’, ‘herbal incense’, ‘synthetic cannabis’, ‘legal
I International control measures weed’ and ‘K2’. Common street names used include ‘magic
tobacco’ in Hungary, ‘chimique’ in France, ‘Bonsai’ in Turkey
The following synthetic cannabinoids are included in the and, in Birmingham (United Kingdom), ‘Black Mamba’ or
list of substances in Schedule II of the United Nations simply ‘Mamba’. ‘Legal high’ products containing synthetic
Convention on Psychotropic Substances of 1971 (INCB, cannabinoids have been subject to innovative marketing
2020): approaches and are widely and openly available on the
 AM-2201 (JWH-2201) and JWH-018 (AM-678) (since web. During the first few years of the phenomenon, similar
2015), products were also available in some countries in bricks-
and-mortar (‘head’ and ‘smart’) shops.
 5F-AKB-48 (5F-APINACA), MDMB-CHMICA and XLR-11
(5F-UR-144) (since 2017), Owing to the number and variety of synthetic cannabinoids
 AB-CHMINACA, AB-PINACA, 5F-MDMB-PINACA emerging on the drug market, one of the challenges
(5F-ADB), AM-2201 carboxylate analogue quinolinyl associated with their appearance is their naming. As the
derivative (5F-PB-22) and UR-144 (since 2018), structures of most synthetic cannabinoids can be broken
down into four components – tail, core, linker and linked
 ADB-FUBINACA, AMB-FUBINACA (FUB-AMB), CUMYL- group – the EMCDDA has introduced a semi-systematic
4CN-BINACA and ADB-CHMINACA (since 2019), approach to assigning common names to them (EMCDDA,
2017). Each component of the structure is assigned
 AB-FUBINACA, 5F-AMB (5F-AMB-PINACA), 5F-MDMB-
a code name, and the ordered combination of code
PICA and 4F-MDMB-BINACA (since 2020).
names for the linked group, tail, core and linker allows the
chemical structure of the substance to be ciphered.
In 2020, MDMB-4en-PINACA (WHO, 2020a) and CUMYL-
PeGACLONE (WHO, 2020b) were assessed at the
43rd meeting of the WHO Expert Committee on Drug I Availability and size of the market
Dependence and were recommended to be included
in Schedule II of the 1971 Convention on Psychotropic Synthetic cannabinoids are the largest group of new
Substances (WHO, 2020c). psychoactive substances monitored by the EMCDDA
through the EU Early Warning System, with 209 identified
on the drug market over the 13 years between 1 January
2008 and 31 December 2020. This includes 11 that were
I Synthetic cannabinoids in Europe identified for the first time in 2020. An average of 27
cannabinoids appeared each year in Europe between 2011
and 2015, but since 2016 the annual number has dropped
I Emergence as new psychoactive substances to around 10 (Figure 1).

A product called ‘Spice’, containing synthetic cannabinoids, In 2019, over 18 700 seizures of synthetic cannabinoids
appears to have emerged around 2004 as a legal were reported to the EU Early Warning System, which
alternative to cannabis and started to gain popularity represents around 54 % of the total number of seizures
in European countries. By 2008, these products were reported during that year (29 % in the Member States).
gaining wider popularity and were associated with In the European Union, most synthetic cannabinoids
numerous poisonings. Towards the end of 2008, the active seized were in the form of herbal plant material (5 208
substances in these Spice products were identified as cases, 112 kg) or powders (684 cases, 78 kg) (Figure 2).
JWH-018 and CP-47,497-C8, two synthetic cannabinoids The number of seizures is unevenly distributed across
developed decades ago in the context of research on the Europe, with Turkey accounting for the large majority of
endocannabinoid system (Auwärter et al., 2009; Uchiyama the seizures of synthetic cannabinoids reported in 2019
et al., 2009). These products were found to contain (65 %).

6
 Synthetic cannabinoids in Europe – a review

FIGURE 1
Number of synthetic cannabinoids formally notified to the EU Early Warning System for the first time, 2008–2020
35
31
30
29
30

24
25 23

20

15
11 11 11 11
10
10 8
6
5
1
0
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

FIGURE 2
Seizures of synthetic cannabinoids reported to the EU Early Warning System: trends in (a) the number of seizures of
synthetic cannabinoids and (b) the quantity seized, in weight (kg), 2005–2019 (all forms including powders and herbal
smoking mixtures – EU-27 and EU-27 + 2)
(a) 40 000

35 000

30 000

25 000

20 000

15 000

10 000

5 000

0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

EU-27 + 2 EU-27

(b) 3 000

2 500

2 000

1 500

1 000

500

0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

EU-27 + 2 EU-27

7
Synthetic cannabinoids in Europe – a review

Box 1. Responses in Germany

Legislation Impact on the market

The first identification of synthetic cannabinoids in Shortly after the inclusion of recently emerged synthetic
herbal blends in Germany was reported by Auwärter and cannabinoids in the annexes of the German Narcotics
colleagues in 2008 (Auwärter et al., 2009). The synthetic Act, new substances with structural modifications
cannabinoids detected were JWH-018, CP-47,497 and appeared on the market, presumably as a response by
CP-47,497-C8. In January 2009, JWH-018, CP-47,497 producers to the control measures. Common strategies
and three of its homologues were scheduled under the were the substitution of a hydrogen atom by a fluorine
German Narcotics Law because of their potential for atom at the terminal position of the side chain or
abuse and their widespread use. In the following years, modifications at the linked group.
further synthetic cannabinoids emerged and were
subsequently scheduled. Owing to the time lag between In December 2016, Angerer et al. (2018a) test-purchased
the emergence of new substances and their scheduling, herbal smoking mixtures containing the synthetic
distributors of new, unscheduled synthetic cannabinoids cannabinoid CUMYL-PeGACLONE, which was not
were prosecuted using the German Medicines Law. covered by the NpSG at that time. Furthermore, other
However, an appeal to the German Federal Supreme synthetic cannabinoids with core structures not covered
Court led to the European Court of Justice reviewing the by the NpSG emerged on the German drug market,
classification of herbal products containing synthetic such as those containing 7-azaindole cores. CUMYL-
cannabinoids as medicines according to the Medicines PeGACLONE was added to the annex of the Narcotics
Law. The European Court of Justice announced its Law in July 2018 by an amendment. With the emergence
decision on 10 July 2014 and concluded that, owing of its fluorinated analogue (5F-Cumyl-PeGaClone), the
to the absence of therapeutic potential and the control measures in place were again circumvented.
associated harms, the products could not be regarded However, with the amendment to the NpSG of July 2019,
as medicinal products as defined in Article 1 No 2 of azaindoles and the γ-carbolinones are now included, the
Directive 2001/83/EC. The resulting regulatory gap latter by modifying the definition of the linker.
led to the German ‘Act to combat the distribution of
new psychoactive substances’ (NpSG) which became Following the introduction of the NpSG, some new
effective on 26 November 2016. In contrast to the synthetic cannabinoids that are not covered by
Narcotics Law, which controls single substances as the generic definitions have appeared on the drug
enumerated in the annexes of the law, the NpSG uses market. These gaps in the definitions can be closed by
a generic approach by defining groups of substances amendments to the NpSG.
based on their chemical structure. Particularly
dangerous substances continue to be placed under the In the future, as producers continue their attempts to
Narcotics Act and, if a substance falls under both laws, circumvent control measures in Europe and elsewhere, it is
the stricter Narcotics Act is applied. The definition of a unclear what new synthetic cannabinoids may be developed
synthetic cannabinoid according to the NpSG comprises and what risks they may pose to health, especially with
four structural elements: core structure, side chain, linker regard to the potential introduction of remote structural
and a linked group. In the original version of the NpSG candidates. It is important that early warning systems can
from November 2016, five core structural elements were detect such substances in a timely manner so that public
defined. On 13 July 2019, an amendment came into health agencies can respond through timely and effective
force in which further core structures that had emerged actions to prevent or reduce the risk of harm.
on the market since 2016 were added. In response to
the identification, shortly after, of cyclobutylmethyl side Figure 3 shows a heat map in which the relative
chains, which were not covered by the act, another positivity rate of 20 selected synthetic cannabinoids
amendment was prepared, which came into force in urine samples analysed in the Institute of Forensic
on 9 July 2020. Meanwhile, synthetic cannabinoids Medicine Freiburg (Germany) is presented for 2015 to
carrying bicyclic side chains have emerged, and a third 2019, including the five compounds described in detail
amendment is currently in preparation. in Annex 1 of this report (i.e. CUMYL-PeGACLONE,
CUMYL-5F-P7AICA/5F-CUMYL-P7AICA, AB-FUBINACA,
AMB-FUBINACA, and 5F-MDMB-PICA).

8
 Synthetic cannabinoids in Europe – a review

In recent years, there has been a marked decrease in both I Response to synthetic cannabinoids
the number of new synthetic cannabinoids appearing on
the market for the first time and the quantity of powders Since 2016, a total of seven synthetic cannabinoids
and herbal material containing synthetic cannabinoids have been formally risk assessed by the EMCDDA. These
seized in the European Union (Figure 2). Overall, these were MDMB-CHMICA, in 2016; AB-CHMINACA, ADB-
developments may in part reflect a decrease in large-scale CHMINACA, 5F-MDMB-PINACA and CUMYL-4CN-BINACA,
processing of synthetic cannabinoids into herbal smoking during 2017; and MDMB-4en-PINACA and 4F-MDMB-
mixtures, particularly the ‘legal high’ products that typified BICA, in 2020.
a large part of the new psychoactive substances market in
Europe between 2008 and 2015. Nonetheless, relatively Across the world, many countries have implemented legal
large amounts of bulk powders sufficient to make many responses to control synthetic cannabinoids, with many
hundreds of thousands of street doses continue to be countries having used or amended existing legislation
seized at Europe’s borders each year, including throughout and others having introduced innovative legal instruments
the COVID‑19 pandemic. including generic definitions (by chemical structure or
pharmacological effects). An example is given in Box 1.

FIGURE 3
Heat map presenting the relative positivity rate of 20 selected synthetic cannabinoids in urine samples analysed in the
Institute of Forensic Medicine Freiburg (Germany), 2015 to 2019

9
Synthetic cannabinoids in Europe – a review

FIGURE 5
I Replacement Potential core structures of synthetic cannabinoids that
might be used for the production of new psychoactive
substances, as proposed by (a) Diaz et al. (2017) and (b)
Synthetic cannabinoids that may emerge as new Leftheris et al. (2003)
psychoactive substances

In the past, legal restrictions on synthetic cannabinoids –

regardless of whether a substance-by-substance approach
or a generic approach was used – led to the continual
appearance of structurally modified compounds, as
shown by many examples, such as the γ-carbolinones
(e.g. CUMYL-PeGACLONE) or the more recent norbornyl
derivatives (e.g. Cumyl-NB-MeGaClone, also known as
Cumyl-BC-HpMeGaClone-221). A different strategy for
the drug market could be the use of previously described
‘classical’ or ‘non-classical’ synthetic cannabinoids that
show higher structural similarity to Δ9-THC (Howlett et al.,
2002). As a possible reaction to the ongoing amendments producing countries. This was seen, for example, in
to the German NpSG, O-774 (7-[(6aR,10aR)-1-hydroxy- Germany in the shift from 5F-ADB to 5F-MDMB-PICA and
6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c] 4F-MDMB-BINACA in 2019 after a ban on 5F-ADB was
chromen-3-yl]-7-methyloctanenitrile) (Figure 4) has been introduced in China (Halter et al., 2020).
discussed as a compound of interest in relevant online
discussion boards. However, such structures might not
be very attractive for producers owing to comparatively
complicated and expensive syntheses.

Another alternative might be the synthesis of synthetic

I Physical, chemical and
pharmacological description
cannabinoids with new, non-regulated core structures as
described in the patent literature. For example, Diaz et
al. (2017) and Leftheris et al. (2003) described tricyclic I Physical and chemical description
or bicyclic heteroaromatic compounds as depicted in
Figure 5a and b.
Structural/chemical classification
Although not likely, other strategies could include targeting
the degradation of endocannabinoids by inhibiting fatty Synthetic cannabinoids derive from chemically quite
acid amide hydrolase (FAAH) enzymes or the reuptake different classes of substances, because binding and
of endocannabinoids by uptake inhibitors such as LY- activation of the cannabinoid receptors can be achieved
2183240 (N,N-dimethyl-5-[(4-phenylphenyl)methyl]-1- with a wide range of molecules. Historically, the first
tetrazolecarboxamide), which has already been detected in synthetic cannabinoids that occurred on the drug
‘legal high’ products in Japan (Uchiyama et al., 2014). market were cyclohexylphenols (e.g. CP-47,497-C8) and
naphthoylindoles (e.g. JWH-018). Substances from the
Finally, the market could shift towards compounds already broader group of aminoalkylindoles, including halogenated
controlled by national law, depending on regulations in the derivatives and linker groups other than carbonyl (e.g.
carboxyl), were then introduced (e.g. AM-2201, 5F-
FIGURE 4 UR-144 (XLR-11), UR-144 and AM-2201 carboxylate
Chemical structure of O-774 analogue quinolinyl derivative (5F-PB-22)). Later, indole
derivatives with amino acid-like groups linked via a
carboxamide linker (e.g. MDMB-CHMICA and 5F-MDMB-
PICA) and their indazole analogues (e.g. 5F-AKB48,
AB-CHMINACA, AB-PINACA, 5F-MDMB-PINACA (5F-ADB)
and AB-FUBINACA) emerged and began to dominate the
market. Recent developments include the introduction
of cumyl derivatives, often linked to indoles or indazoles
by a carboxamide linker (e.g. CUMYL-5F-PINACA/5F-

10
 Synthetic cannabinoids in Europe – a review

CUMYL-PINACA), 7-azaindoles (e.g. 5F-AB-P7AICA and of results, particularly of hair analysis. Nash et al. (2019)
CUMYL-5F-P7AICA/5F-CUMYL-P7AICA), carbazoles (e.g. recently showed that CUMYL-PeGACLONE is thermally
EG-018 and MDMB-CHMCZCA), γ-carbolinones (e.g. degraded by loss of the cumyl moiety.
CUMYL-PeGACLONE, 5F-Cumyl-PeGaClone, Cumyl-CH-
MeGaClone) and compounds with modified side chains Kneisel et al. (2013) tested the stability of 11 synthetic
(e.g. CUMYL-CBMINACA or Cumyl-NB-MeGaClone). cannabinoids in oral fluid stored in glass or polypropylene
tubes. They pointed out that adsorption at the plastic
surface might lead to considerable loss of analytes. Hess
Identification and analytical profile et al. (2017) investigated the freeze–thaw stability of
82 synthetic cannabinoids and found that most were
Comprehensive guidance on the recommended methods stable in spiked serum samples for at least 1 month at
for use in forensic laboratories for the identification and – 20 °C when undergoing three freeze–thaw cycles.
analysis of synthetic cannabinoids in seized materials is However, substances of the ‘AMB’ and the ‘SDB’ type
provided in the United Nations Office on Drugs and Crime showed instability at higher temperatures, probably
manual (Tettey et al., 2021). due to hydrolysis (Hess et al., 2017). Fort et al. (2017)
investigated the stability of 5F-UR-144 (XLR-11), UR-
144, AB-PINACA and AB-FUBINACA in spiked human
Physical description whole-blood specimens. They found all analytes to be
Synthetic cannabinoids in their pure form are usually stable for at least 12 weeks when stored frozen (– 20 °C).
described as white or yellowish, odourless, crystalline However, stored at ambient temperature (22 °C) or
powders. Less pure substances may show brownish refrigerated (4 °C), 5F-UR-144 (XLR-11), but not the other
discoloration and have an unpleasant ‘chemical’ smell due three analytes, showed significant degradation. Kevin
to impurities from synthesis and solvent residues. Most et al. (2019a) investigated the thermal degradation of
synthetic cannabinoids are highly lipophilic and generally various carboxamide synthetic cannabinoids (CUMYL-
insoluble in water, but are soluble in aliphatic alcohols and PICA, 5F-CUMYL-PICA (CUMYL-5F-PICA), AMB-
non-polar organic solvents such as methanol, ethanol, FUBINACA, MDMB-FUBINACA, NNEI (AM-6527) and
acetonitrile, ethyl acetate, acetone or isooctane (Tettey MN-18) and found a range of potentially toxic degradants
et al., 2021). Typical octanol−water partition coefficients (naphthalene, 1-naphthylamine, toluene and cyanide)
(expressed as log KOW or log P) as predicted in silico (ACD/ at the temperatures typically reached when smoking
Labs Percepta Platform – PhysChem Module) range between herbal material. Stability varied among the compounds
4.5 (MDMB-CHMINACA) and 7 (JWH-018). Melting points investigated, with some showing ‘extensive degradation’ at
typically range from 55 °C (5F-AKB48) to 145 °C (AM-2233). temperatures between 400 and 600 °C.

Chemical stability Analytical profile

In general, pure and dried synthetic cannabinoids can Owing to the presence of conjugated π-electron systems,
be regarded as chemically stable. However, in solutions synthetic cannabinoids can generally be detected by
or when heated they can be unstable, in particular when ultraviolet (UV) spectroscopy; however, UV spectra can be
containing structural elements prone to hydrolysis, such very similar for compounds with the same chromophore,
as esters or primary amides, or when constrained ring which then requires a chromatographic separation for
moieties are present (e.g. UR-144). unambiguous identification. Mass spectrometric techniques,
nuclear magnetic resonance (NMR) and infrared or Raman
Hutter et al. (2013) analysed smoke condensates of spectroscopy are also suitable for identification.
cigarettes laced with the synthetic cannabinoid AM-2201
and found small amounts of JWH-018 and JWH-022 as It is reported that heating synthetic cannabinoids
thermal degradation products. In another study, smoking of containing a tetramethylcyclopropyl ring, such as UR-
3,5-AB-CHMFUPPYCA (AB-CHMFUPPYCA) was shown to 144, as occurs during smoking or on exposure to high
result in thermal cleavage of the terminal amide (Franz et temperatures inside a gas chromatography–mass
al., 2017a). A further study, by Franz et al. (2016), showed spectrometry (GC-MS) injection port, results in opening of
that 5F-PB-22 (AM-2201 carboxylate analogue quinolinyl the cyclopropyl ring, which is thermally unstable, creating
derivative) and AB-CHMINACA undergo ester and amide the thermodynamic product 2,3,3-trimethyl-1-butene
cleavage, respectively, when smoked, and it was highlighted side chain (Adamowicz et al., 2013; Eckre et al., undated;
that the cleavage products were also formed during Grigoryev et al., 2013a; Kaizaki-Mitsumoto et al., 2017;
metabolism, leading to the potential for misinterpretation Thomas et al., 2017). Thermal rearrangement produces two

11
Synthetic cannabinoids in Europe – a review

peaks with similar mass spectra when using GC-MS, and it precursors are 1-alkylindoles, 1-alkylindazoles and
has been suggested that it should be treated as a GC-MS 1-alkyl-7-azaindoles (alkyl is often a pentyl, 5-fluoropentyl
artefact (Adamowicz et al., 2013; Kaizaki-Mitsumoto et or cyclohexylmethyl, but can also be replaced by
al., 2017). During analysis, it was confirmed that UR-144 4-fluorobenzyl or other substituents), which can be
is almost completely changed to its degradant by heating easily obtained by N-alkylation of indole, indazole or
at 300 °C for 10 minutes (Kaizaki-Mitsumoto et al., 2017). 7-azaindole using, for example, an alkyl bromide. These
However, ring-opening reactions in substances containing can be acylated at C3 by a Friedel–Crafts reaction using
tetramethylcyclopropyl rings have also been reported activated carboxylic acids (e.g. 1-naphthoyl chloride,
to occur during prolonged storage and not only during which reacts to JWH-018 with 1-pentylindole). For the
heating (Creary et al., 1977; Thomas et al., 2017). synthesis of carboxamide-type synthetic cannabinoids,
Banister et al. (2016) described an effective pathway
It is also reported that the use of solvents such as using trifluoroacetic acid anhydride for the formation of
methanol or ethanol for extraction of cannabimimetic the 3-carboxy-alkylindole (can also be applied to indazoles
quinolinyl carboxylates, such as PB-22 (JWH-018 and 7-azaindoles) followed by establishing the amide bond
quinolinecarboxylate analogue), 5F-PB-22 (AM-2201 (e.g. the reaction of cyclohexylmethylindazole with methyl
carboxylate analogue quinolinyl derivative) and FUB- tert-leucinate leads to MDMB-CHMINACA).
PB-22, may cause transesterification to occur (Tettey et al.,
2021). 8-Quinolinol has been observed as a degradation There is no information on the actual manufacturing
product during GC-MS analysis (Uchiyama et al., 2013a). methods used to make the synthetic cannabinoids
that have been identified on the drug market in Europe.
For the analysis of biological samples, liquid chromatography– However, the synthesis of 5F-MDMB-PICA and 5F-MDMB-
tandem mass spectrometry (LC-MS/MS) or liquid PINACA, for example, has been described by Banister et al.
chromatography–high-resolution mass spectrometry (2016). The synthesis of 5F-MDMB-PICA starts with indole,
(LC-HRMS) is usually applied after liquid–liquid or solid- which is reacted with methyl L-tert-leucinate, yielding (S)-
phase extraction. Given the immense structural variability of 5F-MDMB-PICA. The synthesis of 5F-MDMB-PINACA starts
synthetic cannabinoids, the dynamic market and the expected with methyl 1H-indazole-3-carboxylate, which is reacted
concentrations in the low or sub-nanograms per millilitre with methyl L-tert-leucinate, yielding (S)-5F-MDMB-
range, immunoassays cannot be recommended to screen PINACA. The (R)-enantiomers of both substances may
biological materials such as serum or urine (Franz et al., be synthesised under identical conditions using methyl
2017b). Another group claimed ‘good diagnostic efficiency’ for D-tert-leucinate instead of methyl L-tert-leucinate. Using
an enzyme-linked immunosorbent assay (ELISA) kit (Spinelli methyl tert-leucinate as a racemate would lead to the
et al., 2015), but it has to be acknowledged that the study production of the racemic substance.
was carried out retrospectively, and by the time of the study
the substances available on the market had already changed. The synthesis of 4F-MDMB-BICA may be carried out in
In contrast to blood or serum samples, in urine samples the the same way as the synthesis of its higher homologue,
parent compound is often not detectable after exposure to 5F-MDMB-PICA (EMCDDA, 2020a), and synthesis of
synthetic cannabinoids. Therefore, in abstinence screening, MDMB-4en-PINACA may be carried out in the same way as
the main metabolites have to be targeted. Most laboratories the synthesis of 5F-MDMB-PINACA (EMCDDA, 2020b).
perform an enzymatic cleavage before the analysis and target
the main phase I metabolites. Potential precursors of 4F-MDMB-BICA are indole-3-
carboxylic acid, indole-3-carboxylic acid methyl ester,
Methods and chemical precursors used for the indole, L-tert-leucine methyl ester (for the synthesis of the
manufacture (S)-enantiomer) and 1-bromo-4-fluorobutane (EMCDDA,
2020a). Potential precursors of MDMB-4en-PINACA are
Aminoalkylindoles, aminoalkylindazoles and aminoalkyl- methyl 1H-indazole-3-carboxylate, 5-bromo-1-pentene and
7-azaindoles are currently the most prevalent synthetic L-tert-leucine methyl ester (for the synthesis of the (S)-
cannabinoids on the drug market, and routes of synthesis enantiomer; EMCDDA, 2020b).
are well described in the patent literature. Typical

12
 Synthetic cannabinoids in Europe – a review

I Physical and pharmaceutical form FIGURE 7

A4-sized printouts, seized in a prison in Scotland, United
Kingdom, during 2019, that were impregnated with
Currently, three main types of products containing
MDMB-4en-PINACA and 5F-MDMB-PICA
synthetic cannabinoids are sold on the drug market in
Europe: smoking mixtures, e-liquids and papers. Most
commonly, synthetic cannabinoids are sprayed onto or
mixed with herbal plant material or tobacco to produce a
mixture that is then smoked as a joint or inhaled from a
vaporiser or bong. In recent years, there has also been an
increase in e-liquid products, in which a solution of the
synthetic cannabinoid is mixed with a solvent, which is
then vaped using an electronic cigarette (Figure 6).

In addition, it appears that in some countries an

increasingly common method of smuggling synthetic
cannabinoids into prison is by means of impregnating Photos © Dr Craig McKenzie, Leverhulme Research Centre for Forensic
paper with the cannabinoids – including letters, greeting Science, University of Dundee, United Kingdom.
cards, photographs, children’s drawings and printouts
(Figure 7) (EMCDDA, 2020c). The impregnated paper is FIGURE 8
then smoked with tobacco or vaped using an electronic MDMB-CHMICA concentration mapping across
cigarette. To a lesser extent, users may prepare their impregnated paper showing a significant variation in
concentration across the paper sheet
own similar products using cannabinoids in powder form
purchased from a vendor or dealer. Paper impregnated
with synthetic cannabinoids can pose a high risk of
poisoning because the amount of cannabinoid can vary
greatly in different parts of the paper (Figure 8) (Angerer et
al., 2018b; Norman et al., 2020).

FIGURE 6
E-liquid containing 5F-MDMB-PICA intended for vaping in
an electronic cigarette, seized by Italian Carabinieri in
June 2020

Source: Originally presented by Angerer et al. (2018b)

Photo © Forensic Toxicology Department, Institute of Forensic Medicine,
Medical Center, University of Freiburg, Germany.

To a much smaller extent, clothing and other textiles

impregnated with synthetic cannabinoids have been also
reported (Figure 9).

Photo © Italian National Institute of Health.

13
Synthetic cannabinoids in Europe – a review

FIGURE 9 with the wider availability and use of e-cigarettes and

Socks impregnated with 4F-MDMB-BINACA seized by vaporisers. e-Liquids generally consist of a polar mixture
Lithuanian police in January 2019 of propylene glycol, vegetable glycerin and ethanol;
aroma compounds; and an active substance (e.g.
synthetic cannabinoids; Münster-Müller et al., 2020). A
prerequisite for the production of e-liquids is the solubility
of the synthetic cannabinoids in the liquid base (usually
propylene glycol and/or glycerol). Therefore, often relatively
polar compounds such as CUMYL-5F-PINACA (5F-CUMYL-
PINACA) (Angerer et al., 2019; Münster-Müller et al., 2020)
are used to prepare such formulations.

Production of impregnated papers

Photo © Forensic Science Centre of Lithuania. An increasingly common method of smuggling synthetic
cannabinoids into prisons in some countries is by
impregnating paper with the cannabinoids. The variation in
Production of smoking mixtures synthetic cannabinoid concentration in these papers has
been attributed to the method employed for the preparation
The most common type of products containing of synthetic cannabinoid-impregnated papers, with the
synthetic cannabinoids are herbal smoking mixtures. synthetic cannabinoid solution likely to have been added
For the production of smoking mixtures, the synthetic to the centre of the paper and diffusing outwards (Norman
cannabinoids are usually dissolved in an organic solvent et al., 2020). In a simulated test, the authors demonstrated
(e.g. acetone or ethanol) and sprayed onto or mixed with that the distribution of a synthetic cannabinoid across an
the plant material. Plants such as damiana (Turnera impregnated paper was less variable when the paper was
diffusa) and marsh-mallow (Althaea officinalis) are laid flat than when hung up to dry, which method resulted
often used as the herbal basis owing to their low cost. in concentrations considerably higher at the bottom of the
Cement mixers have sometimes been used to mix the papers hung up to dry (Norman et al., 2020).
plant material with the dissolved synthetic cannabinoids
(EMCDDA, 2016a). The soaked plant material is Another study investigated preparation techniques of
subsequently dried and packaged in units of typically soaking paper with synthetic cannabinoid solutions with
1–5 g before being sold to consumers. The process of a focus on visibility of this manipulation. The authors
adding the synthetic cannabinoids to the plant material demonstrated that soaking paper with a 25 mg/ml
can lead to products containing dangerous amounts of MDMB-CHMICA solution did not lead to visible changes.
substances. This is because producers have to guess In contrast, soaking with a 100 mg/ml solution produced
the amount of cannabinoids(s) to add, while the mixing visible anomalies on the paper (Angerer et al., 2018b).
process makes it difficult to dilute the substances
sufficiently and distribute them consistently throughout
the plant material. This can result in both products that I Pharmacology
contain toxic amounts of the substances in general
(Ernst et al., 2017; Frinculescu et al., 2017; Langer et
al., 2014: Langer et al., 2016) and products in which Endocannabinoid system and cannabinoid receptors
the cannabinoids are clumped together, forming highly
concentrated pockets of the synthetic cannabinoid within The expression of two types of cannabinoid receptors
the plant material (Frinculescu et al., 2017; Moosmann et (CB1 and CB2) plays a fundamental part in the human
al., 2015; Schäper, 2016). endocannabinoid system, with endogenous compounds
being referred to as endocannabinoids (e.g. anandamide
and 2-arachidonoylglycerol), which bind to these receptors
Production of e-liquids and activate them. While CB1 receptors are most abundant
in central neuronal tissue (with low abundance in
e-Liquids (liquids used in electronic vaping devices) peripheral tissue, e.g. endocrine cells), CB2 receptors are
containing synthetic cannabinoids have become mainly expressed in immune cells. The psychological and
increasingly popular over the past few years, coinciding physiological functions influenced by the modulation of

14
 Synthetic cannabinoids in Europe – a review

CB1 receptor activity include pain perception, appetite, a crucial role in the desensitisation of GPCRs. Binding
cognition, motivation, mood, memory and neuromotor of β-arrestin to a receptor initiates internalisation of
functioning. The influence on these functions can be the GPCR (Jin et al., 1999; Kouznetsova et al., 2002), a
explained by the main localisations of CB1 receptors in the compensatory process that is believed to play a role in the
brain (the cortex, amygdala, hippocampus, basal ganglia development of tolerance. This biomolecular mechanism
and cerebellum). The psychotropic effects of cannabinoid is often observed after the activation of CB1 receptors
receptor agonists are mainly mediated through stimulation through efficacious cannabinoid receptor agonists (Hsieh
of CB1 receptors. In contrast, stimulation of CB2 receptors et al., 1999). Case reports suggest that tolerance and
is suggested to result in anti-inflammatory and analgesic withdrawal symptoms may develop quickly after repeated
effects, and CB2 receptors are regarded as a potential consumption of synthetic cannabinoids (Zimmermann et
target for the development of medicines for the treatment al., 2009).
of pain and inflammation (Greco et al., 2014). Selective
agonists at CB2 receptors are believed to have promising Inactivation of endocannabinoids, especially in the
therapeutic potential while avoiding the adverse synaptic gap, is catalysed by FAAH (Deutsch and Chin,
psychotropic effects of CB1 agonists. 1993). FAAH has turned out to be a possible target
for the indirect activation of the endocannabinoid
The cannabinoid receptors are members of the family of system. Inhibitors of this enzyme can potentially lead
Gi/o protein-coupled receptors (GPCRs). In most tissues to an increase in endocannabinoid concentrations in
and cells, activation of CB1 receptors inhibits adenylyl the central nervous system and produce cannabis-like
cyclase, resulting in a decrease in the intracellular second effects. In 2016, a clinical trial (phase I) investigating the
messenger cyclic adenosine monophosphate (cAMP). clinical safety of an inhibitor of FAAH (BIA-102474) was
Following this, depending on the type of neuron, different halted after 4 out of 90 test subjects developed severe
ion channels are regulated, leading to the inhibition neurological injuries and one death case (Chin, 2016). The
of glutamatergic, GABAergic, glycinergic, cholinergic, mechanism responsible for these adverse events remains
noradrenergic or serotoninergic neurotransmission (Szabo unknown. Of note is that two FAAH inhibitors, URB597
and Schlicker, 2005). The inhibition of neurotransmitter and LY2183240, have been detected on the European
release may lead to excitatory (GABAergic neurons) or drug market, including in ‘legal high’ products (EMCDDA,
inhibitory (glutamatergic) effects. However, evidence exists 2016b).
showing that some isoforms of the cannabinoid receptors
are GsPCRs, thus leading to stimulation of adenylyl cyclase
(Mukhopadhyay et al., 2000). Additional pathways (e.g. Pharmacodynamics
leading to the activation of mitogen-activated protein
kinases) have been described (Powles et al., 2005). Synthetic cannabinoids are functionally similar to the main
Some studies also suggest that CB1 receptor activation active substance of Δ9-THC found in Cannabis sativa.
might lead to tissue-dependent formation of intra- and While THC acts as a partial agonist at the cannabinoid
transcellular dimers, oligomers and heterodimers as receptors, synthetic cannabinoids are often full agonists
a potential explanation for different pharmacological at CB1 and sometimes CB2 receptors (see the subsection
outcomes in various tissues (Wager-Miller et al., 2002). ‘In vitro studies’). In the 1990s, the identification of
Although it has become clear in recent decades that the cannabinoid receptors and their endogenous ligands
endocannabinoid system regulates numerous somatic triggered an exponential growth of studies exploring the
and mental functions, the complexity of the underlying endocannabinoid system. The CB1 receptor turned out
biomolecular mechanisms remains to be investigated. to be a promising target for a wide range of pathological
conditions. Activation of the neuronal endocannabinoid
Cannabinoid receptors are activated by the endogenous system showed potential for the treatment of a variety of
eicosanoids anandamide and 2-arachidonylglycerol. While diseases, ranging from neuropathic pain and neuromotor
anandamide acts as a selective agonist at CB1 receptors, disorders, such as amyotrophic lateral sclerosis, multiple
2-arachidonylglycerol shows affinity to both CB1 and sclerosis, Parkinson’s disease and Huntington’s disease,
CB2 receptors. The promiscuity and pleiotropic effects of to conditions such as anorexia and emesis (e.g. induced
these endocannabinoids in the central nervous system by chemotherapy). However, the therapeutic application of
have been shown through experiments with CB1 receptor cannabinoid receptor modulators is still limited to pure Δ9-
knockout mice by Di Marzo et al. (2000). THC (dronabinol – active ingredient of Marinol); nabilone
(e.g. Cesamet), which is chemically similar to Δ9-THC;
Stimulation of CB1 receptors also leads to the association cannabidiol (e.g. Epidiolex); and Cannabis sativa (the pure
with intracellular β-arrestin. These complex molecules play

15
Synthetic cannabinoids in Europe – a review

herbal drug, usually the flowers of the female plant) and its strength. To illustrate this principle, rimonabant, an inverse
extracts (e.g. Sativex) (EMCDDA, 2018a). antagonist at the CB1 receptor, shows a high binding
affinity towards CB1 receptors, but leads to no activation
Although synthetic cannabinoids were first developed with of the Gi/oPCR. Since the affinity of rimonabant to the
the intention of treating the previously stated diseases and receptor in its inactive state is much higher than in the
their symptoms, most of them are not used as therapeutics active state (and vice versa for synthetic cannabinoids),
owing to their high potency at the CB1 receptor (high the activity of CB1 receptors is decreased in its presence.
affinity and efficacy), which has been associated with
psychoactive side effects with the potential for abuse, thus For the determination of receptor binding affinity, the
resulting in an unfavourable risk–benefit profile for medical most commonly used method is the competitive ligand-
applications. binding assay using radioactively labelled cannabinoid
receptor agonists (e.g. [3H]CP-55,940, [3H-HU]243 or
Since the endocannabinoid system turned out to be a [3H]WIN-55,212-2). Firstly, the affinity of the competitive
promising target for the treatment of eating disorders radioligand towards the respective receptor needs to
such as anorexia, it seems plausible that antagonism of be determined (KD through saturation binding assay).
cannabinoid receptors is a reasonable approach for the Secondly, the competitive binding assay is conducted
treatment of obesity. Rimonabant (Acomplia), a selective with varying concentrations of the test compound in the
inverse CB1 receptor agonist, was developed for the presence of the radioligand (bound to the receptor), which
treatment of patients with a body mass index of over is then replaced by the test compound in a concentration-
27 kg/m2. The approval for rimonabant as a medicine dependent manner. The turning point of the resulting
was withdrawn in 2008 by the European Medicines binding curve represents the half-maximal inhibitory
Agency owing to its psychiatric side effects (depression concentration (IC50). The calculation of the Ki value is
and anxiety). While rimonabant increases the likelihood performed with the Cheng–Prusoff equation (parameters:
of depressive and anxiogenic conditions, this effect KD, IC50 and the concentration of radioligand). The resulting
is more pronounced in patients with a predisposition Ki value is a measure of the affinity of a test compound
to depression, suggesting that blocking CB1 receptors towards the receptor investigated (Cheng and Prusoff,
through an inverse agonism is more likely to intensify 1973).
existing conditions rather than to cause them in healthy
individuals (Moreira and Crippa, 2009). In contrast to The determination of the intrinsic activity of a test
a neutral antagonist, rimonabant acts as an inverse compound can be achieved through various assay
agonist at the CB1 receptor. This means that not only systems. The most common methods are the [35S]
does it prevent the activation of the receptor, but it GTPγS-mediated receptor activation assay (Nakajima et
also decreases the constitutive activity of the neuronal al., 2011), the fluorometric imaging plate reader (FLIPR)
endocannabinoid system (Erdozain et al., 2012; Fong, membrane potential assay (Banister et al., 2015) and the
2014), and this may explain the serious psychiatric side cAMP accumulation assay (Drabczyńska et al., 2011).
effects of rimonabant. A decrease in CB1 receptor activity These assays reveal concentration-dependent activation/
implies the presence of constitutive or basal activity, inactivation of a GPCR caused by a ligand (half-maximal
which was shown in both expression systems and native effective concentration (EC50) values).
tissues in the absence of endocannabinoids (Pertwee,
2004). Although cannabinoid receptor antagonists did The properties of Δ9-THC in these assays are shown
not pass the risk–benefit assessment for the treatment of in Table 1. The activation of human CB1 receptors is
obesity, they might be of interest for the use as antidotes observed with EC50 values between 154 nM and 171 nM.
in cases of synthetic cannabinoid poisoning with highly Δ 9-THC acts as a partial agonist at the CB1 receptors
potent compounds (described in Section 5.1, ‘Acute (61 % maximal effect when compared to the maximal
toxicity’). effect of CP-55,940). While the data regarding intrinsic
activity appear to be reproducible, investigations on
receptor-binding affinity have produced widely varying
In vitro studies Ki values for Δ9-THC (3.87–80.3 nM). This finding should
The pharmacological characteristics of many synthetic be kept in mind when comparing affinity data received
cannabinoids have been investigated in in vitro receptor under different assay conditions (human versus rat
binding studies. While receptor affinity describes the ability or mouse CB 1 receptors; assay principle; and used
of a ligand to bind to the receptor, the intrinsic activity concentrations).
describes the effects produced after binding and their

16
 Synthetic cannabinoids in Europe – a review

TABLE 1
Pharmacological properties of Δ 9 -THC towards CB1 receptors

Receptor affinity Receptor activation KD (in nM) of the

Receptor types Assay principle Source
(Ki in nM) (EC 50 in nM) radioligand
171 Human (murine FLIPR membrane Banister et al. (2016)
neuroblastoma cells) potential

154 (maximal effect Human (fragments of [35S]GTPγS Own data

compared to human embryonic
CP-55,940 = 61 %) kidney cell
membrane)
3.87 Human (Chinese [3H]CP-55,940 Hess et al. (2016) 2.40
hamster ovary cells)
5.05 Human (Chinese [3H]CP-55,940 Iwamura et al. (2001) 0.57
hamster ovary cells)
8.33 Mouse [3H-CP-55,940 Iwamura et al. (2001) 0.70

13.5 Rat [3H]CP-55,940 Iwamura et al. (2001) 0.16

6.6 Human (fragments of [3H]CP-55,940 Own data —

human embryonic
kidney cell
membrane)
80.3 Rat [3H]HU243 Rhee et al. (1997) —

40.7 Rat [3H]CP-55,940 Compton et al. 0.68

(1992)
10.2 Rat [3H]WIN-55212-2 Kuster et al. (1993) 2.00

Animal studies observed in the animals tested (hypothermia, catalepsy,

One of the most common animal models for investigating Straub tail and ptosis) were consistent with CB1 receptor
the pharmacological potency of cannabinoids is activation. Similar observations after inhalation of JWH-018
the observation of behavioural and physiological (hypomotility, antinociception, catalepsy and hypothermia)
changes in mice. Inhibition of locomotor activity, were made by Wiley et al. (2017) and Wiebelhaus et al.
antinociception, hypothermia and catalepsy are typical (2012). Interestingly, in the latter study, 2.7 mg of JWH-
effects of cannabinoids and are known as the ‘tetrad’ of 018 produced antinociceptive and hypothermic effects
cannabimimetic effects in the mouse model. Another that were similar to the effects caused by 14.8 mg of
technique commonly employed in animal studies is Δ9-THC (in marijuana). MDMB-FUBINACA and 5F-AMB
known as the drug discrimination model, in which animals (5F-AMB-PINACA) induced dose-dependent hypothermia
are trained to discriminate between two substances, and bradycardia in mice (0.1–1 mg/kg body weight). The
placebo and Δ9-THC, injected intraperitoneally, using effects were reversed by pretreatment with the inverse CB1
food reinforcement. The animals are first conditioned, receptor agonist rimonabant (Banister et al., 2016).
using food rewards, to produce a particular response
to a stimulus while under the influence of Δ9-THC and In drug discrimination studies, Järbe et al. (2011)
a different response to the same stimulus when given examined synthetic cannabinoids for their cannabimimetic
the placebo. Thus, the pharmacological effect of the (Δ9-THC-like) effects. JWH-018 and AM-5983 appeared to
cannabinoid controls the animal’s behaviour, making be eight times more potent than Δ9-THC, followed by AM-
them produce the appropriate response in order to gain a 2233 (twice as potent as THC), and equipotent to WIN-55-
food reward. The choice the animal takes after application 212-2. While the effects of JWH-018, AM-5983 and AM-
of a test compound has shown to be conclusive for the 2233 were completely blocked by pre-administration of
similarity of the effects between the substance the mice rimonabant, WIN-55-212-2 seemed to interact differently
were trained with and the test compound (e.g. synthetic with rimonabant, probably because these two compounds
cannabinoids compared to Δ9-THC; Martin et al., 1991). bind to different sites on the CB1 receptor. Ginsburg et al.
(2012) used Δ9-THC-trained monkeys for the evaluation of
Poklis et al. (2012) studied the effects caused by inhalation JWH-018 (which is about three to four times as potent as
of the smoke of a herbal blend (0.2 g), containing JWH- Δ9-THC) and JWH-073 (which is approximately equipotent
018 (7.2 mg) as the active ingredient, in mice. The effects to Δ9-THC). The duration of action was shown to be 4 hours

17
Synthetic cannabinoids in Europe – a review

for Δ9-THC, 2 hours for JWH-018 and 1 hour for JWH-073. to 75 µg/kg body weight (up to 6.2 mg) in 17 volunteers
The authors concluded that these findings suggested a (Theunissen et al., 2019), resulting in a mean maximal
greater dependence liability for the synthetic cannabinoids JWH-018 concentration of 7.5 ng/ml (1.7–22.3 ng/ml).
investigated. Again, no serious side effects were experienced although
some participants reported dissociation, amnesia and
Cannabinoids are also known to be effective antiemetic confusion. Effect size and cognitive impairment were more
drugs. Nabilone (e.g. Cesamet) and dronabinol (e.g. pronounced than in the pilot study, which had lower doses.
Marinol) are approved for the treatment of chemotherapy-
induced nausea and vomiting (EMCDDA, 2018a). As rats
are unable to vomit, a selective measure for nausea in Pharmacokinetics
this species is the state of conditioned gaping. Studies
show that gaping under the influence of emetic agents
can be effectively erased by the application of natural Absorption
and synthetic cannabinoids. Parker and Mechoulam The most common form of consumption of synthetic
(2003) studied the antiemetic effects of Δ9-THC and the cannabinoids is the inhalation of burned or heated plant
synthetic cannabinoid HU-210 in rats. They showed that material laced with synthetic cannabinoids (‘herbal
these substances interfered with the establishment and smoking mixtures’). Such mixtures are usually smoked
expression of lithium-induced conditioned gaping in rats. like cannabis, often combined with tobacco in a joint or a
Furthermore, the antiemetic effects were reversed by the water pipe. Another method of administration is inhalation
application of the CB1 receptor antagonist rimonabant. after vaporisation of the substance using a ‘vaporiser’ or by
using e-liquids vaporised in electronic cigarettes. The rapid
absorption through pulmonary alveoli usually leads to
Human studies maximum concentrations (Cmax) after a few minutes. In an
Systematic research on the pharmacology of synthetic administration study with 4 mg of JWH-018, the Cmax was
cannabinoids in humans has not been published so far. reached after 5 minutes (accompanied by the occurrence
of psychotropic effects; Teske et al., 2010), and this finding
However, there are some reports on self-experiments has been confirmed in other studies (Theunissen et al.,
conducted with synthetic cannabinoids. Auwärter et 2018, 2019).
al. (2009) smoked a herbal blend containing JWH-018
and CP-47,497-C8 and reported cannabis-like effects As oral consumption can lead to unpredictable poisonings
that began 10 minutes after smoking and lasted for due to erratic absorption, this route of administration is
about 6 hours. Teske et al. (2010) reported on a self- not common among users of synthetic cannabinoids. The
experiment that involved the smoking of about 4 mg absorption of the drug is influenced by a wide range of
of JWH-018 by cannabis-naive individuals, resulting factors (e.g. fasted versus fed state of the stomach, the
in cannabis-like effects including thought disruptions. activity of multidrug resistance proteins, passive or active
Further self-experiments involving the oral application of transport through intestinal barriers and the dissolution
various synthetic cannabinoids have also been reported rate of the formulation). Compared with inhalation, Cmax
(e.g. Angerer et al., 2019; Hutter et al., 2013). In these is delayed and is usually achieved between 30 minutes
studies, the individuals did not experience noticeable and several hours after administration (Castaneto et al.,
effects, probably because of the relatively low doses, in 2015). Hutter et al. (2013) observed that Cmax was reached
combination with a pronounced first-pass effect, which approximately 1.5 hours after a single oral administration
can be expected after oral administration. of AM-2201. A wide range of xenobiotics are partly
eliminated after intestinal absorption by a first-pass effect
In a recent pilot study (placebo-controlled, cross-over), in the liver, thereby reducing the bioavailability. Therefore,
six volunteers (occasional cannabis users) vaped 2 mg the dose needed for the desired effects after oral uptake
or 3 mg of JWH-018 (Theunissen et al., 2018), resulting exceeds the amount needed when inhaling. In the study of
in maximum serum concentrations of 2.9–9.9 ng/ Hutter et al. (2013), 5 mg of AM-2201 orally taken did not
ml (Toennes et al., 2017). The effects occurred within result in psychotropic effects, although – considering the
the first 2 hours after application, and no serious side potency of AM-2201 – this dose, if smoked, would lead to
effects were reported. Effects were mild compared with a perceptible effects.
typical recreational dose of cannabis (probably because
of delivery by the vaping device was suboptimal) and So far, there appear to have been no reports of users of
included behavioural impairment. In a similar study, the synthetic cannabinoids using intravenous injection or
same group investigated the effects of doses equivalent rectal application as the route of administration. However,

18
 Synthetic cannabinoids in Europe – a review

anecdotal data suggest that marginalised, high-risk drug leucinates, valinamides and tert-leucinamides using a
users do, on rare occasions, intravenously inject synthetic pooled human liver microsome assay. Compounds with
cannabinoids. a valine moiety generally underwent more pronounced
hydrolysis than their tert-leucine analogues, probably
caused by the additional methyl group leading to higher
Metabolism and excretion metabolic stability. Furthermore, hydrolytic dehalogenation
Synthetic cannabinoids are metabolised differently of the alkyl chain was more predominant in tert-leucine
depending on their structure. The main metabolic reactions analogues. Compounds containing a terminal methyl
include the oxidation of aromatic and alkyl structures. ester at the amino acid tail showed higher hydrolysis
Aromatic core structures such as indole, indazole, rates than their amide analogues. Methyl tert-leucinate-
7-azaindole and γ-carbolinone are known to be oxidised to derived synthetic cannabinoids showed the highest mean
mono-/dihydroxylated or dihydrodiol metabolites (Franz relative abundance for oxidative N-dealkylation. In addition,
et al., 2019; Mogler et al., 2018a). Terminal hydroxyalkyl dehydrogenation was predominantly observed in the
groups are often further oxidised to the corresponding valinamide derivatives, probably leading to energetically
carboxylic acids, probably catalysed by alcohol / aldehyde favoured structures (Franz et al., 2019).
dehydrogenases or CYP450 enzymes (Chimalakonda
et al., 2012; Holm et al., 2016). In some cases, further Thomsen et al. (2015) showed enzymatic activity of the
degradation of the carboxylic acid metabolite by carboxyl esterase 1b (CES1b) towards BB-22 (JWH-
decarboxylation has been observed. The γ-carbolinone- methylcyclohexane-8quinolinol), PB-22 (JWH-018
derived synthetic cannabinoids CUMYL-PeGACLONE and quinolinecarboxylate analogue), 5F-PB-22 (AM-2201
5F-Cumyl-PeGaClone have been shown to be metabolised carboxylate analogue quinolinyl derivative) and the
to their propionic acid metabolites by gradual alkyl chain valinamide synthetic cannabinoids AB-PINACA and AB-
degradation, as detected in human urine specimens FUBINACA.
(Mogler et al., 2018a, 2019).
Glucuronidation is the most common phase II
The replacement of hydrogen by a fluorine atom is biotransformation of synthetic cannabinoids. 5F-MDMB-
a strategy commonly applied by manufacturers to P7AICA and PB-22 (JWH-018 quinolinecarboxylate
circumvent legal restrictions and increase pharmacological analogue) / 5F-PB-22 (AM-2201 carboxylate analogue
potency at the same time (Banister et al., 2015). quinolinyl derivative) are conjugated with glucuronic acid
Defluorination of terminally fluorinated alkyl groups leads after phase I functionalisation (linked to the hydroxyl
to ω-hydroxyalkyl metabolites. This biotransformation or carbon acid function; Richter et al., 2019; Wohlfarth
has been described for AM-2201 (Hutter et al., 2013), et al., 2014). Therefore, when analysing human urine
5F-AKB48 (Holm et al., 2015), 5F-MDMB-PICA (Mogler specimens, cleavage of glucuronic acid conjugates with
et al., 2018b) and 4F-MDMB-BINACA (Haschimi et al., β-glucuronidase is essential.
2019). Although some studies show that defluorination
is catalysed by CYP1A2, CYP2C9 and CYP2C19 Most synthetic cannabinoids undergo renal excretion only
(Chimalakonda et al., 2012), the formal reaction of after metabolic transformation. Therefore, the detection
fluoroalkyl to hydroxyalkyl is chemically not an oxidation of metabolites is essential for the unambiguous proof of
but a hydrolytic substitution, and the exact mechanism of exposure in forensic urine analysis. Nonetheless, in some
defluorination remains to be investigated. In contrast to cases, the parent compound is eliminated in urine, with the
synthetic cannabinoids with a terminally fluorinated alkyl highest abundance relatively to the metabolites detected.
group, oxidation of substances with a non-fluorinated alkyl Giorgetti et al. (2020) observed that 5F-AB-P7AICA, the
chain occurs only rarely at the terminal carbon atom, and, 7-azaindole derivative of 5F-AB-PINACA, shows lower
instead, occurs mainly at C2. Differentiation between the metabolic degradation than its indazole analogue.
uptake of a fluorinated and a non-fluorinated analogue can
therefore be achieved through analysis of these different
hydroxylated metabolites in urine. Interindividual genetic variability in metabolising
enzymes and pharmacokinetic interactions
The structure–metabolism relationships of the subclass Chimalakonda et al. (2013) described the pharmacokinetic
of synthetic cannabinoids with valine- and tert-leucine- interactions between JHW-018 and medicines, especially
derived structures (emergence in 2012; Uchiyama et regarding their metabolism. Co-administration of JWH-018
al., 2013b) have been described comprehensively by and inhibitors of the metabolising enzymes CYP1A2 (e.g.
Franz et al. (2019). Their study included data about the ciprofloxacin and fluvoxamine) or CYP2C9 (e.g. fluconazole
in vitro metabolism of methyl valinates, methyl tert- and valproic acid) may lead to slower elimination of JWH-

19
Synthetic cannabinoids in Europe – a review

018 and thus to higher serum concentrations and longer studied by Huffman et al. (2005). They mainly investigated
lasting effects of the synthetic cannabinoids (Chimalakonda the position of the methoxy group at the naphthoyl
et al., 2013). CYP1A2 and CYP2C9 are involved in the residue. While methoxy substitution at C4 enhanced
metabolism of several xenobiotics and endogenous affinity towards the CB receptor, substitution at C6 and
substances. Genetic polymorphisms (a poor metaboliser C7 seemed to have little effect, and the introduction of a
versus an extensive and ultrarapid metaboliser) may 2-methoxy substituent completely revoked affinity towards
also influence serum levels of synthetic cannabinoids the CB1 receptor.
(Gunes and Dahl, 2008). Higher serum levels of synthetic
cannabinoids might increase the risk of poisoning. The side chain of indazole-based tert-leucine synthetic
cannabinoids has a large influence on CB1 receptor
affinity. 5F-MDMB-PINACA (5F-ADB), MDMB-FUBINACA
Interactions and MDMB-CHMINACA differ only in the presence of a
5-fluoropentyl, fluorobenzyl and cyclohexylmethyl group
Interactions regarding pharmacodynamics were as substitution at N1 of the indazole core structure.
described by Brents et al. (2013) for JWH-018 and All show high receptor binding, but the 5-fluoropentyl
JWH-073. Combining both synthetic cannabinoids moiety (5F-MDMB-PINACA) leads to the highest potency
showed synergistic and additive effects in mice regarding at the CB1 receptor (EC50 0.59 nM), followed by MDMB-
analgesia and hypothermia (a leftwards shift of dose– FUBINACA (EC50 3.9 nM) and then MDMB-CHMINACA
response curves). Luszczki and Florek-Łuszczki (2012) (EC50 10 nM) (Banister et al., 2016).
described a synergistic interaction between pregabalin
and the synthetic cannabinoid WIN-55,212-2 in a fixed The work of Longworth et al. (2017) demonstrated that
dose ratio of 1:1 in the mouse model of acute thermal valine- and tert-leucine-derived synthetic cannabinoids,
pain. The review article of Manzanares et al. (1999) with a substituted indole or indazole core structure, exhibit
summarises studies demonstrating the phenomena of high cannabimimetic potency in vivo and in vitro. The
cross-tolerance and mutual potentiation of hypothermia, activity of the most abundant metabolites of the synthetic
sedation, hypotension, inhibition of motor activity and cannabinoids APICA (JWH-018 adamantyl carboxamide)
antinociception between cannabinoids and opioids. and ADB-PINACA were measured in a FLIPR assay of
membrane potential. The formation of a free carboxylic
group (through oxidation of the alkyl chain or hydrolysis
Structure–activity relationships and drug design of amide or ester functionality) generally reduces
pharmacological activity (Longworth et al., 2017).
Since the identification of the cannabinoid receptors CB1
and CB2 and their corresponding endogenous ligands The bioisosteric substitution of hydrogen by a fluorine atom
(see Section 4.3, ‘Pharmacology’), numerous structurally is a common strategy used by manufacturers to circumvent
diverse synthetic cannabinoids have been discovered. In legal restrictions and increase pharmacological potency.
addition, systematic investigations of structure–activity The synthetic cannabinoids JWH-018, UR-144, JWH-
relationships have been undertaken to identify high- 018 quinolinecarboxylate analogue (PB-22) and APICA
potency cannabinoids with high specificity for one or both (JWH-018 adamantyl carboxamide) and their respective
cannabinoid receptors. fluorinated analogues (AM-2201, 5F-UR-144 (XLR-11), AM-
2201 carboxylate analogue quinolinyl derivative (5F-PB-22)
The influence on CB1 and CB2 binding affinities of alkyl and STS-135) do all bind as agonists to the CB1 receptor.
chain length at N1 of cannabimimetic indoles was The substitution of hydrogen with fluorine commonly
studied by Aung et al. (2000). For this purpose, the results in increased potency (Banister et al., 2015).
morpholinoethyl moiety of WIN-55,212-2 was substituted
by alkyl chains of varying length (homologous series from Recently, the crystal structure of the human CB1 receptor
methyl to heptyl). These structural changes revealed that (hCB1R) was revealed by Hua et al. (2017). The hCB1R
the pentyl chain showed the highest cannabinoid receptor was crystallised in a complex with the agonists AM-11542
affinity, and that the core structure of WIN-55,212-2 and AM-841, and the resulting structure provided insight
afforded a chain length of three to six carbon atoms, into the binding mode of endogenous ligands, synthetic
resulting in high binding affinity. cannabinoids and naturally occurring cannabinoids. The
utility of the crystal structure may provide a fundamental
The structure–activity relationship of compounds with base for structure-based drug design of novel hCB1R-
1-pentyl- and 1-propyl-3-(1-naphthoyl)indole-core targeting pharmaceuticals.
structures towards the cannabinoid receptors were

20
 Synthetic cannabinoids in Europe – a review

I Health and social risks The high potency of synthetic cannabinoids, coupled with
the unintentionally high doses that users are exposed
The scientific data related to the acute toxic effects to, is also responsible for outbreaks of mass poisonings
of synthetic cannabinoids are still limited, despite the involving this group of substances. Such outbreaks have
relatively widespread use of these compounds, as reflected ranged in size from four or five to hundreds of victims,
by multiple reports on poisonings, including deaths, including some deaths. While many of the outbreaks that
involving the substances. The toxicity profile of these have been reported so far have been in the United States,
substances seems to have some similarities to that of mass poisonings have also occurred in Russia, Canada
cannabis, although more serious adverse health effects and Europe (Adams et al., 2017; Kasper et al., 2015;
are often seen with the former. Some of the reasons Schwartz et al., 2015; Shevyrin et al., 2015; Springer et
for synthetic cannabinoids’ greater potential for harm al., 2016; Trecki et al., 2015; Tyndall et al., 2015). Mass
compared with cannabis include their typically full agonism poisonings can rapidly overwhelm emergency responders
at the CB1 and CB2 receptors and the extremely high and other local healthcare systems.
potency of many synthetic cannabinoids. The type and
amount of synthetic cannabinoids in products can differ For most of the synthetic cannabinoids that have
within smoking mixtures sold under the same name, and emerged on the drug market, prospective or controlled
several examples of false labelling have been reported. animal or human studies are scarce or missing, although
In an online survey, 11 % of synthetic cannabinoid users some in vitro cellular studies have been performed.
reported having experienced unpredicted effects, despite Studies conducted in human-derived cell lines with an
consumption of the same brand of ‘Spice’ (Vandrey et al., assessment of the cytotoxic/genotoxic effects of synthetic
2012), which might in part be caused by inhomogeneity cannabinoids (JWH-018, JWH-073, JWH-122, JWH-210,
of the distribution of synthetic cannabinoids in herbal JWH-250 and AM-694) and the influences on hormone
blends, producing a higher risk of overdoses even in highly levels and the immune system have demonstrated only
experienced users (Moosmann et al., 2015). Unknown weak cytotoxicity, as such effects generally were observed
to users, synthetic cannabinoids have also been mis- at concentrations much higher than those expected in
sold as ecstasy/3,4-methylenedioxymethamphetamine synthetic cannabinoid users (Koller et al., 2013, 2014).
(MDMA), other illicit drugs, and CBD and THC e-liquids. The compounds investigated did not cause oxidative
In some cases, this has led to severe poisoning (Allibe damage to the DNA, but affected processes such as the
et al., 2016; Brenneman et al., 2016; Horth et al., 2018; synthesis of proteins and the homeostasis of membranes,
Pap, 2016). Another concerning development is the ultimately leading to chromosomal damage. Neither
increase in the identification of synthetic cannabinoids modifications of the oestrogen levels nor abnormalities of
in low-THC cannabis products, which was first reported immunomodulation were seen in the same study (Koller
in Switzerland (Saferparty, 2020). Since July 2020, the et al., 2013). Chromosomal aberrations, but no oxidation-
EMCDDA has received an increasing number of reports of induced damage, were found in a study conducted
the adulteration of cannabis products with highly potent by Ferk et al. (2016) involving 5F-UR-144 (XLR-11).
synthetic cannabinoids, such as MDMB-4en-PINACA Oxidative stress due to the production of reactive oxygen
(EMCDDA, 2021a). Typically, the adulterated cannabis species in human endometrial stromal cells was recently
products are low-THC herbal material or resins. While the demonstrated for JWH-122, UR-144 and WIN-55,212-2
prevalence of these adulterated products is unknown, at (Fonseca et al., 2019). While this effect was compensated
least six countries that are part of the EU Early Warning for by the consumption of glutathione for JWH-122 and
System have reported this type of adulteration. In terms of UR-144, WIN-55,212-2 induced apoptotic cell death.
look, smell and flavour, these adulterated products would
be very difficult to distinguish from ‘genuine’ illicit cannabis
products and, as a result, users may be unaware that they I Acute toxicity
are using synthetic cannabinoids. For this reason, and as
synthetic cannabinoids are highly potent substances, users The acute toxicity of a limited number of synthetic
of these products could be at high risk of poisoning – an cannabinoids has been partially studied in the non-
issue reflected by reports of poisonings in some countries. clinical setting, and animal models are extremely
The reason for adulteration is unclear, but one possibility is useful both to compare adverse effects of synthetic
that low-THC industrial hemp is cheap, is widely available cannabinoids with those produced by cannabis and to
and has a similar look, smell and flavour to ‘genuine’ tentatively assess the dose at which adverse or lethal
cannabis (making it easy to dupe unsuspecting users), effects may occur. Furthermore, animal models can help
while only a small amount of synthetic cannabinoids would to establish a tentative dose–dependence relationship.
be required to give a potent cannabis-like high. However, data mainly refer to relatively ‘old’ compounds,

21
Synthetic cannabinoids in Europe – a review

such as WIN-55,212-2, while novel substances that A decrease in the respiratory rate (oligopnoea) and
have appeared on the drug market, for example those behaviour effects (including seizure-like behaviour) were
bearing a cumyl substituent, have not been tested. The observed after intraperitoneal injection of 5 and 15 mg/
interpretation of animal data is complicated by differences kg MAM-2201 in 6-week-old rats. A decrease in glutamic
in pharmacokinetic behaviour and differences in the CB acid (one of the main excitatory brain neurotransmitters)
receptors between various species. In addition, models of and changes in energy metabolism were demonstrated by
synthetic cannabinoid intake used in animal experiments, a mass spectrometry-based metabolomics study and were
such as intraperitoneal application, do not have a direct suggested as a possible underlying cause of such acute
correlate in humans. symptoms (Zaitsu et al., 2015). Within 20 minutes of acute
administration of AM-2201 (2 mg/kg) and AB-CHMINACA
Clinical studies and studies involving human participants (1 mg/kg), abnormal spike waves were seen in mice
are extremely rare because of the unpredictability of monitored by electroencephalography (EEG). Epileptic
effects, which pose a serious risk to the health of the behaviour with rigidity and tonic–clonic movements were
subjects involved, leading to ethical issues. Therefore, also noted. Thirty minutes after administration, catalepsy
evidence on acute toxicity is mainly derived from case also developed. These effects, which were antagonised
reports and case series or from clinical reviews reporting by selective CB1, but not CB2, receptor antagonists,
on acute poisonings and/or deaths. One major limitation of were also accompanied by a change in glutamate
case reports is that the exposure to synthetic cannabinoids concentration, further confirming the possible role of
is often self-reported, or only circumstantial evidence this neurotransmitter (Funada and Takebayashi-Ohsawa,
exists, rather than analytical confirmation from a biological 2018). JWH-018, administered at doses of 1.5, 2.5 and
sample or epidemiologically linked physical sample. 5 mg/kg, also triggered seizures in mice, as recorded
by EEG and videography, in a dose-dependent manner
(Malyshevskaya et al., 2017). More recently, myoclonic
Animal data jerks, ‘gasping’ reaction and other seizure-like activities
were demonstrated in mice 2–3 minutes after the injection
Based on in vitro and animal studies, the potency of of a novel synthetic cannabinoid (CUMYL-4CN-BINACA) at
synthetic cannabinoids has been estimated to be 2–100 doses of 0.3 and 1 mg/kg (Kevin et al., 2019b).
times that of Δ9-THC (Castaneto et al., 2014).
In an experiment designed to test the acute toxicity of a
Some preclinical studies have focused on the evaluation single dose of the THJ-2201 (AM-2201 indazole analogue),
of the effects of synthetic cannabinoids on cognitive mice were administered THJ-2201 orally at a dose of 5,
processes such as attention. Sixty rats were trained for a 50, 300 or 2 000 mg/kg (Bakdash et al., 2018). Several
period of 5 months to detect visual stimuli (a lateralised symptoms, including tachycardia, seizures, locomotor
reaction time task). They were then administered WIN- agitation and dyspnoea developed, and their occurrence
55,212-2 intraperitoneally (1.0 or 2.5 mg/kg) and was seen in a dose-dependent manner. By contrast, only
compared with a negative control. Accuracy, errors slight modifications of the haematological parameters,
and response times were monitored. WIN-55,212-2 with an increase of lymphocyte counts, were noted. Even
was shown to decrease the number of correct choices, at low doses, histological examination of the liver and, to
increase omissions and increase response times in a a minor extent, of the kidneys of the treated mice showed
dose-dependent manner; thus, it was suggested that WIN- congestion, lymphocytic infiltration and necrosis. Finally, a
55,212-2 induced impairments in attention performances median lethal dose (LD50) of 822.20 mg/kg was calculated
(Arguello and Jentsch, 2004). Deleterious effects on for THJ-2201 (Bakdash et al., 2018), which points towards
sustained attention were also seen in the trial performed a relatively low acute toxicity.
by Miller et al. (2013), who tested rats with a two-choice
reaction time task 30 minutes after intraperitoneal Taken together, these data support the hypothesis that
administration of 0.02, 0.04, 0.08 or 0.16 mg/kg AM 4054. cognitive and behaviour effects, with the development
Several investigations have also shown a significant effect of seizures and agitation, respiratory depression and
of synthetic cannabinoids on working memory in rodents cardiovascular abnormalities, are toxic effects dose-
after the administration of JWH-081 and HU-210, with dependently occurring after an acute intake of synthetic
worsening of performances in maze-based tasks and of cannabinoids.
cognitive flexibility (i.e. the ability to think more than one
thing simultaneously or to switch between concepts) after To assess the cardiovascular effects of synthetic
a single administration of 0.2 mg/kg HU-210 (Cohen and cannabinoids, several groups have experimented on
Weinstein, 2018). isolated heart muscle preparations. For example, Bonz

22
 Synthetic cannabinoids in Europe – a review

et al. (2003) found that anandamide and the synthetic 19 % of cases. This effect was much more common after
cannabinoid HU-210 decreased the contractility of human reported synthetic cannabinoid intake than with accidental
atrial muscles when stimulated by an electrical field. More cannabis or CBD intake. Agitation/irritability, mydriasis,
recently, incubation with CB1/2 receptor agonists (WIN- tremors and twitching movements were described in
55,212-2 and the selective CB2 agonist JWH-133) was 12–16 % of cases. Surprisingly, bradycardia was more
shown by Maggo and Ashton (2018) to have a moderate frequently reported than tachycardia, occurring in about
positive chronotropic effect on isolated rat atria. The 16 % of cases (Brutlag and Hommerding, 2018). Effects on
authors suggest that tachycardia, a well-known effect of neuromotor and cardiovascular function were confirmed
synthetic cannabinoids that is believed to be mediated in one case, namely the poisoning of a dog after alleged
by central CB1 stimulation, could in part be provoked by exposure to a herbal smoking mixture (‘Potpourri’), with the
myocardial CB1 receptor activation. dog developing progressive ataxia, marked hypothermia
and bradycardia (Williams et al., 2015).
In vivo studies include that by Schmid et al. (2003),
who evaluated cardiovascular and respiratory effects in
urethane-anaesthetised rats that received 0.03, 0.1, 0.3 Human data
or 1 mg/kg WIN-55,212-2, WIN-55,212-3 or CP-55,940
intravenously. Arterial pressure reduction, a decrease in Data on humans are mostly available from retrospective
heart rate and a decrease in the plasma noradrenaline studies of patients who seek medical attention after the
levels were seen in animals challenged with synthetic consumption of synthetic cannabinoids, from calls to
cannabinoids, and the effects appeared to be dose related. poison information centres or from case reports and case
Changes were accompanied by a reduction in respiratory series of poisonings. However, these cases may not be
rate, a decrease in the partial pressure of oxygen and a fully representative, as serious poisonings are typically
decrease in blood pH. Two out of nine animals immediately overrepresented. Although many cases of poisonings
stopped breathing after administration of the highest are described in the literature, it is also important to
dose of CP-55,940. In another study, a dose of 0.01 mg/ highlight that in only some of these cases was exposure
kg HU-210 produced a reduction in mean blood pressure, to synthetic cannabinoids analytically confirmed from
while not significantly affecting heart rate, and decreased analysis of biological samples taken from the patients.
the cardiac index in anaesthetised rats (Wagner et al., This represents a further limitation in the evaluation of
2001). Finally, bradycardia lasting up to 10 minutes was human data, as the reliability of circumstantial data is low
seen in conscious and freely moving rats administered and the co-consumption of other synthetic cannabinoids
WIN-55,212-2 (0.15 mg/kg), while different cardiovascular or other drugs (possibly without involvement of synthetic
effects were described in spontaneously hypertensive rats cannabinoids) cannot be excluded. In some cases, the
(Wheal et al., 2007). intake of synthetic cannabinoids is self-reported by
the patients, and test results of general toxicological
Some data on animals are also available owing to screenings are negative (often performed only in a clinical,
accidental poisonings of domestic pet animals with ‘Spice’ not a forensic, setting) or synthetic cannabinoids are
products, which may occur following the ingestion of identified in exhibits such as smoked products (Zawilska
synthetic cannabinoid-containing food or plant material and Wojcieszak, 2014). Moreover, no data on the precise
or after the inhalation of side-stream smoke (Brutlag and dose ingested can be obtained from such cases.
Hommerding, 2018). Clinical signs might be reported
to pet poison helplines, although the limitations of such Controlled administration studies are much rarer. In a
data are that co-ingestants cannot be ruled out and self-experiment, 0.3 g of a ‘Spice’ product containing
synthetic cannabinoid intake is not analytically confirmed CP-47,497 was smoked, and the two participants
by laboratory tests in all cases reported. However, such showed increased pulse rates and alterations of mood
data may allow for a comparison of effects in animals and perception within 10 minutes after intake. They
and humans. In a study involving almost 60 cases of pet also reported cognitive impairment, which subjectively
(mostly canine) poisonings with synthetic cannabinoids, continued, with minor effects, until the next day (Auwärter
lethargy (41 %) and ataxia (52 %) were the symptoms et al., 2009).
most commonly reported, followed by vomiting (21 %).
The sedative effect sometimes also led to a reduction One male and one female volunteer smoked a cigarette
in the level of consciousness (stupor) and to respiratory containing 100 (female volunteer) and 150 mg (male
depression in 5–7 % of the cases. Depressant neuromotor volunteer) of a smoking mixture containing 2.9 % JWH-
effects were also seen, with lateral recumbency (i.e. 018 (2.9 and 4.3 mg, equivalent to a dose of 40 and
animals were unable to rise, once lying down) reported in 50 µg/kg, respectively) and reported sickness, sedation

23
Synthetic cannabinoids in Europe – a review

and xerostomia immediately after the self-administration, extrapolation to synthetic cannabinoids used as ‘legal
followed by a state of light tiredness and exhaustion highs’ might not be justified.
attenuating 6–12 hours after intake. Increased pulse rate,
in accordance with previous data, mydriasis and altered
pupil reaction were also noted. Maximum concentrations Acute poisonings
were approximately 10 ng/ml 5 minutes after smoking In a retrospective study involving 29 emergency department
(Teske et al., 2010). patients, whose exposure to synthetic cannabinoids
(mainly JWH series) was analytically confirmed, central
Mood and perception alterations, subjective impairment, nervous system and cardiovascular effects, and particularly
anxiety and loss of concentration were also experienced tachycardia, were the most commonly reported symptoms
by more than half of six volunteers after inhalation of (Hermanns-Clausen et al., 2013a). Among nervous system
0.3 g of herbal blends containing JWH-018 and JWH- effects, restlessness/agitation was seen in 41 % of the
073. Sedation and paranoia were seen in a minority of patients. In terms of frequency, these effects were closely
cases. Tachycardia was confirmed in all subjects, who also followed by changes in perception (38 %), including
showed a reddening of the conjunctivae and manifested hyperreactivity to light and external stimuli, vertigo and
xerostomia. A hangover effect lasted for 6–12 hours in anxiety attacks (24 % and 21 %, respectively). However,
three volunteers (Logan et al., 2011). depression of the nervous system with somnolence,
often lasting for several hours, confusion/disorientation
In further experiments involving oral ingestion of 10 mg and unconsciousness were also frequent (17 %, 14 %
of AM-694, 26 mg of JWH-018 adamantoyl derivative and 17 %, respectively). Apart from tachycardia (heart
(AB-001), 5 mg of AM-2201 and 2.5 mg of 5F-AB- rates between 90 and 170 beats/minute), other common
P7AICA, despite the known potency of these synthetic effects on cardiovascular function included hypertension
cannabinoids, no effects were noted (Giorgetti et al., 2020; (median values: 160 mmHg systolic and 85 mmHg diastolic
Grigoryev et al., 2012; Grigoryev et al., 2013b; Hutter et al., pressure), dyspnoea and electrocardiographic changes.
2013), probably because of a pronounced first-pass effect. Among gastrointestinal symptoms, nausea and vomiting
were encountered in 28 % of patients. While the majority of
Recently, Theunissen et al. (2021) published the results these effects are consistent with those of intake of a high
of a placebo-controlled, double-blind, within-subjects trial dosage of Δ9-THC, this is not the case for agitation and
in which 24 healthy participants with no history of mental epileptic seizures, which seem, for some reason, to be more
illness inhaled vapour of placebo or JWH-018 at a dose of common with synthetic cannabinoids (Hermanns-Clausen
75 μg/kg body weight. On average, participants received et al., 2013a). In a large survey with 15 200 responses,
a total dose of 5.52 mg of JWH-018 (regarded by the users reported more and stronger negative effects after
authors as a ‘moderate’ dose). The findings demonstrated smoking synthetic cannabinoids than after taking cannabis,
that healthy volunteers who are intoxicated by a moderate with worse hangover effects and paranoia (Winstock and
dose of the synthetic cannabinoid JWH-018 experience Barratt, 2013). However, prospective studies in synthetic
pronounced psychedelic and dissociative symptoms and cannabinoid users, especially in comparison with cannabis,
feelings of confusion. have not been conducted so far; thus, the relative risk
cannot be precisely characterised.
Some data on the toxicity of synthetic cannabinoids
can also be derived from patients receiving chronic According to the available studies, tachycardia (37–40 %),
pain treatment. Adverse effects reported in the short- agitation (18–23 %), drowsiness (13–18.5 %), nausea/
term treatment of chronic pain with cannabis (Vučković vomiting (9.9–15.7 %) and hallucinations (9.4–10.8 %)
et al., 2018) or nabilone (McGolrick and Frey, 2018) are the symptoms most frequently reported by poison
were mostly mild or moderate in severity. Dizziness, information centres (Forrester et al., 2011; Hoyte et al.,
drowsiness, faintness, cognitive impairment and fatigue 2012). Despite the usefulness of such data, it has to be
were among the most commonly reported adverse effects. remembered that, in studies based on data from poison
Nausea, xerostomia and cardiovascular effects such as information centres, the exposure of patients to synthetic
tachycardia and hypertension also occurred. The reasons cannabinoids is often not analytically confirmed (Forrester
for withdrawal mostly consisted in the occurrence of et al., 2011; Hoyte et al., 2012).
psychiatric effects. It has to be stressed that Δ9-THC and
nabilone are partial agonists at the CB1 receptor and that
no such data are available for the structurally different Neurological and respiratory effects
synthetic cannabinoids that have been sold on the drug Neurological symptoms can vary widely in synthetic
market and that are typically full agonists. Therefore, an cannabinoid-poisoned patients and range from agitation

24
 Synthetic cannabinoids in Europe – a review

to various grades of central nervous system depressant analytically confirmed to contain JWH-018, JWH-081,
effects including ataxia, confusion, drowsiness, dizziness, JWH-250 and AM-2201 (Schneir and Baumbacher,
muscle weakness, numbness, slurred speech, paralysis, 2012). The analysis of a plasma sample showed JWH-
respiratory depression, lethargy and coma. methylcyclohexane-8quinolinol (BB-22), AM-2233, JWH-
018 quinolinecarboxylate analogue (PB-22), AM-2201
Respiratory depression requiring intubation was reported in carboxylate analogue quinolinyl derivative (5F-PB-22) and
a series of calls to poison information centres, and occurred JWH-122 in a patient admitted twice to hospital because
only in association with alcohol and/or benzodiazepines co- of seizures after smoking ‘K2’ (Schep et al., 2015). Tonic–
consumption (Forrester et al., 2011). In a survey, synthetic clonic seizures were also reported immediately after the
cannabinoid users reported non-serious symptoms such consumption of a ‘Bonzai’ herbal blend, with serum and
as a sensation of light-headedness, impairment of memory urine confirmation of JWH-122, JWH-210 and JWH-018
functions and troubles with ‘thinking clearly’ (Gunderson (Hermanns-Clausen et al., 2013b). Seizures and refractory
et al., 2014; Vandrey et al., 2012). Somnolence, confusion supraventricular tachycardia were seen in a patient
and retrograde amnesia were reported in three adolescents hospitalised after ingestion of JWH-018, analytically
whose blood serum samples tested positive for MAM- confirmed in urine by detection of its metabolites (Lapoint
2201 and UR-144; JWH-081 and JWH-073; and JWH-122 et al., 2011).
(Hermanns-Clausen et al., 2013b). Lethargy was observed
in several patients during an outbreak in New York, United Some of the features of poisoning associated with
States, where analysis of serum samples confirmed the synthetic cannabinoid consumption –particularly loss of
presence of the AMB-FUBINACA acid metabolite in 8 out of consciousness, respiratory depression and behavioural
18 patients in concentrations ranging from 77 to 636 ng/ effects – may place users at additional risks, such
ml (Adams et al., 2017). Confusion, psychomotor agitation as choking on / aspirating vomit, drowning, falling,
and psychosis were seen in five patients after smoking hypothermia as a result of falling unconscious outside in
herbal blends containing 5F-MDMB-PINACA (5F-ADB) and cold weather and self-inflicted violence/injury (Tait et al.,
5F-AMB-PICA (MMB-2201) (Barceló et al., 2017). 2016).

Alon and Saint-Fleur (2017) reported on a series of four

patients who presented to an intensive care unit with Cardiovascular effects
acute respiratory distress after alleged consumption Adverse cardiovascular effects associated with exposure
of synthetic cannabinoids (which was not analytically to synthetic cannabinoids include tachycardia as well
confirmed). All patients required endotracheal intubation as a range of dysrhythmias and electrocardiographic
in the absence of a concomitant pulmonary disease and (ECG) changes including bradycardia, although the latter
two had seizure activity. The respiratory distress resolved seems to be relatively rare (1.3 % of 464 cases (Forrester
in less than 24 hours and the patients presented agitated/ et al., 2001) and 1.5 % of 1 898 cases (Hoyte et al.,
aggressive behaviour. Subsequently, aspiration pneumonia 2021)). Hypertension, chest pain and, to a lesser extent,
occurred in three of the four cases. hypotension are also reported by users, as determined
from calls to poisoning centres (Forrester et al., 2011;
In a case series of six patients who reported the use Hoyte et al, 2012). Hypertension and tachycardia were
of synthetic cannabinoids, two patients presented to demonstrated in two cases of exposure to ‘Spice’ and
the emergency department with seizures, two with JWH-018 and JWH-073 were detected in the urine
tachycardia and two with hallucinations (Harris and (Simmons et al., 2011). Myocardial infarction was
Brown, 2013). Perceptual changes and anxiety were diagnosed based on electrocardiogram changes and
also described as ‘the main psychoactive findings’ in a elevated troponin levels in four adolescents seeking
series of 16 adolescents seeking medical attention after medical attention owing to chest pain, within 2 hours
synthetic cannabinoid use (Besli et al., 2015). Psychotic and 1 week after exposure to ‘Spice’ products. However,
episodes may occur particularly in patients with known exposure to cannabinoids was not confirmed analytically
psychiatric disorders, as shown by Every-Palmer (2011) (Mir et al., 2011; McKeever et al., 2015). In addition,
through semi-structured interviews with patients with a Young et al. (2012) reported the case of an individual
history of serious mental illness in a forensic facility. The who experienced chest pain 10 minutes after smoking a
data presented suggested that 9 of the 13 patients who herbal blend containing JWH-018 and JWH-073 and in
repeatedly smoked a product most likely containing JWH- whom tachycardia and bradycardia were later confirmed in
018 experienced symptoms consistent with psychotic hospital. Analytical confirmation of the presence in urine of
relapse caused by JWH-018. Convulsions were witnessed an adamantyl-type synthetic cannabinoid (not specified)
in an adolescent after smoking a herbal blend that was was achieved in one individual with chest pain and ST-

25
Synthetic cannabinoids in Europe – a review

elevation on ECG (McIlroy et al., 2016). Cardiac arrest or minor dermal manifestations, and reddening of the
in a 56-year-old man with multiple cardiovascular risk conjunctivae, both in self-administration studies and in
factors (past myocardial infarction, treated with four-vessel cases with analytically confirmed exposure to synthetic
bypass) and a history of increasing ‘K2’ consumption has cannabinoids (Auwärter et al., 2009; Hermanns-Clausen
also been reported (Ibrahim et al., 2014). Finally, cases et al., 2013b; Kersten and McLaughlin, 2015; Teske et al.,
of ischaemic stroke connected to synthetic cannabinoid 2010).
use deemed to be cardioembolic in nature and triggered
by cardiac arrhythmia have also been reported in the
literature (Tait et al., 2016). Death cases
Since their appearance on the NPS market, a number of
case reports and case series of deaths involving synthetic
Gastrointestinal effects cannabinoids have been published (Labay et al., 2016;
Gastrointestinal effects of synthetic cannabinoids include Kraemer et al., 2019). Clearly, the number of publications
nausea and vomiting, which according to a literature cannot reflect the full dimension of the issue, as not all
review, are symptoms seen in 13–94 % of presentations. cases involving synthetic cannabinoids are detected,
Furthermore, two cases of hyperemesis following alleged let alone published. Furthermore, since the detection of
synthetic cannabinoid use have been reported (Tait et synthetic cannabinoids requires a continuous update of
al., 2016). While food craving and increased appetite are analytical methods, it is also possible that new compounds
commonly experienced in association with cannabis, are not detected in post-mortem cases, depending on the
these were reported far less after smoking synthetic type of analysis performed. Additionally, the results from
cannabinoids (Winstock and Barratt, 2013). Very few investigations into death cases are difficult to compare,
patients complained about abdominal pain, anorexia/ owing to differences related to a number of factors,
weight loss or haematemesis (Forrester et al., 2011). such as the timing of post-mortem sampling, type of
toxicological analyses, cause of death, co-consumption
of other substances, and so on. Recently, a case series
Other effects involving 5F-Cumyl-PeGaClone also showed that even the
Rhabdomyolysis, accompanied by psychomotor agitation results of analysis of post-mortem blood using LC-MS/MS
and hyperthermia, has also been clinically assessed in methods fully validated for serum samples should not be
cases of alleged exposure to synthetic cannabinoids used uncritically, owing to the possibility of strong matrix
(Adedinsewo et al., 2016; Durand et al., 2015). effects. Whenever possible, the standard addition method
Rhabdomyolysis and an increase in creatinine kinase should be preferred for quantitation in post-mortem
serum levels can be associated with kidney damage. investigations (Giorgetti et al., 2020). The interpretation
of blood concentrations is, per se, difficult, and this
The Centers for Disease Control and Prevention reported finding further confirms that valid interpretation affords
5F-UR-144 (XLR-11) involvement in 7 of 16 patients a comprehensive analysis of all of the data available on
diagnosed with acute kidney injury (AKI) after presenting the case (Angerer et al., 2016; Kraemer et al., 2019). So
to the emergency department with nausea, vomiting far, it has not been possible to clearly correlate synthetic
and flank pain within days/hours after allegedly smoking cannabinoid levels in the blood with toxic effects. Thus,
synthetic cannabinoids. Renal biopsy confirmed acute it is not possible to delineate toxic or fatal concentration
tubular injury and acute interstitial nephritis in eight of ranges, as have been reported for many drugs and
these patients, five of whom required haemodialysis. None medicines, despite several intrinsic limitations (Kraemer et
of these patients died (CDC, 2013). Similarly, in another al., 2019).
study, AKI was diagnosed in nine patients presenting to the
emergency department with nausea and flank/abdominal Labay et al. (2016) reported 25 death cases involving
pain. One clinical and two product samples were positive synthetic cannabinoids and asked different evaluators to
for 5F-UR-144 (XLR-11) (Buser et al., 2014). AKI without assess the contributory role of the compounds involved
signs of rhabdomyolysis was seen in an agitated patient regarding the cause of death. This kind of evaluation
who was brought to the emergency department. He had demonstrates how challenging it can be to attribute an
allegedly consumed ‘synthetic weed’ in the previous 2 days interpretative weight to a substance, especially when, as
(Gudsoorkar and Perez, 2015). for synthetic cannabinoids, pharmacological knowledge
is limited. Indeed, in all but three cases, synthetic
Other adverse effects include anticholinergic symptoms, cannabinoids were deemed to have contributed to the
such as xerostomia, warm/dry skin, mydriasis, cause of death through two or more of the following
hyperglycaemia, hypokalaemia, hypothermia, pallor categories: ‘behavioural and physical’, ‘behavioural’,

26
 Synthetic cannabinoids in Europe – a review

‘contributed’, ‘sole poisoning’ and ‘contribution unknown’; was assumed because of the short interval between
in only a minority of cases was there unanimous consent. smoking and the onset of behavioural symptoms.
Behavioural toxicity was the category that was most likely
to lead to a fatal outcome, while cardiopulmonary diseases In a case reported by Rojek et al. (2017), the development
represented the most important contributing factors of behavioural symptoms is considered to have led
(Labay et al., 2016). Finally, the authors also stated that, as to death, as a fall from height was attributed to drug-
the knowledge of the effects is poor and the blood levels induced psychosis. The deceased had smoked a cigarette,
do not seem to correlate well with toxic effects, caution manifested hallucinations and jumped out of a second-
should be exercised whenever synthetic cannabinoids are floor window. Post-mortem blood analysis revealed UR-
involved in a death case (Labay et al., 2016). 144 (2.1 ng/ml) but no other drugs (Rojek et al., 2017). In
a similar case, in which an individual who had consumed
Synthetic cannabinoids have been involved in a number MDMB-CHMICA (the post-mortem blood level was 1.7 ng/
of mono- and mixed-drug poisonings. Polydrug use cases ml) died after falling from a height, blood analysis revealed
can involve alcohol and antidepressant/neuroleptic drugs, the presence of amphetamine (1 050 ng/ml), MDMA
such as quetiapine, amitriptyline, pregabalin, gabapentin, (275 ng/ml) and 3,4-methylenedioxyamphetamine (MDA)
cathinones, amphetamines, opioids and dissociative (22 ng/ml) (Gaunitz et al., 2018).
anaesthetics such as diphenidine (Kraemer et al., 2019).
In such cases, the interpretation of the contributory role of Poisonings involving synthetic cannabinoids may also lead
synthetic cannabinoids is further complicated, especially to death by inducing a state of reduced consciousness,
when other NPS are co-consumed. with subsequent aspiration of gastric content and
asphyxia. This was the case for a 34-year-old man who was
As clinically cardiovascular effects are among the most found unresponsive at his home, where three packages
commonly reported harms, cardiac toxicity with a fatal of herbal blends were retrieved. ADB-CHMINACA (MAB-
outcome can be expected. Indeed, cardiac arrhythmia CHMINACA) (6.05 ng/ml) was detected in post-mortem
and/or cardiac death are frequently reported as the blood of the deceased, whose airway was found at
cause/mechanism of death in cases involving synthetic autopsy to be occluded by a mass of material consistent
cannabinoids. For example, Paul et al. (2018) reported on with gastric content, suggesting that aspiration of gastric
two death cases of adolescents, involving AB-CHMINACA content was the cause of death (Hasegawa et al., 2015).
in one case and UR-144, 5F-UR-144 (XLR-11) and JWH-
022 in the other. The drug concentrations were relatively In many of the reported death cases, the precise
high (8.2 ng/ml for AB-CHMINACA and 12.3 ng/ml for mechanism of death and/or the likely contribution of
UR-144). In both cases, the cause of death was deemed synthetic cannabinoids was not specified owing to a lack
sudden death, probably due to cardiovascular toxicity, of circumstantial information or lack of knowledge of the
and in the first case a pre-existing cardiomyopathy specific drug potency/toxicity.
was considered to be a contributory factor (Paul et al.,
2018). An acute circulatory failure due to poisoning with
synthetic cannabinoids was reported in a 23-year-old male Occupational exposure
who died 3.5 hours after multiple drug intakes, having Occupational exposure to synthetic cannabinoids
experienced a cardiopulmonary arrest. In this case, the mainly involves seizures of synthetic cannabinoids by
presence of mepirapim (950 ng/ml), in combination with law enforcement personnel from illicit laboratories or
α-ethylaminopentiophenone (EAPP) (3 100 ng/ml), was shops, customs or postal seizures, and staff involved
detected in serum samples collected at the hospital (Fujita in processing the evidence. Given the large number
et al., 2016). A sudden cardiac death following the intake of seizures, it is surprising that very little is known so
of MDMB-CHMICA (1.4 ng/ml, as confirmed in a serum far regarding occupational exposures to synthetic
sample collected before death) occurred in a 22-year-old cannabinoids.
man, who was found asystolic 15 minutes after smoking a
herbal blend. He eventually died of hypoxic brain damage Recently, a study was undertaken focusing on nine law
(Westin et al., 2016). Shanks et al. (2016) reported a case enforcement agents following a raid on a laboratory
of a 41-year-old female who smoked a product known manufacturing illicit substances in the United States,
as ‘Mojo’, developed agitation and started to behave which aimed to evaluate the occupational health hazards
aggressively, and then suddenly became unresponsive and from synthetic cannabinoid exposure. Disposable
died. At the autopsy, the cause of death was ruled to be protective clothing was not used systematically and
a coronary artery thrombosis after synthetic cannabinoid the agents ate and drank during the handling of the
intake (ADB-FUBINACA, 7.3 ng/ml). A potential causality evidence. Urine samples from four agents tested positive

27
Synthetic cannabinoids in Europe – a review

for AB-PINACA and from six agents tested positive for with anxiety, panic attacks or agitation, treatment with
mitragynine, whereas pre-raid collected urine samples benzodiazepines can be of benefit. Aggressive and
were negative for both compounds (Tapp et al., 2017). agitated patients with a history of psychotic disorders
Under such working conditions, seven of the nine agents might be medicated with neuroleptic agents. Owing to the
reported symptoms such as a cough or eye/nasal/skin/ lack of an antidote, symptomatic and supportive treatment
throat irritation, four reported having felt ‘light-headed’ and is recommended. In the case of seizures, intravenous
‘high’, and three reported having experienced memory and benzodiazepines have been reported to be effective. In the
concentration impairment at least once during previous majority of cases, the effects of consumption of NPS seem
drug raids. to be self-limiting and can be treated symptomatically with
intravenous fluids, benzodiazepines, supplemental oxygen
Symptoms including dizziness, blurred vision, weakness, and antiemetics.
confusion and lethargy lasting for up to 2 days were
reported by three customs inspectors working at an airport The management of synthetic cannabinoid poisonings
whose hands accidentally came into contact with a liquid might be complicated by the fact that typical symptoms
(Dobaja et al., 2017). NMR analysis of the liquid revealed are unspecific and might be confused with symptoms
that it contained CUMYL-PINACA. The men presented arising from other types of medical conditions or
with mydriasis and tachycardia and blood samples tested poisonings (Tait et al., 2016). This overlap in clinical
positive for CUMYL-PINACA. The patients recovered 2 days features, however, has also led to the realisation that
after the transdermal poisoning and reported amnesia and patients presenting with somnolence and hypoventilation,
slowed perception of time after exposure (Dobaja et al., with confirmation of acute synthetic cannabinoid
2017). poisoning, might show a positive response to naloxone
infusion, similar to patients presenting with acute opioid
poisoning (Richards et al., 2017). In some cases, symptom
Managing poisoning improvement was reported after naloxone administration
to patients who had reported ‘Spice’ consumption and
Currently, there is no authorised antidote that can tested negative for opioids. However, these results are
reverse the effects of synthetic cannabinoids. It seems preliminary and should viewed with caution, especially
plausible that, for example, rimonabant would be effective, as it is not known if the improvement in symptoms would
but a formal protocol for the treatment of synthetic have occurred spontaneously, even without any form of
cannabinoids poisoning has not yet been established. pharmacotherapy (Jones et al., 2017).
The inhomogeneity of herbal blends, which sometimes
also contain other illicit or licit drugs, and the continual In clinical settings, diagnosis of synthetic cannabinoid
emergence of novel compounds in the market could poisonings should be approached with caution, and an
further limit the possibility of identifying a suitable in-depth study of the case is needed. Therapy remains
antidote for synthetic cannabinoids (Müller et al., 2016). supportive and symptom related (Castellanos and Gralnik,
Future studies should investigate if the application of CB1 2016). The clinical presentation alone may not be sufficient
receptor antagonists might be an option for the treatment to demonstrate synthetic cannabinoid intake, and multiple
of synthetic cannabinoid toxicity. Studies have been illnesses such as hypoglycaemia, infections, thyroid
conducted with selective CB1 antagonists, such as AM- hyperactivity, head trauma, other types of poisoning and
11503. This substance was shown to reverse hypothermia mental diseases can cause similar symptoms (Tait et al.,
induced by acutely administered JWH-018 (6 mg/kg) in 2016). Owing to similarities in the clinical presentation, the
mice, as well as to block tremors and convulsions caused treatment of acute poisoning partly overlaps with that of
by a ‘suprapharmacological’ dose of 18 mg/kg (Vemuri et withdrawal symptoms.
al., 2019).
The majority of poisoned patients present with relatively
Guidance on the management of acute and chronic mild symptoms and do not require hospitalisation (Tait
harms of new psychoactive substances is provided in the et al., 2016; Castellanos and Gralnik, 2016). According
Novel Psychoactive Treatment UK Network (NEPTUNE) to a study of synthetic cannabinoid exposures reported
guidelines (Abdulrahim and Bowden-Jones, 2015). Part V to the poison center, symptoms resolved within 8 hours
of the guidelines is dedicated to synthetic cannabinoids in 78.4 % of the cases and within 24 hours in 16.6 % of
and suggests some measures for the clinical management the cases (Hoyte et al., 2012). In another survey, among
of acute synthetic cannabinoid toxicity. Case reports users of cannabis and synthetic cannabinoids who had
suggest that hydration and monitoring may be sufficient sought medical attention (n = 21), there was no difference
for patients with mild to moderate poisoning. In patients between groups in the number of users who reported

28
 Synthetic cannabinoids in Europe – a review

having been admitted to hospital or in time to recovery. (25–475 g for, on average, 8 days) to counteract
The majority recovered within 24 hours; however, 28.6 % withdrawal symptoms, patients described antipsychotics
of synthetic cannabinoid-poisoned patients took 2 weeks as more effective than benzodiazepines (Macfarlane and
to recover (Winstock et al., 2015). Indeed, the setting in Christie, 2015). Similar results were reported by Nacca
which poisoning is managed (i.e. in an outpatient clinic et al. (2013): relief of withdrawal symptoms in a patient
or in hospital) strongly depends on the severity of the who was unresponsive to benzodiazepines, hydroxyzine
symptoms (Castellanos and Gralnik, 2016). In a study and diphenhydramine was achieved by quetiapine
performed by Hermanns-Clausen et al. (2013a), severe administration.
symptoms, assessed by the Poisoning Severity Score, were
seen in only 1 case out of 29. Phenobarbital, for the treatment of anxiety and
prophylaxis of seizures, was used in a detoxification
Monitoring is a fundamental part of the clinical case in combination with naltrexone to control drug
management of synthetic cannabinoid poisonings, and cravings (Rodgman et al., 2014).
should be carried out in a quiet environment, focusing on
cardiovascular function, as poisoning commonly results Antiemetics can be administered in the presence of
in cardiovascular symptoms (often tachyarrhythmia). nausea or hyperemesis syndrome, although such
Accurate monitoring of neurological functions is also compounds have not always proven beneficial (Hermanns-
useful, given that poisoning is likely to result in central Clausen et al., 2013a), as in the case reported by Ukaigwe
nervous system depression to some degree and the risk et al. (2014), in which the use of ondansetron was
of respiratory depression, which may eventually require not an effective approach. The role of gastrointestinal
protection of the airways (Müller et al., 2016). ECG decontamination, in the context of synthetic cannabinoids
monitoring, pulse oximetry and a wide range of clinical and poisoning, is limited by two factors: the preferential
laboratory tests, depending on the particular case, are also parenteral intake through smoking and the limited toxicity,
suggested, including screening for other drugs of abuse which is self-resolving in most cases. In the series reported
and medications that might have been co-ingested (Müller by Forrester et al. (2011), less than 5 % of patients were
et al., 2016). treated with some kind of decontamination (e.g. activated
charcoal, lavage or irrigation/dilution).
As shown in some retrospective case series, supportive
care, with intravenous fluid administration and eventually Finally, intravenous lipid emulsion was administered in
potassium supplementation, is the preferred method of four users rushed to the emergency department after
treatment (Forrester et al., 2011; Hermanns-Clausen et reported use of synthetic cannabinoids (Aksel et al. 2015).
al., 2013a; Hoyte et al., 2012) and is generally sufficient Cardiovascular recovery, with normal blood pressure and
in patients presenting with mild to moderate symptoms pulse rate, as well as neurological recovery (testified by an
(Castellanos and Gralnik, 2016). Supportive care could be improvement in Glasgow Coma Scale score), was seen in
particularly helpful in the case of vomiting and dehydration three out of the four patients, but treatment was ineffective
or for the recovery of renal function (Müller et al., 2016). in the one individual in whom co-consumption of heroin
Furthermore, fluids were sufficient to treat hypotension was considered likely. Intravenous administration of lipid
and bradycardia in the cases presented by Forrester et emulsion is useful in the setting of highly lipophilic drugs,
al. (2011). Intravenous fluids, airways protection, cardiac and intoxicated unstable patients may benefit from it,
monitoring and the prevention of rhabdomyolysis were according to a case series published by Aksel et al. (2015).
described as the primary goals in cases of synthetic However, it has to be kept in mind that there is no high-
cannabinoids poisoning by Tait et al. (2016). level evidence to support the use of this therapy in the
context of synthetic cannabinoids poisoning.
Further therapies are influenced by the specific symptoms
manifested by patients. In particular, benzodiazepines
represent a first-line treatment for patients who present I Chronic toxicity
with agitation, anxiety, acute psychosis and seizures
(Cooper, 2016), coupled with neuropsychiatric supportive The effects of chronic exposure to synthetic cannabinoids
assessment (Müller et al., 2016). Antipsychotics such as are largely unknown. No study has clearly documented the
haloperidol and quetiapine can also be applied in cases effects in humans of long-term consumption of synthetic
of acute panic, hallucinations (Hermanns-Clausen et al., cannabinoids, which – unlike cannabis – are not used as
2013a), delusion and psychosis (Müller et al., 2016). In prescription medicines (with the exception of nabilone)
one detoxification centre that administered diazepam (EMCDDA, 2018a). However, as already mentioned, some
(5–25 mg orally for, on average, 4 days) and quetiapine studies on animals or cell models and case reports on

29
Synthetic cannabinoids in Europe – a review

humans suggest that synthetic cannabinoids can cause led to deficiency in object recognition memory and in
certain forms of chronic toxicity. sensorimotor gating, which is a model to study sensory
overstimulation. Cognitive fragmentation, attention
Koller et al. (2013) demonstrated that JWH-018, JWH- impairments and anhedonia were also assessed in the
073, JWH-122, JWH-210 and AM-694 did not show same animal study. These functions are all involved in
cytotoxic or genotoxic effects in various human cell lines the development of schizophrenia; thus, their disruption
at concentrations reached in the body of consumers. CP- in cases of adolescent chronic cannabinoid exposure
47,497-C8 was shown to have weak cytotoxic properties, indicates that synthetic cannabinoids could be implicated
but is known to cause chromosomal damage (Koller et al., in the development of signs of mental disease (Schneider
2014). Bileck et al. (2016) found that CP-47,497-C8 has and Koch, 2003). Chronic administration of WIN-55,212-
pro-inflammatory effects and can induce DNA damage. 2 (1.2 mg/kg for 25 days) induced cellular long-term
In another study, Koller el al. (2015) investigated the modifications in areas of the brain involved in the
genotoxic properties of AM-2201, UR-144, 5F-AKB48 and development of substance abuse and behavioural effects,
AM-2201-IC at elevated concentrations and demonstrated which included the disruption of sensorimotor gating,
chromosomal damage, but no gene mutations. Tomiyama increased motor activity and reduced anxious behaviour
and Funada (2014) showed potential neurotoxic effects (Wegener and Koch, 2009). As many of these effects were
of eight synthetic cannabinoids (CP-55,940, CP-47,497, proven in adolescent animals and not in adults, the chronic
CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201 effects of synthetic cannabinoids seem to be dependent
and MAM-2201) in a mouse brain cell line. Ferk et al. on the age at exposure and on the dose administered
(2016) found that 5F-UR-144 (XLR-11) and RCS-4 (Castaneto et al., 2014).
induced micronuclei, which are formed as a consequence
of chromosomal aberrations. Chronic use of synthetic
cannabinoids has been associated with a greater risk of Human data
developing a mental health disorder than use of cannabis
(Cohen and Weinstein, 2018; Skryabin and Vinnikova, While there are no data on the long-term safety of
2018), which may include dependence. Acute and chronic synthetic cannabinoids, long-term effects may partially
use of synthetic cannabinoids has also been associated be inferred from what happens following the prolonged
with detrimental effects on cardiovascular health (Ozturk consumption of cannabis, which is associated with an
et al., 2019; Pacher et al., 2018). increased risk of psychosis and hallucinations (McGrath et
al., 2010). Signs of psychosis with perceptual alterations
and hallucinations were experienced by 10 otherwise
Animal data healthy young men who reported having consumed
synthetic cannabinoids on several occasions (from four
The cognitive effects of the long-term administration of times over 3 weeks up to daily use over 1.5 years), and
CP-55,940 were studied in adolescent and adult mice, symptoms persisted for up to more than 5 months (Hurst
which were challenged with increasing doses of 0.15, 0.20 et al., 2011).
and 0.30 mg/kg, each administered for 7 consecutive
days. Animals were tested in tasks of object recognition Heavy and prolonged cannabis consumption can also be
(i.e. discrimination of a novel object from a familiar one) associated with changes in brain volume, especially the
and object location (i.e. the ability to identify an object hippocampus, which plays a major role in memory, and
moved to a new place). While no significant effects were the amygdala, a region known to be crucial for emotional
seen in adult mice, the chronic exposure to CP-55,940 in processing. Similar effects might be expected from
adolescence led to impairments in the cognitive processes synthetic cannabinoids, although no data on humans are
investigated, involving spatial and short-term memory available so far (Seely et al., 2012).
(Renard et al., 2013). A lasting impairment of memory,
together with the development of anxiety (as assessed Recently, Cohen et al. (2017) compared executive function
through social interaction tests) resulting in a decrease in in non-users, recreational cannabis users and synthetic
social interaction, was seen in adolescent, but not adult, cannabinoid users (38 individuals who had consumed
rats exposed to incremental doses of CP-55,940 (0.15, synthetic cannabinoids at least 10 times in the last year
0.20 and 0.30 mg/kg for 3, 8 and 10 days) (O’Shea et al., without binge consumption). Computerised cognitive
2004). The effects of repeated administration of WIN- function tests, the classical Stroop word–colour task, the
55,212-2 have also been studied in a number of animal n-back task and a free-recall memory task were used. In
models. Pubertal treatment with the synthetic cannabinoid the synthetic cannabinoids group, impairment of cognitive
at a dose of 1.2 mg/kg in a chronic administration setting function, and particularly of working memory, long-term

30
 Synthetic cannabinoids in Europe – a review

memory and inhibitory control, abilities was demonstrated Chronic treatment with CP-55,940 (0.4 mg/kg
to be greater among synthetic cannabinoid users than intraperitoneally twice a day for 6.5 days) produced
among cannabis users (Cohen et al., 2017). tolerance to synthetic cannabinoid-mediated analgesic
effects in rats and downregulation of CB receptors in
several parts of the brain; in addition, in the case of
I Psychological and behavioural effects CB1 receptor antagonist administration, an abstinence
syndrome was precipitated (Rubino et al., 2000).
The typical effects of synthetic cannabinoids are similar
to the known effects of cannabis and include relaxation, As for physical dependence induced by synthetic
mild euphoria, lethargy, sedation, confusion, anxiety, fear, cannabinoids, a withdrawal syndrome could be
amnesia, derealisation, depersonalisation, psychotropic precipitated after 4 days’ treatment with WIN-55,212-2
effects (changed perception), cognitive dysfunction, at any dose (1–16 mg/kg/day) by the administration of a
impaired motor performance and ataxia (Theunissen CB1 receptor antagonist (with symptoms occurring within
et al., 2021). However, users of synthetic cannabinoids 1 hour). Furthermore, spontaneous withdrawal symptoms
often exhibit agitation, rather than sedation, particularly were seen 24 hours after stopping the administration
after consumption of higher doses. Severely intoxicated of medium doses (2–16 mg/kg/day) without the
patients may also present with hallucinations, panic administration of an antagonist. In contrast, following 4
attacks and psychosis. These dose-dependent effects days’ treatment with Δ9-THC, only precipitated (but no
appear to be much more pronounced and severe than spontaneous) withdrawal effects were demonstrated
those of cannabis (Ford et al., 2017; Zaurova et al., 2016). (Aceto et al., 2001), suggesting that full agonist synthetic
Specifically, psychotic episodes, confusion, paranoia, and cannabinoids having greater potential to produce
aggressive and violent behaviour have been reported for dependence than cannabis.
a number of synthetic cannabinoids, including 5F-MDMB-
PINACA (EMCDDA, 2018b; WHO, 2017).
Human data

I Dependence and abuse potential The limited data available on synthetic cannabinoids
suggest that the consumption of synthetic cannabinoids
can produce tolerance and withdrawal-like symptoms
Animal in vivo and in vitro data when regular use is discontinued. These include anxiety,
unstable mood, crying fits, feelings of inner emptiness,
The limited data available on synthetic cannabinoids spatial disorientation, hyperacusis (i.e. an increased
suggest a high potential for abuse and the potential sensitivity to ordinary environmental sounds), somatic
for tolerance, dependence and withdrawal symptoms pain, shortness of breath, hyperventilation, intense
after chronic or long-term consumption. In general, sweating and sensations of motor and inner restlessness.
drug discrimination studies, preference test studies and Regular use of synthetic cannabinoids can lead to
particularly the assessment of tolerance and reinforcement dependence, as seen in a case report of a patient who
would be suitable tools to evaluate the dependence and reported continued and escalating consumption of ‘Spice
abuse potential of synthetic cannabinoids. Gold’ for 8 months. Owing to the tolerance developed, the
patient progressively increased the dose, finally reaching
Chronic administration of WIN-55,212-2 (1.2 mg/kg for 3 g/day. Despite cognitive impairment and negative effects
25 days) induced cellular long-term modifications in areas on his professional life, he continued to use the substance
of the brain involved in the development of substance (Zimmermann et al., 2009).
abuse and behavioural effects, which included the
disruption of sensorimotor gating, increased motor activity In a survey of synthetic cannabinoid users, some
and reduced anxious behaviour (Wegener and Koch, 2009). participants reported the use of ‘Spice’ in hazardous
situations, inability to stop consumption despite
Sim-Selley and Martin (2002) found that administration interference with daily life and use for a longer period than
of escalating doses of WIN-55,212-2 for 15 days in mice intended (Vandrey et al., 2012). Difficulty in stopping use,
led to tolerance to acute injection of cannabinoids, as together with the development of withdrawal symptoms,
demonstrated by behavioural effects such as hypoactivity, was reported by 41 of 47 patients with problematic
nociception and hypothermia. Moreover, autoradiographic daily synthetic cannabinoids use who presented to a
studies showed that [35S]GTPγS binding in all brain detoxification centre (Macfarlane and Christie, 2015). The
regions was decreased after chronic treatment. most commonly reported symptoms included agitation/

31
Synthetic cannabinoids in Europe – a review

irritability (83–89 %), anxiety (55%), and mood swings cannabis. Such risks include negative impacts on social
(55 %). Nausea and vomiting (44 %) and loss of appetite functioning and criminal activities, such as the involvement
(17 %) were also frequently reported (Macfarlane and of organised crime in the manufacture, trafficking and
Christie, 2015). Neurological examination and ECG in distribution of the substance. Social risks connected
two patients who reported smoking 3 g of herbal smoking to the long-term use of cannabis include, but are not
mixture daily for more than 1 year revealed severe anxiety restricted to, (reversibly) impaired cognitive functioning,
and sinus tachycardia as withdrawal symptoms (Nacca amotivational syndrome and dependence.
et al., 2013). Nervousness, irritability, insomnia and
impatience were also reported by 11–15 % of synthetic Of particular note is that synthetic cannabinoids are
cannabinoid users experiencing withdrawal syndrome increasingly used by vulnerable groups, such as people in
(Vandrey et al., 2012). prison and people experiencing homelessness. Reports
suggest that this has caused new health and social
problems and has exacerbated existing problems among
I Effects on ability to drive and operate machines these groups. For example, in prisons, alongside the
adverse health effects of these substances, such as acute
Owing to the psychological and behavioural impairment poisonings, the market in synthetic cannabinoids has
they induce, synthetic cannabinoids can negatively affect been linked to an increase in bullying and debt, as well as
ability to drive and safely operate machines (Capron, aggression and violence. In some cases, this has caused
2016; Griffiths and Griffin, 2016; Kaneko, 2017; Karinen a serious threat to the overall safety and security of the
et al., 2015; Musshoff et al., 2014; Peterson and Couper, prison environment (Blackman and Bradley, 2017; HMIP,
2015). Driving while under the influence of synthetic 2015; Ralphs et al., 2017; User Voice, 2016).
cannabinoids places users and others at risk of injury.
In addition, the detection of synthetic cannabinoids in
In a case series of 36 drivers suspected of driving under cases of suspected driving under the influence of drugs
the influence of drugs in Washington, United States, where indicates a potential for a wider risk to public safety.
5F-MDMB-PINACA was the predominant psychoactive
substance identified, 50 % of drivers were found
unconscious and 28 % had been involved in collisions with
one or more cars (Capron, 2016).

Peterson and Couper (2015) reported 33 cases of

I Extent and patterns of use, availability
and potential for diffusion
suspected driving under the influence of drugs in which
AB-CHMINACA was detected in blood samples. In 23
of these samples, no further drugs were detected. Drug I Prevalence of use
recognition expert exams were performed in 10 of the 33
cases. The most common finding was extreme lane travel Data on the prevalence of use of synthetic cannabinoids
with near collisions and, in nine cases, the driver was are based on population and subpopulation surveys.
found unconscious or slumped over the wheel. Horizontal In population-based studies, the prevalence of current
gaze nystagmus was detected in 50 % and a lack of synthetic cannabinoid use is generally found to be less
convergence was observed in 30 % of the drug recognition than 1 %. The most recent national surveys found that last
expert cases (Peterson and Couper, 2015). year use of synthetic cannabinoids among 15- to 34-year-
olds ranged from 0.3 % in Spain and Lithuania to 0.6 % in
Similarly, the operation of machinery while under the Italy (EMCDDA, 2020d). In the case lifetime prevalence,
influence of synthetic cannabinoids may place the people the numbers can be higher and, in a population of German
who use these substances, and others, at risk of injury. pupils aged 15–18 years in the area of Frankfurt/Main,
reached 5–7 % when considering use over previous years,
although the prevalence of use in the last month was
I Social risks much lower (about 1 %) (Werse et al., 2014). In the most
recent European School Survey Project on Alcohol and
While studies on the social risks of synthetic cannabinoids Other Drugs (ESPAD) ,in 2019, 3.1 % of students (average
are rare, the available data from acute poisonings and calculated across 20 out of 35 countries) reported having
self-reported user experiences suggest that the acute used synthetic cannabinoids at least once in their lifetime,
behavioural effects of synthetic cannabinoids and the ranging from 1.1 % in Slovakia to 5.2 % in France (ESPAD
associated social risks might be similar to those of Group, 2020).

32
 Synthetic cannabinoids in Europe – a review

In the United States, prevalence was found to be psychiatric patients, and in particular psychotic patients,
particularly high in high school students during 2011, when than in other populations. Welter et al. (2017) found
these substances first emerged in the country, although that 7.2 % of psychiatric patients in Germany enrolled
the available data suggest a steady decline since then. in a prospective pilot study (n = 332) reported synthetic
Palamar et al. (2017) found the prevalence of use among cannabinoids consumption, with psychotic patients
a group of high school seniors in the United States to showing a higher prevalence than non-psychotic patients
be 2.9 % (past 30-day use) for the period 2014–2015 (10 % versus 4.5 %, respectively).
(n = 7 805). In that study, synthetic cannabinoid users
were more likely to report the use of other (non-cannabis) Although limited, there is some information to suggest a
drugs (Palamar et al., 2017). In a sample of 54 865 high recent increase in the vaping of synthetic cannabinoids
school students (aged 13–19 years), the prevalence of using electronic cigarettes by young people, including
past-year synthetic cannabinoid use was found to decrease teenagers, in some parts of Europe; in some cases,
across the study period. For example, past-year use among the users believed that they were using CBD or THC
12th grade students decreased from 11.86 % in 2011 to (EMCDDA, 2020c).
4.75 % in 2015 (Keyes et al., 2016). In another study, the
prevalence of synthetic cannabinoid use among attendees
of electronic dance music parties in New York City in 2015 I Patterns of use
(n = 682) was reported to be 16.3 % (Palamar et al., 2016).

Route of administration
Characteristics of user groups
The most common way of using synthetic cannabinoids
Synthetic cannabinoids may be sold and used as a is by smoking either ready-to-use or homemade ‘smoking
‘legal’ replacement for cannabis (EMCDDA, 2009, 2017). mixtures’ as a cigarette (‘joint’) or by using a vaporiser,
Because products containing synthetic cannabinoids ‘bong’ or pipe. Some synthetic cannabinoids have
rarely state the ingredients, some users will not know that also been offered in the form of e-liquids for vaping in
they are using synthetic cannabinoids, and most who e-cigarettes. In addition, users might also prepare e-liquids
do know will be unaware of what substances they are containing synthetic cannabinoids at home. In prison
consuming. Some users specifically seek out synthetic settings, papers impregnated with synthetic cannabinoids
cannabinoids because these have a reputation for causing are then smoked with tobacco or vaped using an electronic
profound intoxication and they can be comparatively cigarette. Other routes of administration, such as oral
cheaper than other drugs. administration or by injection, appear to be rare.

It is known that synthetic cannabinoid users tend to also

use cannabis (Gunderson et al., 2014), and that polydrug Dosage
use is also common among this group (Joseph et al., 2019).
Doses of synthetic cannabinoids that produce
Several subpopulations of cannabis users show a relatively psychoactive effects vary with the potency of the
high prevalence of synthetic cannabinoids use, among substance. Many highly potent substances, such as
them marginalised people (e.g. people experiencing MDMB-CHMICA, can cause psychoactive effects at doses
homelessness, prisoners and injecting drug users) less than 1 mg. Typical doses of less potent compounds,
(Campbell and Poole, 2020; Gray et al., 2021). People such as JWH-018, have been reported to be 2–5 mg
who undergo regular drug testing (such as people in drug (WHO, 2014). The dosage regimens used for synthetic
treatment, prisoners and drivers) may seek out synthetic cannabinoids can differ within and between individuals
cannabinoids because some drug tests/screens will be depending on the tolerance of the user, the concomitant
unable to detect some cannabinoids (especially those use of other drugs and the desired effects. The purity,
that are relatively new to the drug market). People who amount and/or composition of the substance ingested
use synthetic cannabinoids may also include recreational are not typically known by the user. In addition, the actual
users (including cannabis users) and groups who composition of the substance may differ over time and
experiment with substances (sometimes referred to as place.
‘psychonauts’).
Products containing synthetic cannabinoids rarely state
There is some evidence that, in some countries, the the correct ingredients and/or their concentrations.
prevalence of synthetic cannabinoids use is higher among Consequently, people who use such products will be

33
Synthetic cannabinoids in Europe – a review

unaware that they are using this substance and will be networks or from friends. The supply of bulk quantities of
unable to obtain accurate dosage information. synthetic cannabinoids (pure substances) that are used
to make products such as smoking mixtures and e-liquids
In addition, in the case of herbal smoking mixtures, the largely appears to be from companies based in China.
process for mixing the synthetic cannabinoids with the
plant material can lead to heterogeneity of composition
and dangerous amounts of the substances in the Production
products. This is because producers have to determine
what quantity of substances should be added, while the The production of the pure substances and the
mixing process makes it difficult to dilute them sufficiently manufacture of (ready-to-use) products containing
and distribute them consistently throughout the plant synthetic cannabinoids such as herbal mixtures and
material. This can result both in products that contain e-liquids have to be differentiated.
toxic amounts of the substances in general (Ernst et al.,
2017; Frinculescu et al., 2017; Langer et al., 2014: Langer In general, most of the synthetic cannabinoids that emerge
et al., 2016) and in products in which the solid particles on the European drug market are patented substances
of synthetic cannabinoids are clumped together, forming originally synthesised for medical research. The majority
highly concentrated areas (‘hot’ pockets) within the plant of bulk powders of synthetic cannabinoids appear to be
material (Frinculescu et al., 2017; Moosmann et al., 2015; produced in laboratories based in China. From here, the
Schäper, 2016). In fact, in the latter case, simply tapping synthetic cannabinoids are shipped to distributors, who
a packet containing a smoking mixture can dislodge the process the powders into products, as well as to online
substances from the plant material. Paper (e.g. blotters retailers and, to a lesser extent, consumers in Europe and
and cards) impregnated with synthetic cannabinoids can elsewhere (EMCDDA and Europol, 2019).
pose a similar high risk of poisoning because the method
of soaking and drying the paper, for example, can result
in the synthetic cannabinoid being unevenly distributed Trafficking
in different parts of the paper, sometimes forming highly
concentrated sections on the paper (Norman et al., 2020). The available information suggests that synthetic
These issues are made worse because the products are cannabinoids are typically ordered from chemical
smoked or vaped, allowing the substances to be rapidly companies based in China, which ship the substances,
absorbed into the bloodstream and to reach the central typically as powders, by mail and courier services to
nervous system and other parts of the body to cause their distributors and retailers in Europe. Similar to other
effects. Accounts from patients and people who witness NPS, in some cases consignments containing synthetic
poisonings suggest that, in some cases, a small number of cannabinoids are misdeclared or concealed (EMCDDA and
puffs from a cigarette (‘joint’) have been sufficient to cause Europol, 2019).
severe or even fatal poisoning.
Distribution among users, so called ‘social supply’, also
Together, these factors, coupled with the typically high seems to play an important role, in particular for polydrug
potency of synthetic cannabinoids, make it difficult for users (Gunderson et al., 2014; Higgins et al., 2019; Werse
users to control the dose that they are exposed to. This can et al., 2019).
lead to the unintentional administration of a toxic dose.

Internet markets

I Availability, supply and involvement of organised

crime The drug market has changed significantly over the last
decade. While illicit drug markets have in the past been
The overall availability of synthetic cannabinoids on the located on physical locations, the internet as a drug market
market remains high, despite legal steps taken in many has become increasingly popular. At least initially, the
European countries and elsewhere. During the first years majority of synthetic cannabinoids were offered as herbal
of the phenomenon, open sale in bricks-and-mortar head blends, e-liquids or research chemicals via internet shops
shops was permitted in some countries, but as result of on the surface web. However, synthetic cannabinoids
the implementation of legal restrictions this practice has and products containing synthetic cannabinoids have
been stopped, or severely restricted, in many countries. also become available on the darknet. The shops on the
Herbal smoking mixtures can be obtained from online surface web offer a range of delivery and payment options.
retailers but may be also be acquired through dealer Payment options include debit and credit cards, bank

34
 Synthetic cannabinoids in Europe – a review

transfer and e-commerce payment systems. More recently, PINACA and MDMB-CHMICA. In CUMYL-5F-PINACA, 12
payment by cryptocurrency, such as bitcoin, has also been synthesis-related impurities were detected during the
accepted. Delivery is usually by express mail and courier study. Several of these impurities could lead back to an
services, as well as postal services. incomplete reaction and therefore to intermediate reaction
products (e.g. the molecules without the fluorpentyl
Darknet markets have many similarities to marketplaces side chain or without the linked group). Cumylamine
such as eBay and Amazon. As on the surface web, dimers and fluoropentyl indole carboxamide dimers
customers are able to compare and rate the various were also detected as common impurities. Additionally,
vendors and their products. However, in contrast to the compounds with the fluoropentyl chain in an undesired
surface web, buyers can act anonymously in the darknet. position could be identified during the study. In another
Both information about payment and the location of the study by the same authors (Münster-Müller et al., 2019),
servers that are involved in a transaction are concealed. impurities from the synthesis of MDMB-CHMICA were
Therefore, sellers’ and buyers’ privacy is better protected investigated. In this case, 15 synthesis-related impurities
on the darknet. It is estimated that about two thirds of could be identified. Similar to the previous case, most
the offers on darknet markets are drug related, with the impurities were undesired intermediate products or
remainder related to a range of other illicit goods and compounds with some moieties found in another part of
services (EMCDDA and Europol, 2017). Darknet markets the target molecule. Interestingly, 5F-MDMB-PICA could
are most often global and operate in English, although be detected as an impurity during this study, although
some cater for a particular country or language group. it technically constitutes a contaminant. Oberenko et al.
(2019) detected three types of synthesis-related impurities
While attention is often focused on the use of the darknet in a study that was conducted in the Siberian region of
for drug trafficking, the use of mainstream applications Russia: unreacted main reagents for synthesis, purification
may be equally important, and such applications are reagents (used at the final stage of individual synthetic
more readily accessible. Following the development of cannabinoid synthesis) and supplementary reagents (e.g.
social platforms such as Facebook, YouTube and Twitter, pH regulators).
and their widespread use among young people, these
platforms are being increasingly used by drug suppliers
and dealers (EMCDDA and Europol, 2019). Contaminants and adulterants
In March 2018, the United States Centers for Disease
At present, online markets are believed to account for Control and Prevention reported an outbreak of
a small proportion of the trade in illicit drugs, and many life-threatening coagulopathy associated with the
of the transactions are at the consumer level. However, consumption of synthetic cannabinoids. Toxicological
the potential exists for further expansion of online drug testing indicated that the affected individuals had been
trading. exposed to brodifacoum, a long-acting anticoagulant
rodenticide. Overall, there were at least 324 cases of
severe poisoning including eight deaths in 10 states
Quality of the products on the market (CDC, 2018). It was speculated that synthetic cannabinoid
products were laced with brodifacoum to extend the ‘high’
after smoking, although there are no data supporting this
Typical impurities assumption.
Impurities are defined as compounds that were
intentionally added as reactants to a synthesis but were On occasion, opioids (e.g. U-47,700 and furanylfentanyl)
not completely turned into products of the reaction. have also been identified in smoking mixtures / plant
Intermediate products of the synthesis could also be material. Users will be unaware of this, and the use of
impurities. such opioid-containing products could pose a risk of
life-threatening respiratory depression. This risk will be
Münster-Müller et al. (2020) investigated synthesis-related especially high in individuals with no tolerance to opioids
impurities in the synthetic cannabinoids CUMYL-5F- (Coopman and Cordonnier, 2017).

35
Synthetic cannabinoids in Europe – a review

I Conclusions recently introduced to the market highly potent, but there

are increasing reports of these substances being mis-sold
Synthetic cannabinoids are the largest group of new or used to adulterate illicit drugs. For example, with the
psychoactive substances monitored by the EMCDDA increased popularity of CBD and THC products, synthetic
through the EU Early Warning System, with 209 reported cannabinoids have been identified in e-liquids sold as
between 2008 and 2020. When synthetic cannabinoids CBD and THC in Europe. Another concerning development
first appeared on the market in Europe, around 2006, is the adulteration of low-THC cannabis products with
they were sold as legal replacements for cannabis. While synthetic cannabinoids. Overall, such adulterated products
this continues to be the case, they have also gained a pose a high risk of poisoning to users.
reputation for having powerful intoxicating effects and, as
a result, some users use them specifically for this reason. In the future, it can be expected that compounds with a
Although synthetic cannabinoids are used recreationally, high potency and that are easy to synthesise will continue
in some places they are also used by people experiencing to be introduced into the market. In addition, there might
homelessness, prisoners and other vulnerable groups be a continuation of current efforts by manufacturers
because of the profound intoxication they can cause while to circumvent the (chemical) definition of generic
being comparatively cheaper than other drugs. They also approaches, as has been seen for other NPS.
continue to be used by those who are subjected to drug-
testing procedures, including those in prison or undergoing The ongoing COVID‑19 pandemic and the related response
drug treatment, as some tests cannot detect synthetic measures may affect, in unpredictable ways, existing
cannabinoids that have recently appeared on the drug markets in synthetic cannabinoids, their use and their
market. patterns of use. It is possible that, in the event of reduced
availability of cannabis in Europe, criminal groups, as well
In Europe, since 2015, there has been a decrease in the as people who use drugs, may use a range of replacement
number of synthetic cannabinoids identified for the first substances, including synthetic cannabinoids.
time each year and an overall decrease in seizures of the
substances by law enforcement agencies. In part, these Given the growing complexity of the NPS market and its
changes appear to be related to a disruption in the ‘legal strong links with the broader illicit drug market, there is
high’ trade, which for a period saw synthetic cannabinoids a need to ensure that Europe continues to strengthen its
being sold openly as ‘legal’ replacements to cannabis ability to detect, assess and respond to existing and new
on the high street and on the internet in many countries threats in a timely and effective way to prevent or reduce
in Europe. More generally, broader policy responses the public health and social harms caused by synthetic
designed to restrict the availability of new psychoactive cannabinoids, whether this is through detecting and
substances are also likely to have had an effect. This responding to a specific, immediate threat or via longer
positive development, however, has taken place in the term inputs into drug policy. The EU Early Warning System,
context of increasing concerns associated with the use operated by the EMCDDA and Europol, plays a central
of these substances. As noted, in some areas there has role in supporting national- and EU-level preparedness
been an increase in use by vulnerable groups, such as and responses to new psychoactive substances, including
prisoners and people experiencing homelessness. In synthetic cannabinoids.
addition, not only are some of the synthetic cannabinoids

36
 Synthetic cannabinoids in Europe – a review

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Pharmacology, Vol. 152, No 5, pp. 717–724 (https://doi.
www.uservoice.org/consultations/spice-use-in-prison).
org/10.1038/sj.bjp.0707410).
I Vandrey, R., Dunn, K. E., Fry, J. A. and Girling, E. R. (2012), ‘A
I WHO (World Health Organization) (2014), ‘Critical review
survey study to characterize use of Spice products (synthetic
report – JWH-018’, Expert Committee on Drug Dependence
cannabinoids)’, Drug and Alcohol Dependence, Vol. 120, No 1–3,
Thirty-sixth Meeting, Geneva, 16–20 June (https://www.who.int/
pp. 238–241 (https://doi.org/10.1016/j.
medicines/areas/quality_safety/4_5_review.pdf).
drugalcdep.2011.07.011).
I WHO (2017), ‘Review report – 5F-ADB’, Expert Committee on
I Vemuri, K., Raghav, J. and Makriyannis, A. (2019), ‘Antidotes for
Drug Dependence Thirty-ninth Meeting, Geneva, 6–10 November
acute cannabinoid intoxication’, The FASEB Journal, Vol. 33,
(https://www.who.int/medicines/access/controlledsubstances/
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Critical_Review_5F-ADB.pdf).
supplement.804.2).
I WHO (2020a), ‘Critical review report – MDMB-4en-PINACA’,
I Vučković, S., Srebro, D., Vujović, K. S., Vučetić, Č. and Prostran, M.
Expert Committee on Drug Dependence Forty-third Meeting,
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Geneva, 12–20 October (https://www.who.int/docs/default-
molecules’, Frontiers in Pharmacology, Vol. 9, p. 1259 (https://
source/controlled-substances/43rd-ecdd/mdmb-4en-pinaca-
doi.org/10.3389/fphar.2018.01259).
review-2020.pdf?sfvrsn=5cd6e97e_6).

49
Synthetic cannabinoids in Europe – a review

I WHO (2020b), ‘Critical review report – CUMYL-PEGACLONE’, incubation and high-resolution mass spectrometry’, Analytical
Expert Committee on Drug Dependence Forty-third Meeting, and Bioanalytical Chemistry, Vol. 406, No 6, pp. 1763–1780
Geneva, 12–20 October (https://www.who.int/docs/default- (https://doi.org/10.1007/s00216-014-7668-0).
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review-2020.pdf?sfvrsn=959c2bcb_6).
I Wouters, E., Walraed, J., Robertson, M. J., Meyrath, M.,
Szpakowska, M., Chevigné, A., Skiniotis, G., et al. (2020),
I WHO (2020c), Letter to the United Nations Secretary-General – ‘Assessment of biased agonism among distinct synthetic
Recommendations of the 43rd ECDD (https://www.who.int/ cannabinoid receptor agonist scaffolds’, ACS Pharmacology &
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secretarygeneral-recommendations-of-the-43rd-ecdd). org/10.1021/acsptsci.9b00069).

I Wiebelhaus, J. M., Poklis, J. L., Poklis, A., Vann, R. E., Lichtman, I Yamagishi, I., Minakata, K., Nozawa, H., Hasegawa, K., Suzuki, M.,
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synthetic “marijuana” produces potent cannabimimetic effects in mixture of synthetic cannabinoids EAM-2201, AB-PINACA and
mice’, Drug and Alcohol Dependence, Vol. 126, No 3, pp. 316– AB-FUBINACA and a synthetic cathinone α-PVP’, Legal Medicine
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legalmed.2018.08.004).
I Wiley, J. L., Marusich, J. A. and Huffman, J. W. (2014), ‘Moving
around the molecule: relationship between chemical structure I Young, A. C., Schwarz, E., Medina, G., Obafemi, A., Feng, S. Y.,
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I Wiley, J. L., Lefever, T. W., Marusich, J. A. and Craft, R. M. (2017),
ajem.2011.05.013).
‘Comparison of the discriminative stimulus and response rate
effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids I Zaitsu, K., Hayashi, Y., Suzuki, K., Nakayama, H., Hattori, N.,
in female and male rats’, Drug and Alcohol Dependence, Vol. 172, Takahara, R., Kusano, M., et al. (2015), ‘Metabolome disruption of
pp. 51–59 (https://doi.org/10.1016/j.drugalcdep.2016.11.035). the rat cerebrum induced by the acute toxic effects of the
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I Williams, K., Wells, R. J. and McLean, M. K. (2015), ‘Suspected
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synthetic cannabinoid toxicosis in a dog’, Journal of Veterinary
Emergency and Critical Care (San Antonio), Vol. 25, No 6, I Zaurova, M., Hoffman, R. S., Vlahov, D. and Manini, A. F. (2016),
pp. 739–744 (https://doi.org/10.1111/vec.12378). ‘Clinical effects of synthetic cannabinoid receptor agonists
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I Winstock, A. R. and Barratt, M. J. (2013), ‘Synthetic cannabis: a
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comparison of patterns of use and effect profile with natural
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org/10.1016/j.drugalcdep.2012.12.011). I Zawilska, J. B. and Wojcieszak, J. (2014), ‘Spice/K2 drugs –
more than innocent substitutes for marijuana’, The International
I Winstock, A., Lynskey, M., Borschmann, R. and Waldron, J.
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pp. 698–703 (https://doi.org/10.1177/0269881115574493). Spanagel, R. and Schulz, K. (2009), ‘Withdrawal phenomena and
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I Wohlfarth, A., Gandhi, A. S., Pang, S., Zhu, M., Scheidweiler, K. B.
Deutsches Arzteblatt International, Vol. 106, No 27, pp. 464–467
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(https://doi.org/10.3238/arztebl.2009.0464).
PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte

50
 Synthetic cannabinoids in Europe – a review

I Annex 1. Profiles of selected synthetic

cannabinoids
to the indole nitrogen by an ethylene bridge, resulting in a
tricyclic core system.

IUPAC International InChI=1S/C25H28N2O/c1-4-5-11-17-

Chemical Identifier 26-21-15-10-9-14-20(21)23-22(26)16-
(InChI) 18-27(24(23)28)25(2,3)19-12-7-6-8-
I CUMYL-PeGACLONE 13-19/
h6-10,12-16,18H,4-5,11,17H2,1-3H3
Standard InChI Key AWHWTKXMUJLSRM-
UHFFFAOYSA-N
Background information
Simplified Molecular- CCCCCN1C2=C(C3=CC=CC=C31)
Input Line-Entry System C(=O)N(C=C2)C(C)(C)
CUMYL-PeGACLONE was the first representative of synthetic (SMILES) C4=CC=CC=C4
cannabinoids based on a γ-carbolinone scaffold. Structurally Chemical Abstract 2160555-55-3
related compounds were originally developed by Bristol- Service Registry Number
(CAS RN)
Myers in 2001 (Leftheris et al., 2003). CUMYL-PeGACLONE
Other names SGT-151
emerged on the European drug market in December 2016,
first detected in herbal blends test-purchased by the Institute
of Forensic Medicine, Freiburg (Germany). It has been
suggested that the substance may have been synthesised for Stereochemistry
the German drug market in order to circumvent a new national CUMYL-PeGACLONE does not contain a chiral centre.
generic drug law that came into force in November 2016
(called NpSG) (Angerer et al., 2018a).
Physical description
Pure CUMYL-PeGACLONE is a crystalline solid. Melting
point, boiling point or solubility data are not available in the
literature. The substance is poorly soluble in water.

Analytical profile
The analytical profile of CUMYL-PeGACLONE has been
described in publications using GC-MS, LC-HRMS, NMR,
and infrared and ultraviolet–visible spectroscopy (Angerer
et al., 2018a; Ernst et al., 2017). A thermal degradation
product (N-pentyl-γ-carbolinone) was detected by Nash et
al. (2019), with the product being produced in significant
CUMYL-PeGACLONE
amounts at temperatures above 250 °C, which are
Molecular formula C25H28N2O
commonly reached during smoking, the preferred route of
Molecular weight 372.5026 g/mol
administration.
Monoisotopic mass 372.2202

Pharmacology
Chemical and physical description
CUMYL-PeGACLONE has been shown to be a full
agonist at both CB receptors, with binding affinities in
Chemical description and names the low nanomolar range (Ki (CB1) = 1.37 ± 0.24 nM;
International Union of Pure and Applied Chemistry (IUPAC) Ki (CB2) = 2.09 ± 0.33 nM) (Angerer et al., 2018a). The
name(s): 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H- substance is extensively metabolised after consumption
pyrido[4,3-b]indol-1-one; 2-(1-methyl-1-phenyl-ethyl)-5- (no parent compound is detected in urine samples).
pentyl-pyrido[4,3-b]indol-1-one Two main metabolites were described as suitable for
urine screenings (hydroxylation of the core structure
CUMYL-PeGACLONE is characterised by a cumyl linking and hydroxylation with further oxidation at the pentyl
group (CUMYL) and a pentyl side chain (Pe) attached to side chain as the main phase I biotransformation steps)
a γ-carbolinone core system (GACLONE). The chemical (Mogler et al., 2018a). No data are available in the
structure lacks an open bridge scaffold. In this compound, literature describing the pharmacokinetic properties of
the frequently used carboxamide linker is directly attached CUMYL-PeGACLONE.

51
Synthetic cannabinoids in Europe – a review

In a panel of 21 synthetic cannabinoids chosen to cover a Epidemiology in Germany

broad diversity in chemical structures, CUMYL-PeGACLONE
was among the most potent and efficacious compounds in During the market monitoring of products test-purchased
two NanoBiT bioassays assessing CB1 receptor activation and analysed in the Institute of Forensic Medicine,
(mini-Gαi assay: EC50 = 0.07 nM (CP-55,940: 0.12 nM), Freiburg (Germany), CUMYL-PeGACLONE was detected
Emax = 261 % (CP55,940 set to 100 %); β-arrestin2 assay: in 25 % of all products between January and December
EC50 = 0.09 nM (CP-55,940: 0.48 nM), Emax = 655 % (CP- 2017 (n = 288). Detections continued to occur during the
55,940 set to 100 %)) (Wouters et al., 2020). first half of 2018, until it was almost completely replaced
by 5F-Cumyl-PeGaClone after CUMYL-PeEGACLONE was
scheduled under the German Narcotics Act in July 2018. In
Toxicology the following years, the compound was no longer detected.
At the Institute of Forensic Medicine in Freiburg, CUMYL-
Twenty-seven non-fatal and fatal poisonings involving PeGACLONE was the synthetic cannabinoid detected
CUMYL-PeGACLONE were reported by Halter et al. (2019), most often in serum and urine screenings in 2017 and in
with serum or femoral blood concentrations ranging from the first half of 2018 (own unpublished data). After July
0.12 to 13 ng/ml. In all six death cases presented, the 2018, the prevalence dropped sharply, with only sporadic
compound was assigned a low toxicological significance, detection of the compound (serum) or its metabolites
suggesting an alternative cause of death (Halter et al., 2019). (urine).

Five CUMYL-PeGACLONE-related fatalities in the Northern

Territory of Australia were recently reported by Tiemensma Structurally related synthetic cannabinoids
et al. (2021), with a concentration range in post-mortem
blood of 0.73–3.0 ng/ml. In most cases, concurrent So far, five structurally related γ-carbolinone derivatives
alcohol use and underlying cardiovascular disease were have emerged on the synthetic cannabinoids market.
considered relevant factors. However, in four of the cases, 5F-Cumyl-PeGaCLone(5F-SGT-151) was first detected in
the presence of CUMYL-PeGACLONE was considered December 2017 in Germany after CUMYL-PeGACLONE
highly significant with respect to the cause of death was scheduled under the German Narcotics Act. Cumyl-
(Tiemensma et al., 2021). CH-MeGaClone was reported to the EMCDDA in November
2018 by Hungary. Cumyl-CB-MeGaClone was formally
notified by the EMCDDA on behalf of Hungary in June
Dependence and abuse potential 2020 and Cumyl-BC-HpMeGaClone-221 (also known as
CUMYL-NB-MeGaClone) was formally notified on behalf of
There are no data available in the literature on the potential Germany in September 2020. ‘MDMB-FUBGACLONE’ is a
of CUMYL-PeGACLONE to produce dependence or on its γ-carbolinone derivative that is sold online, although it has
abuse liability. not been formally notified up to now.

5F-Cumyl-PeGaClone Cumyl-CH-MeGaClone ‘MDMB-FUBGACLONE’

Molecular formula C25H27FN2O C27H30N2O C23H30N2O3
Molecular weight 390.4931 g/mol 398.5399 g/mol 382.4959 g/mol
Monoisotopic mass 390.2107 398.2358 382.2256

52
 Synthetic cannabinoids in Europe – a review

I CUMYL-5F-P7AICA CUMYL-5F-P7AICA can be regarded as the 7-azaindole

(7AI) analogue of the indazole carboxamide synthetic
cannabinoid CUMYL-5F-PINACA (CUMYL-5F-PINACA/
Background information SGT-25). The position of the nitrogen in the pyridine ring
was confirmed by NMR analysis (EMCDDA, 2021b). To
CUMYL-5F-P7AICA is the first synthetic cannabinoid differentiate from possible azaindole isomers, Martek et
showing a 7-azaindole core structure and was first al. (2019) proposed 1H–15N heteronuclear multiple-bond
reported to the EMCDDA in February 2015 by Slovenia. correlation NMR as a tool for rapid and unambiguous
Synthetic cannabinoids comprising cumyl substituents identification. The first azaindole monitored by the
were first mentioned in a patent application of Bowden EMCDDA (5F-PCN) was a 5-azaindole.
and Williamson (2014). However, in this patent, no
synthetic cannabinoid with a 7-azaindole core was
mentioned. The emergence of 7-azaindole synthetic Stereochemistry
cannabinoids appears to have coincided with the CUMYL-5F-P7AICA does not contain a chiral centre.
introduction of generic NPS laws in Europe, which typically
included variations of compounds based on indole or
indazole core structures, and is an indicator of producers’ Physical description
ability to adapt the control measures in place. Pure CUMYL-5F-P7AICA is described as a neat solid. Its
melting point is 174–176 °C (Banister et al., 2019). Boiling
point or solubility data are not available in the literature.
The substance is poorly soluble in water.

Analytical profile
The analytical profile of CUMYL-5F-P7AICA has been
comprehensively described in the literature, including
routes of synthesis and GC-MS, LC-HRMS and NMR data
(Asada et al., 2018; Banister et al., 2019).

Pharmacology
CUMYL-5F-P7AICA
Molecular formula C22H26FN3O
The binding affinities and functional activities of
Molecular weight 367.4597 g/mol
CUMYL-5F-P7AICA were evaluated by Banister et al.
Monoisotopic mass 367.2060
(2019) and compared with corresponding indole and
indazole analogues. CUMYL-5F-P7AICA showed high
binding affinities and activities at both CB receptors (Ki
Chemical and physical description (CB1) = 174 nM, EC50 (CB1) = 4.7 nM, Ki (CB2) = 75.9 nM,
EC50 (CB2) = 11.3 nM), but both affinity and activity were
lower than those of the indole and indazole analogues
Chemical description and names (Banister et al., 2019). Metabolism of the substance in
IUPAC name: 1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)- humans was studied by Staeheli et al. (2019). Major
1H-pyrrolo[2,3-b]pyridine-3-carboxamide in vivo biotransformation steps in human metabolism
were oxidative defluorination followed by carboxylation,
IUPAC International InChI=1S/C22H26FN3O/c1-22(2,17-10- and monohydroxylation followed by sulfatation and
Chemical Identifier 5-3-6-11-17)25-21(27)19-16-26(15-8- glucuronidation. No data are available in the literature
(InChI) 4-7-13-23)20-18(19)12-9-14-24-20
describing the pharmacokinetic properties of the
Standard InChI Key MXJYOUMYJGNQEY-UHFFFAOYSA-N
substance.
Simplified Molecular- O=C(NC(C)(C)C1=CC=CC=C1)
Input Line-Entry System C2=CN(CCCCCF)C3=C2C=CC=N3
(SMILES)
Chemical Abstract —
Service Registry
Number (CAS RN)
Other names SGT-263

53
Synthetic cannabinoids in Europe – a review

Toxicology (Germany), CUMYL-5F-P7AICA has been detected

relatively seldomly (in approximately 2 % of all products
One report of poisoning involving CUMYL-5F-P7AICA between 2016 and 2018 and no further detections since
with unknown causality described has been published, by December 2020; the compound was scheduled under the
Piontek and Hannemann (2018). German Narcotics Act in July 2018). In serum and urine
samples screened at the Institute of Forensic Medicine,
Freiburg, there were very few positives for the compound
Dependence and abuse potential or its metabolites in 2017 and no positives thereafter (own
unpublished data). There were no epidemiological data on
There are no data available in the literature on the potential CUMYL-5F-P7AICA found in the literature.
of CUMYL-5F-P7AICA to produce dependence or its abuse
potential.
Structurally related synthetic cannabinoids

Epidemiology in Germany To date, five 7-azaindole-derived synthetic cannabinoids,

in addition to CUMYL-5F-P7AICA, have emerged on the
During the market monitoring of products test-purchased drug market. All of them are 7-azaindole analogues of well-
and analysed in the Institute of Forensic Medicine, Freiburg known indole- or indazole-based synthetic cannabinoids.

CUMYL-4CN-B7AICA 5F-MDMB-P7AICA 5F-AB-P7AICA 5F-A-P7AICA AB-FUB7AICA

Molecular formula C22H24N4O C20H28FN3O3 C18H25FN4O2 C23H30FN3O C20H21FN4O2
Molecular weight 360.4522 g/mol 377.4530 g/mol 348.4151 g/mol 383.5022 g/mol 368.4047 g/mol
Monoisotopic 360.1950 377.2115 348.1962 383.2373 368.1649
mass

54
 Synthetic cannabinoids in Europe – a review

I AB-FUBINACA Stereochemistry
AB-FUBINACA contains a chiral centre. It is assumed that,
because of the route of synthesis and the availability of
Background information synthesis precursors, AB-FUBINACA occurs mainly as the
(S)-enantiomer, which can be expected to be much more
AB-FUBINACA was one of the first synthetic cannabinoids potent than the (R)-enantiomer (Antonides et al., 2019).
to emerge, in 2012, on the Japanese drug market and
features a valinamide linker group (Uchiyama et al.,
2013c). It is structurally closely related to AB-PINACA Physical description
and other valinamide derivatives that were originally Pure AB-FUBINACA is a crystalline solid. Its melting point
synthesised by Pfizer in 2009 (Buchler et al., 2009). is 163.0–165.5 °C (Longworth et al., 2016). Boiling point
and solubility data are not available in the literature. It is
described as soluble in organic solvents (~0.5 mg/ml in
a 1:1 ratio of dimethyl sulfoxide to phosphate buffered
saline at pH 7.2; ~3, 10 and 5 mg/ml in ethanol, dimethyl
sulfoxide and N,N-dimethyl formamide) (Cayman Chemical
Company, 2019).

Analytical profile
In the literature, AB-FUBINACA was identified for the first
time in drug products by Uchiyama and colleagues in
2012 using NMR, GC-MS and LC-HRMS (Uchiyama et al.,
2013c). A route for the synthesis of AB-FUBINACA and
AB-FUBINACA
of structurally related indole and indazole carboxamide-
Molecular formula C20H21FN4O2
type synthetic cannabinoids has been published in the
Molecular weight 368.4047 g/mol
literature (Banister et al., 2015; Longworth et al., 2016).
Monoisotopic mass 368.1649
Electrospray ionisation fragmentation pathways of
‘FUBINACA’-type synthetic cannabinoids were recently
described by Sekuła et al. (2018).
Chemical and physical description

Pharmacology
Chemical description and names
IUPAC name: N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4- In the studies of Banister et al. (2015), AB-FUBINACA
fluorobenzyl)-1H-indazole-3-carboxamide showed high functional activity at both types of CB
receptors (hCB1 EC50 = 1.8 nM; hCB2 EC50 = 3.2 nM). The
AB-FUBINACA is an indazole carboxamide synthetic administration of AB-FUBINACA and structurally related
cannabinoid (INACA) with a (L)-valinamide linker group (AB). synthetic cannabinoids to mice was performed by Canazza
It is the first synthetic cannabinoid with a 4-fluorobenzyl side et al. (2017). In comparison with Δ9-THC, AB-FUBINACA
chain (FUB) that was notified to the EMCDDA. was shown to be much more potent in the tetrad model. In
higher doses, severe neurological effects, such as seizures,
IUPAC International InChI=1S/C20H21FN4O2/c1- myoclonia and hyperreflexia, including the promotion of
Chemical Identifier 12(2)17(19(22)26)23-20(27)18-15-5-3- aggressiveness, were observed. In this study, the binding
(InChI 4-6-16(15)25(24-18)11-13-7-9-14(21)10-
8-13/ affinities of AB-FUBINACA were determined using Chinese
h3-10,12,17H,11H2,1-2H3,(H2,22,26) hamster ovary membranes (hCB1 Ki = 0.734 ± 0.071 nM;
(H,23,27)/t17-/m0/s1
hCB2 Ki = 0.933 ± 0.082 nM) (Canazza et al., 2017).
Standard InChI Key AKOOIMKXADOPDA-KRWDZBQOSA-N
Simplified Molecular- CCCCCN1C2=C(C3=CC=CC=C31)
The main metabolic reaction of AB-FUBINACA was shown
Input Line-Entry C(=O)N(C=C2)C(C)(C)C4=CC=CC=C4
System (SMILES to be hydrolysis of the terminal amide function, which
Chemical Abstract 1629062-56-1 (racemate); 1185282-01- is mainly catalysed by carboxylesterases (Thomsen
Service Registry 2 ((S)-AB-FUBINACA) et al., 2015). This metabolite was also reported as the
Number (CAS RN
predominant biotransformation product found in human
Other names —
urine samples (Castaneto et al., 2015).

55
Synthetic cannabinoids in Europe – a review

Toxicology Dependence and abuse potential

Supraventricular tachycardia and acute confusion were In a recent study, repeated administration of AB-
reported in a healthy 24-year-old man who ingested FUBINACA was found to induce physical dependence in
e-cigarette fluid purchased on the internet, which was mice. Although mice did not develop tolerance to AB-
later analysed and found to contain AB-FUBINACA and FUBINACA or cross-tolerance to THC, somatic precipitated
ADB-FUBINACA. Somnolence, confusion and agitation, withdrawal signs were observed (Trexler et al., 2020).
coupled with gastrointestinal symptoms, such as vomiting,
developed 30 minutes after consumption and required
attendance at the emergency department, where the Epidemiology in Germany
intake was confirmed by serum analysis (AB-FUBINACA
5.6 ng/ml and ADB-FUBINACA 15.6 ng/ml). The patient During the market monitoring of products test-purchased
presented with high blood pressure, low body temperature and analysed at the Institute of Forensic Medicine,
(36.3 °C) and tachycardia (Lam et al., 2017). He recovered Freiburg, Germany (EU-funded projects SPICE, SPICE II
and was discharged 22 hours after admission. plus and SPICE Profiling), AB-FUBINACA was detected
mainly in 2014 (in more than 20 % of all test-purchased
A case of fatal poisoning was reported in which a products; it was scheduled under the German Narcotics
combination of EAM-2201, AB-PINACA, AB-FUBINACA Act in December 2014). AB-FUBINACA continued to be
and a synthetic cathinone (α-PVP) was identified in post- detected in about 4 % of all products analysed between
mortem samples (Yamagishi et al., 2018). However, AB- December 2015 and September 2018 (n = 2 474).
FUBINACA was not quantified in the blood and information In 2019 and 2020, it was not detected at all. In urine
on the case is limited. A fatality was also reported involving analysis, it is usually not possible to distinguish between
2.0 ng/ml AB-FUBINACA (Fernandez et al., 2016). A the consumption of AB-FUBINACA and AMB-FUBINACA
propensity for sedation, tachycardia and hypothermia was because the main metabolite of both compounds is the
also seen in a case series of four patients who reported same. The common metabolite was detected in more than
ingestion of ‘molly’ and in whom urine samples tested 60 % of all positive urine samples in 2014, about 35 % in
positive for AB-FUBINACA (Brenneman et al., 2016). 2015, more than 20 % in 2016 and about 15 % in 2013,
A blood concentration of 0.97 ng/ml AB-FUBINACA 2017 and 2018. In 2019, the metabolite was detected
was reported in a death case described by Hess et al. in less than 10 % of positive samples, and this dropped
(2015), in combination with AB-CHMINACA (2.8 ng/ml), further, to about 5 %, in 2020. In serum samples, AB-
5F-AMB (0.19 ng/ml), 5F-AKB48 (0.51 ng/ml), STS-135 FUBINACA was last detected in 2017 (about 3 % of the
(0.16 ng/ml) and THJ-2201 (0.16 ng/ml). The 25-year- positive samples; no positives in 2019 and 2020) (own
old male had a history of synthetic cannabinoid use and unpublished data).
died from diabetic ketoacidosis. Synthetic cannabinoids
were considered the main reason for him skipping the
administration of his daily insulin dose (Hess et al., 2015). Structurally related synthetic cannabinoids

Several structurally related valinamide derivatives were

reported to the EMCDDA. Structural modifications are
the exchange of the 4-fluorobenzyl group by pentyl,
5-fluoropentyl or cyclohexylmethyl scaffolds.

AB-PINACA 5F-AB-PINACA AB-CHMINACA

Molecular formula C18H26N4O2 C18H25FN4O2 C20H28N4O2
Molecular weight 330.4246 g/mol 348.4151 g/mol 356.4619 g/mol
Monoisotopic mass 330.2056 348.1962 356.2212

56
 Synthetic cannabinoids in Europe – a review

I AMB-FUBINACA Stereochemistry
Like its valinamide analogue AB-FUBINACA, AMB-
FUBINACA contains a chiral centre. Given the route of
Background information synthesis and availability of synthesis precursors, it is
presumed that AMB-FUBINACA mainly occurs in the form
AMB-FUBINACA is structurally closely related to AB- of the (S)-enantiomer (Antonides et al., 2019).
FUBINACA, with the terminal amide group being replaced
by a methoxy group. AMB-FUBINACA was the first
synthetic cannabinoid with valinate linking groups to Physical description
emerge on the European drug market, in 2014. Pure AMB-FUBINACA is a crystalline solid. In the literature,
it has also been described as a colourless oil (Banister et
al., 2016). Melting point, boiling point or solubility data are
not available in the literature.

Analytical profile
The analytical profile of AMB-FUBINACA has been
described in the literature, including the synthetic
pathway and NMR data (Banister et al., 2016). GC-MS,
high-performance liquid chromatography time-of-flight
(HPLC-TOF) and Fourier-transform infrared spectroscopy
attenuated total reflection (FTIR-ATR) data were reported
to the EMCDDA by the Slovenian National Focal Point
AMB-FUBINACA
(RESPONSE, 2015).
Molecular formula C21H22FN3O3
Molecular weight 383.4161 g/mol
Monoisotopic mass 383.1645
Pharmacology

Chemical and physical description In a study by Banister et al. (2016), AMB-FUBINACA

showed functional activity at both types of CB receptors
(hCB1 EC50 = 2.0 nM; hCB2 EC50 = 18 nM). The receptor-
Chemical description and names binding affinities were determined in a study by
IUPAC name(s): methyl-2-(1-(4-fluorobenzyl)-1H- Schoeder et al. (2018) (hCB1 Ki = 0.387 ± 0.135 nM;
indazole-3-carboxamide)-3-methylbutanoate; methyl hCB2 Ki = 0.536 ± 0.115 nM). AMB-FUBINACA is mainly
2-[[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino]- metabolised to the carboxylic acid metabolite by terminal
3-methyl-butanoate methylester hydrolysis (Apirakkan et al., 2020). In a recent
study, Finlay et al. (2019) compared the activity profile of
AMB-FUBINACA differs from AB-FUBINACA in having a AMB-FUBINACA with ‘traditional research cannabinoids’
methylbutanoate (AMB) scaffold. such as CP-55,940 and Δ9-THC and found significant
discrepancies in the activity of AMB-FUBINACA in different
IUPAC International InChI=1S/C21H22FN3O3/c1- cellular pathways, which might be related to divergent
Chemical Identifier 13(2)18(21(27)28-3)23-20(26)19-16- physiological CB1-mediated effects of AMB-FUBINACA and
(InChI) 6-4-5-7-17(16)25(24-19)12-14-8-10-
15(22)11-9-14/ other synthetic cannabinoids.
h4-11,13,18H,12H2,1-3H3,(H,23,26)
Standard InChI Key FRFFLYJQPCIIQB-UHFFFAOYSA-N
Simplified Molecular- CC(C)C(C(=O)OC)NC(=O) Toxicology
Input Line-Entry System C1=NN(C2=CC=CC=C21)
(SMILES) CC3=CC=C(C=C3)F
In July 2016, an outbreak of mass poisoning caused by
Chemical Abstract 1715016-76-4
Service Registry Number AMB-FUBINACA occurred in New York, United States.
(CAS RN) Thirty-three patients presented with ‘altered mental status’,
Other names FUB-AMB, MMB-FUBINACA including lethargy and a reduction in the Glasgow Coma
Scale score. AMB-FUBINACA was identified in a sample of
product recovered from one of the patients. Metabolite of

57
Synthetic cannabinoids in Europe – a review

AMB-FUBINACA was also detected in biological samples 2019 and 2020), with a maximum between 2015 and
from eight patients (Adams et al., 2017). 2016 (AMB-FUBINACA was scheduled under the German
Narcotics Act in June 2016). In urine analysis, it is not
Adamowicz et al. (2019) reported the fatal poisoning of a usually possible to distinguish between consumption of
27-year-old male involving AMB-FUBINACA. The autopsy AB-FUBINACA and AMB-FUBINACA because the main
revealed pleural adhesions and pulmonary oedema, while metabolite of both compounds is the same. The common
samples collected during post-mortem examinations metabolite was detected in more than 60 % of all positive
showed both AMB-FUBINACA and EMB-FUBINACA in urine samples in 2014, about 35 % in 2015, more than
tissues but not in blood. Concentrations in solid tissues 20 % in 2016 and about 15 % in 2013, 2017 and 2018. In
ranged from 0.2 to 0.9 ng/ml and from 0.2 to 3.5 ng/ml, 2019, the metabolite was detected in less than 10 % of the
respectively (Adamowicz et al., 2019). positive samples, and this dropped further to about 5 % in
2020. In serum samples, AMB-FUBINACA was detected in
about 5 to 10 % of the positive samples until the second
Dependence and abuse potential half of 2019, with only sporadic detection thereafter (own
unpublished data).
There are no data available in the literature on the potential
of AMB-FUBINACA to produce dependence or on its abuse
potential. Structurally related synthetic cannabinoids

Several structurally related synthetic cannabinoids

Epidemiology in Germany showing valinate moieties have been reported to
the EMCDDA. Structural modifications include the
AMB-FUBINACA was regularly detected during the exchange of the 4-fluorobenzyl group by 5-fluoropentyl or
market monitoring of products test-purchased and cyclohexylmethyl scaffolds and/or the replacement by the
analysed in the Institute of Forensic Medicine, Freiburg indazole ring with an indole core.
(Germany), between 2015 and 2018 (not detected in

5F-AMB-PINACA AMB-CHMINACA AMB-FUBICA

Molecular formula C19H26FN3O3 C21H29N3O3 C22H23FN2O3
Molecular weight 363.4264 g/mol 371.4733 g/mol 382.4280 g/mol
Monoisotopic mass 363.1958 371.2210 382.1693

58
 Synthetic cannabinoids in Europe – a review

I 5F-MDMB-PICA Stereochemistry
5F-MDMB-PICA shows a chiral centre. It is assumed
(based on the route of synthesis and the availability of
Background information synthesis precursors) that 5F-MDMB-PICA occurs mainly
in the form of the (S)-enantiomer (Antonides et al., 2019).
5F-MDMB-PICA emerged on the European drug market in
2016 (Mogler et al., 2018b). It was synthesised by Banister
et al. (2016) to study the structure–activity relationship of Physical description
synthetic cannabinoids carrying tert-leucinate scaffolds. Pure 5F-MDMB-PICA is a crystalline solid. Its melting
point is 82–84 °C (Banister et al., 2016). Boiling point and
solubility data are not available in the literature.

Analytical profile
The analytical profile of 5F-MDMB-PICA has been
described in the literature, including the synthetic
pathway and NMR, GC-MS, high-performance liquid
chromatography with diode array detection (HPLC-DAD)
and liquid chromatography quadrupole time of flight mass
spectrometry (LC-QTOF-MS) data (Banister et al., 2016;
Mogler et al., 2018b; Risseeuw et al., 2017).

5F-MDMB-PICA
Molecular formula C21H29FN2O3
Pharmacology
Molecular weight 376.4650 g/mol
Monoisotopic mass 376.2162
A study by Banister et al. (2016) assessed the functional
activity of 5F-MDMB-PICA and 16 other valinate and
tert-leucinate synthetic cannabinoids at human CB1 and
Chemical and physical description CB2 receptors. 5F-MDMB-PICA (EC50 = 0.45 nM) was
found to be about 380 times more potent than Δ9-THC
(EC50 = 171 nM) at the CB1 receptor in the assay. Of all the
Chemical description and names cannabinoids investigated in this study, 5F-MDMB-PICA
IUPAC name(s): methyl 2-[[1-(5-fluoropentyl)indole-3- was reported to be the most potent. Regarding human
carbonyl]amino]-3,3-dimethyl-butanoate; methyl N-{[1-(5- metabolism, the product of ester hydrolysis has been
fluoropentyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate shown to be the main phase I metabolite (Mogler et al.,
2018b).
5F-MDMB-PICA is the indole analogue of the highly
prevalent indazole carboxamide SC 5F-ADB (5F-MDMB-
PINACA). Toxicology

IUPAC International InChI=1S/C21H29FN2O3/c1- Cases of severe and fatal poisonings involving 5F-MDMB-
Chemical Identifier 21(2,3)18(20(26)27-4)23-19(25)16- PICA have been reported in the literature (Kleis et al., 2020;
(InChI) 14-24(13-9-5-8-12-22)17-11-7-6-10-
15(16)17/ Nogee et al., 2019).
h6-7,10-11,14,18H,5,8-9,12-13H2,1-
4H3,(H,23,25)/t18-/m1/s1
Standard InChI Key CHSUEEBESACQDV-GOSISDBHSA-N
Dependence and abuse potential
Simplified Molecular- CC(C)(C)C(C(=O)OC)NC(=O)
Input Line-Entry System C1=CN(C2=CC=CC=C21)CCCCCF
(SMILES) There are no data available in the literature on the potential
Chemical Abstract 1971007-88-1 of 5F-MDMB-PICA to produce dependence or on its abuse
Service Registry Number potential.
(CAS RN)
Other names 5F-MDMB-2201, MDMB-2201

59
Synthetic cannabinoids in Europe – a review

Epidemiology in Germany than 45 % of all positive samples testing positive for its
metabolites. In 2020, the prevalence rose to more than
Shortly after 5F-MDMB-PICA was reported to the 50 % from January to June and dropped in the second
EMCDDA, 25 herbal blends containing 5F-MDMB-PICA half of the year (although it was still more than 20 %
were seized by police during a raid on a head shop in in the final quarter of 2020). A similar trend was seen
Germany. During the market monitoring of products for serum samples positive for AMB-FUBINACA (own
test-purchased and analysed at the Institute of Forensic unpublished data). This might be a consequence of the
Medicine, Freiburg (Germany), 5F-MDMB-PICA was one of control, for example of 5F-ADB and AMB-FUBINACA, but
the most frequently detected synthetic cannabinoids from not 5F-MDMB-PICA, put in place in August 2018 in China
the second half of 2016 onwards. Despite its regulation (UNODC, 2018).
under the German NpSG, which entered into force in
November 2016, it was still detected in approximately
20 % of all test-purchased products in 2019, but with Structurally related synthetic cannabinoids
declining prevalence in 2020 (it was scheduled under
the German Narcotics Act in July 2020). In urine samples Most of the structurally related indole or indazole
analysed at the Institute of Forensic Medicine, Freiburg, carboxamide-type synthetic cannabinoids showing tert-
the first positive samples occurred in 2016 (making up leucinate linker groups emerged on the European drug
about 8 % of all positive samples). In 2017 and 2018, market between 2015 and 2016. The most prominent
the prevalence dropped to less than 5 %. In 2019, the representatives are 5F-ADB (5F-MDMB-PINACA), MDMB-
prevalence in urine samples sharply increased, with more CHMICA and MDMB-FUBINACA.

5F-MDMB-PINACA MDMB-CHMICA MDMB-FUBINACA

Molecular formula C20H28FN3O3 C23H32N2O3 C22H24FN3O3
Molecular weight 377.4530 g/mol 384.5118 g/mol 397.4427 g/mol
Monoisotopic mass 377.2115 384.2413 397.1802

60
 Synthetic cannabinoids in Europe – a review

I Annex 2. Synthetic cannabinoids monitored by the EMCDDA through the EU Early

Warning System on new psychoactive substances (as of 16 April 2021)

Date of formal
Common name IUPAC name
notification
ADB-4en-PINACA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole- 23 March 2021
3-carboxamide
CUMYL-NBMINACA (1-(Bicyclo[2.2.1]heptan-2-yl)methyl)-N-(2-phenylpropan-2-yl)-1H-indazole- 23 February 2021
3-carboxamide
ABO-4en-PINACA N-(1-Amino-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3- 3 February 2021
carboxamide
CUMYL-NBMICA N-[(1-Fenyl-1-methyl)ethyl]-1-(2-norbornyl)methyl-1H-indool-3- 23 December 2020
carboxamide
5B-AKB48 N-(1-Adamantyl)-1-(5-bromopentyl)indazole-3-carboxamide 14 December 2020
4F-ABINACA N-(Adamantan-1-yl)-1-(4-fluorobutyl)-1H-indazole-3-carboxamide 9 October 2020
Cumyl-BC-HpMeGaClone-221 (5-(Bicyclo[2.2.1]hept-2-yl)methyl)-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H- 30 September 2020
pyrido[4,3-b]indol-1-one
5F-EDMB-PICA Ethyl 2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3,3- 8 September 2020
dimethylbutanoate
5F-EMB-PICA Ethyl 2-[[1-(5-fluoropentyl)indole-3-carbonyl]amino]-3-methyl-butanoate 3 July 2020
4F-MDMB-BICA Methyl 2-({[1-(4-fluorobutyl)-1H-indol-3-yl]carbonyl}amino)-3,3- 2 July 2020
dimethylbutanoate/methyl N-[1-(4-fluorobutyl)-1H-indole-3-carbonyl]-3-
methylvalinate
Cumyl-CB-MeGaClone 5-(Cyclobutylmethyl)-2-(1-methyl-1-phenyl-ethyl)pyrido[4,3-b]indol-1-one 30 June 2020
PTI-3 N-({2-[1-(5-Fluoropentyl)-1H-indol-3-yl]-1,3-thiazol-4-yl}methyl)-2- 22 June 2020
methoxy-N-methylethanamine
CUMYL-CBMINACA 1-(Cyclobutylmethyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide 6 May 2020
BENZYL-4CN-BINACA N-Benzyl-1-(4-cyanobutyl)-1H-indazole-3-carboxamide 3 March 2020
UR-144 degradant 3,3,4-Trimethyl-1-(1-pentyl-1H-indol-3-yl)pent-4-en-1-one 18 December 2019
CUMYL-CBMICA 1-(Cyclobutylmethyl)-N-(2-phenylpropan-2-yl)-1H-indol-3-carboxamide 29 November 2019
ADB-BUTINACA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3- 23 September 2019
carboxamide
MDMB-CHMINACA Methyl 2-[1-(cyclohexylmethyl)-1H-indazole-3-carboxamido]-3,3- 12 July 2019
dimethylbutanoate
5F-JWH-398 (CL-2201) 1-(5-Fluoropentyl)-3-(4-chloro-1-naphthoyl)indole 7 May 2019
5F-A-P7AICA N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3- 2 April 2019
carboxamide
2F-QMPSB Quinolin-8-yl 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-methylbenzoate 10 January 2019
APP-BINACA N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-butyl-1H-indazole-3- 9 January 2019
carboxamide
5F-AKB57 Adamantan-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate 6 December 2018
4F-MDMB-BINACA Methyl 2-(1-(4-fluorobutyl)-1H-indazole-3-carboxamido)-3,3- 20 November 2018
dimethylbutanoate
Cumyl-CH-MeGaClone 5-(Cyclohexylmethyl)-2-(1-methyl-1-phenyl-ethyl)pyrido[4,3-b]indol-1-one 14 November 2018
5F-AB-P7AICA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b] 9 October 2018
pyridine-3-carboxamide
AMB-4en-PICA Methyl 3-methyl-2-[1-(pent-4-en-1-yl)-1H-indole-3-carboxamido]butanoate 24 August 2018
MDMB-4en-PINACA Methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido) 23 August 2018
butanoate
MPhP-2201 Methyl 2-{[1-(5-fluoropentyl)-1H-indol-3-yl]formamido}-3- 22 August 2018
phenylpropanoate
A-CHMINACA N-(1-Adamantyl)-1-(cyclohexylmethyl)indazole-3-carboxamide 3 July 2018
MBA-CHMINACA 2-[[1-(Cyclohexylmethyl)indazole-3-carbonyl]amino]-3-methyl-butanoic 22 June 2018
acid
DMBA-CHMINACA 2-[[1-(Cyclohexylmethyl)indazole-3-carbonyl]amino]-3,3-dimethyl-butanoic 22 June 2018
acid
5F-MDMB-P7AICA Methyl 2-{[1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]formamido}-3,3- 16 February 2018
dimethylbutanoate
5F-Cumyl-PeGaClone 5-(5-Fluoropentyl)-2-(1-methyl-1-phenyl-ethyl)pyrido[4,3-b]indol-1-one 21 December 2017

61
Synthetic cannabinoids in Europe – a review

Date of formal
Common name IUPAC name
notification
CUMYL-4CN-B7AICA 1-(4-Cyanobutyl)-N-(1-methyl-1-phenyl-ethyl)pyrrolo[2,3-b]pyridine-3- 4 July 2017
carboxamide
5Cl-MDMB-PINACA Methyl 2-[[1-(5-chloropentyl)indazole-3-carbonyl]amino]-3,3-dimethyl- 29 June 2017
butanoate
5F-3,5-AB-PFUPPYCA N-(1-Carbamoyl-2-methyl-propyl)-2-(5-fluoropentyl-5-(4-fluorophenyl) 8 June 2017
pyrazole-3-carboxamide
SDB-006 N-phenyl analogue 1-Pentyl-N-phenyl-indole-3-carboxamide 22 May 2017
5F NNEI 2′-naphthylisomer 1-(5-Fluoropentyl)-N-(2-naphthyl)indole-3-carboxamide 19 May 2017
MDMB-PCZCA Methyl 3,3-dimethyl-2-[(9-pentylcarbazole-3-carbonyl)amino]butanoate 11 May 2017
5Cl-AB-PINACA N-(1-Carbamoyl-2-methyl-propyl)-1-(5-chloropentyl)indazole-3- 4 May 2017
carboxamide
5-Chloropentyl JWH-018 indazole [1-(5-Chloropentyl)indazol-3-yl]-(1-naphthyl)methanone 6 April 2017
analogue (5Cl-THJ-018)
CUMYL-PeGACLONE 2-(1-Methyl-1-phenyl-ethyl)-5-pentyl-pyrido[4,3-b]indol-1-one 6 February 2017
MO-CHMINACA 1-Methoxy-3,3-dimethyl-1-oxobutan-2-yl 1-(cyclohexylmethyl)-1H-indazole- 20 December 2016
3-carboxylate
MDA 19 N-[(Z)-(1-Hexyl-2-oxo-indolin-3-ylidene)amino]benzamide 19 October 2016
AMB-FUBICA Methyl 2-[[1-[(4-fluorophenyl)methyl]indole-3-carbonyl]amino]-3-methyl- 3 October 2016
butanoate
5F-MDMB-PICA Methyl 2-[[1-(5-fluoropentyl)indole-3-carbonyl]amino]-3,3-dimethyl- 30 September 2016
butanoate
5F-EDMB-PINACA Ethyl-2-[1-(5-fluoropentyl)-1H-indazole-3-carboxamido]-3,3- 21 September 2016
dimethylbutanoate
FUB-NPB-22 8-Quinolyl 1-[(4-fluorophenyl)methyl]indazole-3-carboxylate 9 September 2016
CUMYL-4CN-BINACA 1-(4-Cyanobutyl)-N-(1-methyl-1-phenyl-ethyl)indazole-3-carboxamide 4 March 2016
AKB-57 1-Adamantyl 1-pentylindazole-3-carboxylate 23 February 2016
LTI-701 1-(5-Fluoropentyl)-N-phenyl-1H-indole-3-carboxamide 23 February 2016
EG-2201 (9-(5-Fluoropentyl)-9H-carbazol-3-yl)(naphthalen-1-yl)methanone 22 February 2016
MDMB-FUBINACA Methyl 2-[[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino]-3,3- 11 January 2016
dimethyl-butanoate
JWH-018 cyclohexymethyl derivative [1-(Cyclohexylmethyl)-1H-indol-3-yl](naphthalen-1-yl)methanone 16 December 2015
AMB-CHMICA Methyl 2-[[1-(cyclohexylmethyl)indole-3-carbonyl]amino]-3-methyl- 26 October 2015
butanoate
MDMB-CHMCZCA 9-(Cyclohexylmethyl)-N-(1-methoxycarbonyl-2,2-dimethyl-propyl) 26 October 2015
carbazole-3-carboximidic acid
FUB-JWH-018 [1-(4-Fluorobenzyl)-1H-indol-3-yl](naphthalen-1-yl)methanone 11 September 2015
AB-CHMFUPPYCA (3,5-AB- N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4- 7 August 2015
CHMFUPPYCA) fluorophenyl)-1H-pyrazole-5-carboxamide
5-Fluoropentyl-3-pyridinoylindole [1-(5-Fluoropentyl)-1H-indol-3-yl](pyridin-3-yl)methanone 6 July 2015
CBL-018 Naphthalen-1-yl 1-pentyl-1H-indole-3-carboxylate 2 July 2015
5F-EMB-PINACA Ethyl 2-[[1-(5-fluoropentyl)indazole-3-carbonyl]amino]-3-methyl-butanoate 17 June 2015
EMB-FUBINACA Ethyl 2-[[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino]-3-methyl- 17 June 2015
butanoate
5C-AKB48 N-(1-Adamantyl)-1-(5-chloropentyl)indazole-3-carboxamide 17 June 2015
5F-PY-PINACA [1-(5-Fluoropentyl)-1H-indazol-3-yl](pyrrolidin-1-yl)methanone 17 June 2015
5F-PY-PICA [1-(5-Fluoropentyl)-1H-indol-3-yl](pyrrolidin-1-yl)methanone 12 June 2015
5F-AB-FUPPYCA (5F-5,3-AB- 2-[[1-(5-Fluoropentyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido]-3- 12 June 2015
PFUPPYCA) methylbutanamide
AMB-CHMINACA Methyl 2-[[1-(cyclohexylmethyl)indazole-3-carbonyl]amino]-3-methyl- 28 May 2015
butanoate
MDMB-FUBICA Methyl 2-[[1-[(4-fluorophenyl)methyl]indole-3-carbonyl]amino]-3,3- 4 May 2015
dimethyl-butanoate
APP-CHMINACA N-(2-Amino-1-benzyl-2-oxo-ethyl)-1-(cyclohexylmethyl)indazole-3- 14 April 2015
carboxamide
AB-PINACA N-(2-fluoropentyl) isomer N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(2-fluoropentyl)-1H-indazole-3- 7 April 2015
carboxamide
5F-ADB-PINACA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole- 31 March 2015
3-carboxamide
SDB-005 Naphthalen-1-yl 1-pentyl-1H-indazole-3-carboxylate 31 March 2015

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 Synthetic cannabinoids in Europe – a review

Date of formal
Common name IUPAC name
notification
M-CHMIC Methyl 1-(cyclohexylmethyl)indole-3-carboxylate 10 March 2015
CUMYL-5F-P7AICA 1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-7-azaindole-3-carboxamide 25 February 2015
FUB-144 [1-(4-Fluorobenzyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl) 9 February 2015
methanone
ADAMANTYL-THPINACA N-(1-Adamantyl)-1-(tetrahydropyran-4-ylmethyl)indazole-3-carboxamide 14 January 2015
5F-MDMB-PINACA (5F-ADB) Methyl 2-[[1-(5-fluoropentyl)indazole-3-carbonyl]amino]-3,3-dimethyl- 8 January 2015
butanoate
AMB-FUBINACA Methyl 2-[[1-[(4-fluorophenyl)methyl]indazole-3-carbonyl]amino]-3-methyl- 10 December 2014
butanoate
5F-AMB-PICA Methyl 2-[[1-(5-fluoropentyl)indole-3-carbonyl]amino]-3-methyl-butanoate 5 December 2014
5F-APP-PICA N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluoropentyl)-1H-indole-3- 25 November 2014
carboxamide
APP-FUBINACA N-(2-Amino-1-benzyl-2-oxo-ethyl)-1-[(4-fluorophenyl)methyl]indazole-3- 6 November 2014
carboxamide
5F-APP-PINACA N-(2-Amino-1-benzyl-2-oxo-ethyl)-1-(5-fluoropentyl)indazole-3- 6 November 2014
carboxamide
CUMYL-5FPINACA 1-(5-Fluoropentyl)-N-(1-methyl-1-phenylethyl)-1H-indazole-3-carboxamide 13 October 2014
CUMYL-THPINACA N-(1-Methyl-1-phenylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H- 23 September 2014
Indazole-3-carboxamide
ADB-CHMICA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indole- 23 September 2014
3-carboxamide
CUMYL-PICA 1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide 23 September 2014
CUMYL-5FPICA 1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide 23 September 2014
CUMYL-BICA 1-Butyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide 23 September 2014
CUMYL-PINACA 1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide 23 September 2014
ADB-CHMINACA N-[1-(Aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-1H- 12 September 2014
indazole-3-carboxamide
MDMB-CHMICA Methyl 2-[[1-(cyclohexylmethyl)indole-3-carbonyl]amino]-3,3-dimethyl- 12 September 2014
butanoate
5F-SDB-005 Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate 8 September 2014
NM-2201 Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate 4 September 2014
AB-FUBINACA 2-fluorobenzyl isomer N-(1-Carbamoyl-2-methyl-propyl)-1-[(2-fluorophenyl)methyl]indazole-3- 4 August 2014
carboxamide
FUB-AKB48 N-(1-Adamantyl)-1-[(4-fluorophenyl)methyl]indazole-3-carboxamide 18 July 2014
MN-18 N-(Naphthalen-1-yl)-1-pentyl-1H-indazole-3-carboxamide 9 July 2014
EG-018 Naphthalen-1-yl(9-pentyl-9H-carbazol-3-yl)methanone 20 June 2014
JWH-071 (1-Ethyl-1H-indol-3-yl)(naphthalen-1-yl)methanone 19 June 2014
5F-AMB (5F-AMB-PINACA) Methyl 2-({[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl}amino)-3- 18 June 2014
methylbutanoate
5F-AMBICA N-(1-Carbamoyl-2-methyl-propyl)-1-(5-fluoropentyl)indole-3-carboxamide 29 April 2014
AB-CHMINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3- 10 April 2014
carboxamide
AM-2201 benzimidazole analogue [1-(5-Fluoropentyl)-1H-benzimidazol-2-yl](naphthalen-1-yl)methanone 4 April 2014
(FUBIMINA)
Mepirapim (4-Methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone 25 February 2014
JWH-018 indazole analogue Naphthalen-1-yl(1-pentyl-1H-indazol-3-yl)methanone 21 February 2014
FDU-PB-22 Naphthalen-1-yl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate 12 February 2014
PB-22 indazole analogue Quinolin-8-yl 1-pentyl-1H-indazole-3-carboxylate 21 January 2014
5F-PB-22 indazole analogue Quinolin-8-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate 21 January 2014
FUB-PB-22 1-[(4-Fluorophenyl)methyl]-1H-indole-3-carboxylic acid 8-quinolinyl ester 19 December 2013
SDB-006 N-Benzyl-1-pentyl-1H-indole-3-carboxamide 19 December 2013
5F-SDB-006 N-Benzyl-1-(5-fluoropentyl)-1H-indole-3-carboxamide 19 December 2013
PTI-1 N-Ethyl-N-[[2-(1-pentylindol-3-yl)thiazol-4-yl]methyl]ethanamine 18 December 2013
A-796,260 isomer (E)-3,4,4-Trimethyl-1-[1-(2-morpholinoethyl)indol-3-yl]pent-2-en-1-one 18 December 2013
1-(Cyclohexylmethyl)-2-[(4- 1-(Cyclohexylmethyl)-2-[(4-ethoxyphenyl)methyl]-N,N-diethyl- 18 December 2013
ethoxyphenyl)methyl]-N,N-diethyl-1H- benzimidazole-5-carboxamide
benzimidazol-5-carboxamide

63
Synthetic cannabinoids in Europe – a review

Date of formal
Common name IUPAC name
notification
PTI-2 N-(2-Methoxyethyl)-N-[[2-(1-pentylindol-3-yl)thiazol-4-yl]methyl]propan-2- 18 December 2013
amine
ADB-PINACA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3- 3 December 2013
carboxamide
ADB-FUBINACA N-(1-Carbamoyl-2,2-dimethyl-propyl)-1-[(4-fluorophenyl)methyl]indazole-3- 28 November 2013
carboxamide
AM-2201 indazole analogue [1-(5-Fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone 15 November 2013
AM-6527 5-fluoropentyl derivative 1-(5-Fluoropentyl)-N-1-naphthalenyl-1H-Indole-3-carboxamide 7 November 2013
ADBICA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3- 11 October 2013
carboxamide
AM-1248 Azepane isomer (Adamant-1-yl)[1-(1-methylazepan-3-yl)-1H-indol-3-yl]methanone 26 September 2013
LY2183240 5-([1,1′-Biphenyl]-4-ylmethyl)-N,N-dimethyl-1H-tetrazole-1-carboxamide 10 September 2013
5F-AB-PINACA N-(1-Carbamoyl-2-methyl-propyl)-1-(5-fluoropentyl)indazole-3- 5 July 2013
carboxamide
JTE-907 N-(1,3-Benzodioxol-5-ylmethyl)-2-hydroxy-7-methoxy-8-pentoxy-quinoline- 4 July 2013
3-carboxamide
AB-FUBINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3- 4 July 2013
carboxamide
A-836,339 N-[(2Z)-3-(2-Methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3- 3 June 2013
tetramethylcyclopropanecarboxamide
AB-PINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3- 21 May 2013
carboxamide
URB-597 3′-Carbamoylbiphenyl-3-yl cyclohexylcarbamate 24 April 2013
UR-144 heptyl derivative (1-Heptylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone 17 April 2013
JWH-307 brominated analogue [5-(2-Bromophenyl)-1-pentyl-pyrrol-3-yl]-(1-naphthyl)methanone 4 April 2013
JWH-145 1-Naphthyl-(1-pentyl-5-phenyl-pyrrol-3-yl)methanone 4 April 2013
JWH-030 Naphthalen-1-yl(1-pentyl-1H-pyrrol-3-yl)methanone 4 April 2013
AM-2201 carboxylate analogue 1-(5-Fluoropentyl)-1H-indole-3-carboxylic acid 8-quinolinyl ester 15 March 2013
quinolinyl derivative (5F-PB-22)
EAM-2201 [1-(5-Fluoropentyl)-1H-indol-3-yl]-(4-ethyl-naphthalen-1-yl)methanone 15 February 2013
JWH-368 [5-(3-Fluorophenyl)-1-pentyl-pyrrol-3-yl]-(1-naphthyl)methanone 7 February 2013
JWH-methylcyclohexane-8quinolinol 8-Quinolinyl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate 29 January 2013
(BB-22)
A-834,735 [1-[(Tetrahydro-2H-pyran-4-yl)methyl]-1H-indol-3-yl] 29 January 2013
(2,2,3,3-tetramethylcyclopropyl)-methanone
UR-144 N-(5-chloropentyl) derivative [1-(5-Chloropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone 7 December 2012
4-HTMPIPO 4-Hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one 30 November 2012
JWH-018 quinolinecarboxylate Quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate 20 November 2012
analogue (PB-22)
AB-005 azepane isomer [1-(1-Methylazepan-2-yl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl) 20 November 2012
methanone
AB-005 [1-[(1-Methyl-2-piperidyl)methyl]indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl) 20 November 2012
methanone
AM-2201 indazolecarboxamide 1-(5-Fluoropentyl)-N-1-naphthalenyl-1H-indazole-3-carboxamide 30 October 2012
analogue
5F-AKB48 N-(1-Adamantyl)-1-(5-fluoropentyl)indazole-3-carboxamide 27 September 2012
AM-1248 1-Adamantyl-[1-[(1-methyl-2-piperidyl)methyl]indol-3-yl]methanone 24 September 2012
JWH-018 N-(5-bromopentyl) [1-(5-Bromopentyl)-1H-indol-3-yl](naphthalen-1-yl)methanone 31 July 2012
derivative
JWH-018 N-(5-chloropentyl) [1-(5-Chloropentyl)-1H-indol-3-yl](naphthalen-1-yl)methanone 31 July 2012
derivative
JWH-122 pentenyl 2-methylindole (4-Methyl-1-naphthyl)-(2-methyl-1-pent-4-enyl-indol-3-yl)methanone 18 July 2012
derivative
AM-694 methyl substituted for iodine [1-(5-Fluoropentyl)-1H-indol-3-yl](2-methylphenyl)methanone 18 July 2012
JWH-122 pentenyl derivative (4-Methylnaphthalen-1-yl)[1-(pent-4-en-1-yl)-1H-indol-3-yl]methanone 18 July 2012
AM-694 ethyl substituted for iodine (2-Ethylphenyl)[1-(5-fluoropentyl)-1H-indol-3-yl]methanone 18 July 2012
MAM-2201 chloropentyl derivative [1-(5-Chloropentyl)indol-3-yl]-(4-methyl-1-naphthyl)methanone 18 July 2012
AM-6527 1-Pentyl-N-(naphthalen-1-yl)-1H-indole-3-carboxamide 16 July 2012

64
 Synthetic cannabinoids in Europe – a review

Date of formal
Common name IUPAC name
notification
JWH-018 adamantyl carboxamide N-(1-Adamantyl)-1-pentyl-indole-3-carboximidic acid 13 July 2012
(Apica)
STS-135 N-(1-Adamantyl)-1-(5-fluoropentyl)indole-3-carboximidic acid 26 June 2012
UR-144 (-2H) [1-(Pent-4-en-1-yl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl) 14 June 2012
methanone
Apinaca N-(1-Adamantyl)-1-pentyl-1H-indazole-3-carboxamide 21 May 2012
A-796,260 [1-[2-(4-Morpholinyl)ethyl]-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)- 18 April 2012
methanone
5F-UR-144 (XLR-11) [1-(5-Fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone 30 March 2012
URB-754 6-Methyl-2-[(4-methylphenyl)amino]-4H-3,1-benzoxazin-4-one 27 February 2012
3-(p-Methoxybenzoyl)-N-methylindole (4-Methoxyphenyl)(1-methyl-1H-indol-3-yl)methanone 3 February 2012
Trans-CP-47,497-C8 5-(1,1-Dimethyloctyl)-2-[(1S,3S)-3-hydroxycyclohexyl]phenol 3 February 2012
UR-144 (1-Pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone 1 February 2012
JWH-370 1-Naphthyl-[5-(o-tolyl)-1-pentyl-pyrrol-3-yl]methanone 1 February 2012
AM-679 (2-Iodophenyl)(1-pentyl-1H-indol-3-yl)methanone 27 January 2012
WIN-55,212-2 [(3R)-2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4- 27 January 2012
benzoxazin-6-yl]-1-naphthalenyl-methanone
HU-331 3-Hydroxy-2-(6-isopropenyl-3-methyl-cyclohex-2-en-1-yl)-5-pentyl-1,4- 12 January 2012
benzoquinone
AM-694 chloro derivative [1-(5-Chloropentyl)-1H-indol-3-yl](2-iodophenyl)-methanone 21 December 2011
AM-2232 5-[3-(Naphthalen-1-ylcarbonyl)-1H-indol-1-yl]pentanenitrile 6 December 2011
JWH-022 1-Naphthyl-(1-pent-4-enylindol-3-yl)methanone 30 November 2011
Org 29647 N-(1-Benzylpyrrolidin-3-yl)-5-chloro-3-ethyl-1H-indole-2-carboxamide 5 August 2011
Org 27759 N-[2-[4-(Dimethylamino)phenyl]ethyl]-3-ethyl-5-fluoro-1H-indole-2- 5 August 2011
carboxamide
AM-2233 (2-Iodophenyl){1-[(1-methylpiperidin-2-yl)methyl]-1H-indol-3-yl}methanone 5 August 2011
Org 27569 5-Chloro-3-ethyl-N-[2-[4-(1-piperidinyl)phenyl]ethyl]-1H-indole-2- 5 August 2011
carboxamide
JWH-307 [5-(2-Fluorophenyl)-1-pentyl-pyrrol-3-yl]-(1-naphthyl)methanone 5 August 2011
JWH-412 (4-Fluoronaphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone 20 July 2011
JWH-387 (4-Bromonaphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone 20 July 2011
RCS-4(C4) (1-Butyl-1H-indol-3-yl)(4-methoxyphenyl)methanone 30 June 2011
MAM-2201 [1-(5-Fluoropentyl)indol-3-yl]-(4-methyl-1-naphthyl)methanone 20 June 2011
WIN-48,098 (pravadoline) (4-Methoxyphenyl)-[2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl] 26 May 2011
methanone
AM-1220 [1-[(1-Methyl-2-piperidinyl)methyl]-1H-indol-3-yl]-1-naphthalenyl- 25 May 2011
methanone
JWH-007 (2-Methyl-1-pentyl-indol-3-yl)-(1-naphthyl)methanone 25 May 2011
AM-1220 azepane isomer [1-(Hexahydro-1-methyl-1H-azepin-3-yl)-1H-indol-3-yl]-1-naphthalenyl- 25 May 2011
methanone
RCS-4 ortho isomer (2-Methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone 20 April 2011
JWH-250 1-(2-methylene-N-methyl- 2-(2-Methoxyphenyl)-1-[1-[(1-methyl-2-piperidyl)methyl]indol-3-yl] 17 March 2011
piperidyl) derivative ethanone
JWH-182 (1-Pentylindol-3-yl)-(4-propyl-1-naphthyl)methanone 1 March 2011
JWH-018 adamantoyl derivative 1-Adamantyl-(1-pentylindol-3-yl)methanone 22 February 2011
(AB-001)
JWH-251 2-(o-Tolyl)-1-(1-pentylindol-3-yl)ethanone 22 February 2011
AM-2201 [1-(5-Fluoropentyl)-1H-indol-3-yl](naphthalen-1-yl)methanone 18 January 2011
CRA-13 Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone 11 January 2011
3-(4-Hydroxymethylbenzoyl)-1- [4-(Hydroxymethyl)phenyl](1-pentyl-1H-indol-3-yl)methanone 9 November 2010
pentylindole
JWH-019 (1-Hexylindol-3-yl)-(1-naphthyl)methanone 26 October 2010
JWH-203 2-(2-Chlorophenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone 14 October 2010
JWH-210 (4-Ethyl-1-naphthyl)-(1-pentylindol-3-yl)methanone 22 September 2010
CP-47,497 (C8 C2) N/A 17 August 2010
JWH-015 (2-Methyl-1-propyl-1H-indol-3-yl)(naphthalen-1-yl)methanone 27 July 2010
JWH-122 (4-Methyl-1-naphthyl)-(1-pentylindol-3-yl)methanone 23 July 2010

65
Synthetic cannabinoids in Europe – a review

Date of formal
Common name IUPAC name
notification
AM-694 [1-(5-Fluoropentyl)-1H-indol-3-yl](2-iodophenyl)methanone 19 July 2010
JWH-073 methyl derivative (1-Butyl-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone 30 June 2010
JWH-081 (4-Methoxy-1-naphthyl)-(1-pentylindol-3-yl)methanone 2 June 2010
RCS-4 (4-Methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone 25 May 2010
JWH-200 [1-[2-(4-Morpholinyl)ethyl]-1H-indol-3-yl]-1-naphthalenyl-methanone 3 December 2009
JWH-250 2-(2-Methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone 6 October 2009
JWH-398 (4-Chloronaphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone 6 October 2009
HU-210 (6aR,10aR)-3-(1,1-Dimethylheptyl)-9-(hydroxymethyl)-6,6-dimethyl- 22 June 2009
6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol
JWH-073 (1-Butyl-1H-indol-3-yl)(naphthalen-1-yl)methanone 6 March 2009
CP-47,497 5-(1,1-Dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol 23 February 2009
JWH-018 Naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone 19 December 2008
JWH-302 2-(3-Methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone N/A
Methanandamide (5Z,8Z,11Z,14Z)-N-(2-Hydroxy-1-methyl-ethyl)icosa-5,8,11,14-tetraenamide N/A
JWH-412 5-fluoropentyl derivative (4-Fluoronaphthalen-1-yl)[1-(5-fluoropentyl)-1H-indol-3-yl]methanone N/A
5F-ADBICA N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indole-3- N/A
carboxamide

66
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About this publication

This report provides a technical review of the current

body of knowledge regarding synthetic cannabinoids
that are monitored by the EU Early Warning System.
The aim of this report is to strengthen situational
awareness of synthetic cannabinoids in Europe and to
help stakeholders prepare for, and respond to, public
health and social threats caused by such substances.

About the EMCDDA

The European Monitoring Centre for Drugs and Drug

Addiction (EMCDDA) is the central source and
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