Legal Highs or Illegal Highs? The pharmacology of …...designer drugs is ‘escalating out of...
Transcript of Legal Highs or Illegal Highs? The pharmacology of …...designer drugs is ‘escalating out of...
For peer review only
Legal Highs or Illegal Highs? The pharmacology of substances freely available over the internet and their
impact on public (ill)health.
Journal: BMJ Open
Manuscript ID: bmjopen-2012-000977
Article Type: Research
Date Submitted by the Author: 08-Mar-2012
Complete List of Authors: Ayres, Tammy; University of Leicester, Criminology; University of Leicester, Psychology Bond, John; University of Leicester, Chemistry
<b>Primary Subject Heading</b>:
Public health
Secondary Subject Heading: Health policy, Public health, Addiction, Global health
Keywords: EDUCATION & TRAINING (see Medical Education & Training), PUBLIC HEALTH, TOXICOLOGY, MEDICAL EDUCATION & TRAINING
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BMJ Open
For peer review only
Legal Highs or Illegal Highs? The pharmacology of substances freely available over the
internet and their impact on public (ill)health.
1
Article Summary:
Article Focus:
To analyse the chemical composition of substances brought over the internet, including the
legality of the active ingredients and if products differ between retailers.
To consider the medical implications and adverse health risks associated with legal highs
brought over the internet.
Key Messages:
The most recent examination of the composition of ‘legal highs’, conducted six months after
the introduction of the ban, found no presence of banned cathinone substitutes.
Our study shows that, eighteen months after the introduction of the ban, banned cathinone
substitutes are, readily available for purchase in the UK in large (1Kg) quantities with little
known about their clinical effects.
Strengths and Limitations:
The relatively small sample size (22 products) and the limited number of retailers sampled
in this research are a limitation of this study. However, this study does show that despite
being banned, illicit cathinones remain readily available over the internet, despite their
potential harmfulness.
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Abstract:
Objectives: Public Health England aims to improve the nation’s health and acknowledges
that health and wellbeing are influenced by wider society, particularly unhealthy lifestyles,
which include both problematic and recreational drug use. Recreational drug use has
changed recently to include a range of substances sold as ‘research chemicals’ but known
by users as ‘legal highs’ (legal alternatives to the most popular illicit recreational drugs),
which are of an unknown toxicity to humans and often include prohibited substances
controlled under the Misuse of Drugs Act 1971. Consequently the long-term effects on
users’ health and inconsistent, often illicit ingredients, means this group of drugs presents a
serious risk to public health both now and in the future. Therefore, the aim of this study is
to ascertain what is in legal highs, their legality and safety, while considering the potential
impact these synthetic substances might be having on public health.
Design: A total of 22 products were purchased from 5 different internet sites, 18 months
after the UK ban on substituted cathinones (such as mephedrone) was introduced in April
2010. Each substance was screened to determine its active ingredients using accepted
analytical techniques.
Results: Two products, both sold as NRG-2 from different internet suppliers, were found
to contain the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-
methylmethcathinone (4-MMC), the latter being present in much smaller quantities. The
physical appearance, packaging and chemical analysis of both products suggests they
originated from the same source. Although sold as research chemicals and labeled ‘not for
human consumption’ they are thinly disguised ‘legal highs’, available online in quantities
that vary from one gram to one kilogram.
Conclusions: Despite amendments to legislation, prohibited class B substances are still
readily available in large quantities over the internet. Our findings suggest that these
prohibited substances are being manufactured or imported into the UK on a large scale,
which has serious implications for public health and clinicians who are ill equipped to deal
with this newly emerging problem.
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Introduction
Public Health is inadvertently connected to wider society and the cultural nuances that
influence individual health and well being, which include drug use. From the public health
implications arising from increased heroin use in the 1980s to the more recent furore
surrounding legal highs, pharmacological leisure has always impacted on public health and
medical practitioners. The noughties are no different, as the culture of recreational drug
use has changed to include a group of substances known by users as ‘legal highs’ - a range
of chemical and herbal substitutes marketed as legal alternatives to the most popular but
illicit recreational drugs. Although herbal products (i.e. Salvia Divinorum, Damiana and
Kratom) are widely available, this research will focus on synthetic substances since their
increased popularity has caused a furore in the media and problems for the authorities
who are unable to act quickly enough to monitor and legislate on the vast array of new
substances being created in this burgeoning market. According to the International
Narcotic Control Board (INCB) the growth in production and distribution of these new
designer drugs is ‘escalating out of control’1 with their availability growing at an
unprecedented pace.2 Unlike traditional recreational drugs, little is known about the
chemical composition of these new substances, their toxicity or the long-term effects
associated with their use, meaning they pose a serious challenge to public health agencies
and has the potential to undermine the objectives of Public Health England. Although many
of the first generation of legal highs have been brought under the UK Misuse of Drugs Act
1971 (e.g. mephedrone, BZP and spice), there is some evidence to suggest little has
changed and banned substances are still being sold online under a new guise. Products are
frequently given new names and marketed as superior, but legal, alternatives to the banned
substances they purport to replace.3-6 It is not known how many of these new products
contain newly synthesised and legal chemicals and how many continue to contain illicit
substances like mephedrone, which has been linked to a number of deaths.
Despite the rapid growth in the production and sale of these synthesised chemical products
there is a dearth of research in this area. Excluding the recent research on synthetic
cannabinoids5, only three studies have analysed the chemical composition of legal highs;
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two4,6 within six weeks of the 2010 ban on substituted cathinones and one conducted six
months later3. The research conducted immediately after cathinones were brought under
the Misuse of Drugs Act in April 2010, found prohibited cathinone derivatives, including
mephedrone in 62∙5%4 and 83%6 of the legal highs tested. The same research also found
that 70% of the new generation of legal highs purporting to contain naphyrone (i.e. NRG-1
and NRG-2) and marketed as a legal alternative to mephedrone, actually contained a
mixture of banned cathinones, including mephedrone; the drug it was claiming to replace.
Only one of the NGR products tested contained naphyrone as advertised,4 illustrating that
although marketed as legal products, many of the substances sold were actually illegal.
However, it is possible these findings merely reflect retailers’ response to the ban and their
attempts to sell off surplus stock containing the prohibited cathinones,4 rather than their
widespread availability. Supporting this supposition and in contrast to the research
conducted immediately after the ban, research conducted six months later3 found no
cathinones in the NRG products tested. Instead the products contained piperazines (BZP
and 3-TFMPP) a substance banned in December 2009. Although, this provides erudite
evidence that illicit substances continue to be mis-sold as legal highs, it also demonstrates
the inconsistent and varied ingredients found in these products.8
Therefore the purpose of this study is to develop previous research and ascertain whether
cathinones, such as mephedrone, are still being sold under the guise of newly labelled legal
highs. By conducting the research at this time, the 2010 legislative controls prohibiting
cathinones can be expected to have taken effect and any old stock containing mephedrone
should have been sold. The emergence of forty-one new products in the last year2 also
indicates a prerequisite for continually analysing these substances to facilitate a better
understanding of these products and their potential impact on public health. Although
health professionals are aware of the problems associated with new drugs, the evidence
suggests they are not equipped to deal with these largely unknown synthetic substances.
However, before considering the potential impact legal highs might be having on public
health, our discussion commences with an overview of the research methods and the
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internet and their impact on public (ill)health.
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chemical analyses employed to ascertain the active ingredients present in each substance.
Subsequently this is followed by a discussion of the results, before considering the medical
implications of mislabelling and selling unknown, often illicit substances. Although these
findings have implications for the criminal justice system this paper focuses on the medical
implications and adverse health risks associated with legal highs.
Methods
The research investigated a range of second and third generation legal highs (products
created after the chemical structure of banned substances was modified to bypass the
legislation), which are available to purchase online. A total of 22 products marketed as
research chemicals, plant food or bath salts were purchased from five different internet
sites. All the products were purchased eighteen months after the April 2010 UK ban on
cathinone substitutes and fifteen months after the July 2010 ban on naphyrone. The
products were handled and tested by an analyst with a Chief Officer of Police’s delegated
authority to be in possession of controlled substances. The substances were stored in the
secure drug store of a local police force and retained by them for destruction at the
conclusion of the experiments.
Information concerning the marketing, packaging, ingredients, method of use, dosage and
warnings over use was noted. Each product was, in turn, analysed qualitatively using a
combination of two or more techniques outlined in table 1. For the FTIR and Raman
Spectroscopy, the products were analysed in solid form. Those products supplied as a
tablet were ground to a powder, whilst those supplied as a capsule were emptied. For both
NMR, 0∙1 gm of the powder was dissolved in 0∙6 ml of Deuterated chloroform (CDCl3) for
analysis.
[Insert Table 1]
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Results
The results of the analyses were compared with the information provided by the suppliers
and the legality of the active ingredients ascertained. This information is summarized in
Table 2.
[Insert Table 2]
Advertised Active Ingredients: Consistency in what you get?
The majority of products purchased (91%) provided information pertaining to the active
ingredients present in each substance (either on the website or packaging, or both),
although products purchased from three of the suppliers (A, B and D) did not adhere to the
advertised ingredients. Out of the twenty-two products supplied and analysed, 9% did not
list the active ingredients (Jolly Green Granules) and 23% did not contain the active
ingredients listed on the website or package. Instead of containing 17-alpha,21-Dihydroxy-
16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione-21-acetate, both of the NRG-3
products contained benzofuran (1-benzofuran-6-ylpropan-2-amine). This suggests that
the benzofuran mixture is being sold as a number of different products (benzofuran and
NRG-3), thus supporting previous research.3 Benzofuran was found in 27% of the products
and although it is chemically similar to amphetamines and MDMA, there is little scientific
information on its toxicity, its psychoactive properties or its effect on humans and their
health. Instead of the advertised ingredients, Benzocaine was found in three of the products
(MDAI and both Jolly Green Granules). Benzocaine is a local anaesthetic and a popular
cutting agent for cocaine. In contrast to earlier research4 there were no traces of
mephedrone in either of the Jolly Green Granules. However, both NRG-2 products
contained 4-methylethcathinone (4-MEC) with a smaller, trace, amount of 4-
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methylmethcathinone (4-MMC) or mephedrone, possibly as an unwanted contaminant,
making them illicit.
Legal Highs or Illegal Highs?
The majority of products (91%) were identified as containing either the active ingredients
stated on the packet or a chemical that is not controlled in the UK. Of the four NRG
products analysed further by 13C NMR to confirm their contents, only two were found to
contain the illicit compounds 4-methylethcathinone and 4-methylmethcathinone
(mephedrone). 4-methylethcathinone (4-MEC) is classified as a class B controlled
substance in the UK. Even though it is not named specifically on the class B drug list, it is a
substituted cathinone and therefore subject to the 2010 Misuse of Drugs Act Amendment.
4-MEC is structurally derived from cathinone by substitution in the phenyl ring with an
alkyl substituent and by substitution at the Nitrogen atom with an alkyl group (see figures
1 and 2).
[Insert Figure 1]
[Insert Figure 2]
The contaminant 4-methylmethcathinone (mephedrone) in NRG-2 , is also a substituted
cathinone and a class B controlled substance in the UK, subject to the 2010 Misuse of Drugs
Act Amendment (see figure 3).
[Insert Figure 3]
These findings show illicit cathinones are still being sold online as legal alternatives to
illicit substances, which was also a marketing tool used by all of the suppliers in this
research. Analogies were made between the substances for sale, and either the recently
banned cathinone, mephedrone, or illicit drugs like amphetamine, ecstasy (MDMA) or
ketamine.
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Variation between Retailers
The chemical composition of the products purchased from supplier A and supplier D were
identical, as was the packaging, indicating that either two websites are fronting the same
company, or that both companies purchase goods from the same source. Specifically, the
NRG-2 products tested from supplier A and D and the relative concentration of each
chemical suggested that they originated from the same source. If both suppliers A and D
obtained NRG-2 from the same source this suggests that, given the large quantities
available to purchase (up to one kilogram), the scale of production or importation of these
substances is alarming.
Suppliers varied on the information they provided in terms of contents, instructions on use
and whether the drug was labelled ‘not fit for human consumption’. Out of the twenty-two
products purchased, 68% contained the warning ‘not fit for human consumption’ on the
internet site, but all contained this warning on the packaging. Although 23% had
information on how to use the product, this was of little use if the user intended to ingest it,
as it related to feeding plants or conducting research (see table 2). The information
provided included ‘doses of 0.05g will give your plants incredible growth…to be dissolved
in water’ and ‘very small doses of this research chemical are required for legitimate
research, it is essential that your lab has access to scales that can weigh in increments of
ten milligrams (0∙01g)’. The majority of websites and drug packets contained no safety
information (77%) explaining how to use the substance or the recommended dose, which
is concerning since many of the substances purchased could be bought in amounts that
varied from one gram to one kilogram.
Discussion
This study has shown that substituted cathinones continue to be freely available for
purchase over the internet, some eighteen months after being classified as class B
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controlled substances in the UK. Two products, both sold as ‘NRG-2’ from different
internet suppliers, were found to contain the banned substituted cathinones 4-
methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being
present in trace quantities. The physical appearance, packaging and chemical analysis of
both of these products suggests they originated from the same source. Although sold as
research chemicals and labeled ‘not for human consumption’, neither product contained
the ingredients listed. Of the 22 products supplied and analyzed in this study, 9% did not
list the ingredients and 23% did not contain the ingredients listed on the website or
package, which means consumers are putting their health at risk since the ingredients are
inconsistent the chemical composition and subsequent drug interactions are unknown and
therefore potentially harmful. Disturbingly these substances are available to buy in
quantities of up to 1Kg, including those containing banned cathinones.
Strengths and weaknesses of this study in the wider context
Our study has employed a range of recognized analytical techniques to identify the active
ingredients in each of the products purchased. Whilst the analysis carried out here is not in
itself a weakness, the extent to which substituted cathinones are supplied to, possibly,
unsuspecting purchasers is still unknown. Thus, a limitation of this study is the relative
small sample size. Our study purchased and analyzed 22 random products from five
internet suppliers and, from the packaging and chemical analyses, two of these suppliers
appeared to be selling products from the same source. Thus, at best, we have analyzed
products from four different sources and only found banned substances in 2 of the
products. However, this is the first analysis of the composition and legal classification of
substances, sold under the banner of research chemicals, to be carried out within the last
twelve months, which is eighteen months after the April 2010 amendment to the 1971
Misuse of Drugs Act. Previous work was carried out within six weeks4,6 or six months3 of
the 2010 amendment. Also, the number of products tested here (22) is far in excess of the
number tested in the previous most recent study (7)3. Our findings also show that
research conducted immediately after the 2010 ban, which found cathinones in a number
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of legal highs4,6 that were being sold as ‘NRG’ (particularly NRG-1 and NRG-2) was not
merely indicative of the retailers’ attempts to sell off surplus stockpiles of mephedrone.
Instead, this research indicates that despite being brought under the Misuse of Drugs Act
1971, substituted cathinones are still being sold illegally over the internet, which has
serious public health implications. Therefore, the most significant difference between the
previous most recent research and this study is the identification that substituted
cathinones are still freely available in large quantitites.
Implications for clinicians and policymakers
Despite the perception that ‘legal’ means ‘safe’ to some users,9,10 synthetic drugs appear to
be more harmful than many of their more traditional illicit counterparts. Even though
drugs like benzofuran, bromo-dragonFLY and MPA (N-methyl-1-(thiophen-2-yl)propan-2-
amine) are legal to buy, little is known about the safety of these substances, how they
interact with other drugs, their long-term effects (psychologically and behaviourally) on
humans or their toxicity. This also applies to the banned drugs naphyrone,11-12
mephedrone13-14 and synthetic cannabinoids.15 Although there is emerging medical
research documenting the harmfulness of these synthetic substances11-16 there is also
evidence pertaining to the emergent health risks associated with legal anaesthetics, like
Benzocaine (which was found in three of the products tested here) and Lidocaine, which
are being sold in their place.4 Despite being widely used in pharmaceutical products,
allergic reactions to Benzocaine are common and ingesting more than the recommended
amount can cause an overdose. Benzocaine has also been linked to a toxic blood disorder
methemoglobinemia in adults who take small quantities medicinally17 and unknown
quantities illicitly in adulterated cocaine.18 The presence of Benzocaine in legal highs is well
documented.4,19 However it is never listed as one of the active ingredients and each product
contains indefinite quantities. Consequently the amount of Benzocaine being consumed by
the user is unknown, which is disturbing because research estimates that Benzocaine
induced methemoglobinemia is dose dependent and only 15-25mg/kg is needed to cause
cyanosis18 (a bluish discolouration of the skin caused by a deficiency of oxygen in the
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blood). Although, there have been no known deaths from Benzocaine, in 2010 the coroners
court in Ireland attributed the death of a teenager to cocaine containing four times the toxic
dose of Lidocaine,20 further illustrating the potential health risks arising from the varied
composition of these products.
The arbitrariness of the advertised ingredients exacerbates the detrimental consequences
for the health of the user. This research found the products purchased did not always
contain the advertised ingredients, replicating earlier research in this area,8 which has
consistently found different active ingredients in the same products brought from the
internet. The contents of the NRG products has varied substantially from one type of
cathinone, to a combination of four-five cathinones, to banned piperazines, to inorganic
material or Benzocaine. 3,4,6,28,29 Users are inadvertently being exposed to unidentified drugs
in unknown concentrations, which increases the risk of toxicity. Those repeatedly buying
the same product and expecting the same effects may actually be taking a completely
different and more potent substance. This not only has serious health implications in terms
of pharmacological intoxication and overdose, but also exposes the user to risks arising
from the potentiating effect of any drug interactions and their subsequent metabolites
produced inside the body. These risks are exacerbated further since users suffering from
any adverse effects brought on by these drugs are unlikely to be identified by clinicians, as
drug screening does not identify these new and unique compounds21 and despite recent
publications examining specific case studies of toxicity,22 little is scientifically known about
these drugs, and their toxicological detection in biological specimens is challenging.23 Since
only a small amount is need to elicit an effect, and the minimum amount that can be
purchased is one gram, users will continue to present themselves to A&E departments,
therefore medical practitioners need to be made more aware of these substances, their
effects and potential health risks. Even the healthcare professionals who are aware of the
problems associated with this new genre of drugs are not equipped to deal with the
problems as they arise due to the paucity of scientific and medical research in this area.
Since Public Health England recognises the ‘importance of having an effective, highly
trained and professionally skilled Public Health workforce’31 this is an area that needs
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addressing. Research and reliable medical data on legal highs is sparse there is no
‘centralised system…linking for instance toxicology and forensics across the country to
collate information’ despite requests for such a system.25
The public health risks associated with these drugs are compounded by the lack of safety
guidance (i.e. use and dosage information) provided by websites. All substances are
labelled as not fit for human consumption, with some advocating medical assistance if
swallowed; ‘hazard: not for human consumption, and if ingested consult medical
assistance’. While this does not seem to deter use and is seen by some users as a way of
evading the law and facilitating their sale online,24 in reality it means these substances can
be sold having undergone no checks and adhering to no regulations. If these substances
were marketed for human consumption they would be regulated either as a medicine (after
undergoing years of endless trials) or by the Food Standards Agency to make sure they
were safe for humans. As it stands, these substances could contain anything because the
legal highs market remains uncontrolled and unregulated. The burgeoning market in
synthetic drugs poses insurmountable challenges to clinicians attempting to identify and
diagnose the adverse health effects arising from the ingestion of un-researched, unknown
and unidentifiable chemicals.
Unanswered questions and future research
As this study was limited to analyzing just 22 products purchased from five different
internet suppliers, there remains the question of how many sites are selling products
containing banned substances, how widespread the purchase of these substituted
cathinones actually is and the extent to which they are being taken by unsuspecting
consumers. Since there is an estimated 314 online shops selling legal highs to ‘at least one
EU member state’30, about 80 of which are based in the UK, we sampled products from less
than 2% of these online suppliers. Therefore, future research should investigate a much
wider range of internet suppliers and their products to establish not only the chemical
composition of these substances but to help identify which products contain prohibited
substances like mephedrone. However, this research also highlights the need for more
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medical research to be conducted in this area, examining the potential impact legal highs
have on public health. It also shows that clinicians need specific training on these unknown
chemical substances and demonstrates a need for a centralised system, which collates and
stores information that medical practitioners can draw on when faced with a suspicious
case. Surprisingly there has been no public health campaign highlighting the risks
associated with these widely available synthetic substances, raising awareness among the
public or the medical profession, despite the potential risks to health.
Conclusion
Illicit cathinones continue to be sold online under the guise of ‘legal highs’. The imposition
of legislative controls banning certain substances has had little effect on the chemical
composition of legal highs or their availability, indicating that bringing in new laws on
drugs as quickly as they emerge is not tackling the problem of supply or demand. Instead it
displaces the problem and invites chemists to modify the molecular structure of chemicals
to create legal alternatives to the newly banned substances. The continual evolution of
chemical compounds designed to evade the law is potentially creating more dangerous and
unknown synthetic substances than the ones currently being legislated on. Although, these
substances are potentially more harmful than their illicit counterparts, many remain legal
to buy and consume, thus undermining the scientific calculation of harm that underpins
drug legislation and determines whether a substance is made illegal; a calculation, which
has come under increasing criticism in recent years.26-27 It also poses an infinite challenge
to mainstream healthcare professionals dealing with the adverse health effects arising from
these substances.
Although new substances are constantly being created to evade the law, illicit ones are also
being sold openly on the internet, indicating that the police are unable to enforce current
legislation and prohibit supply. Unsuspecting buyers are not only breaking the law but are
buying substances that are potentially harmful. The genre of legal highs has the potential
to cause serious public health problems to a new generation of drug users who see them as
a safer alternative to their illicit counterparts.9-10 The public health costs of treating users in
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the short- and long-term comes at a time of economic paucity and cut backs in the public
health sector. The medical profession are facing a new genre of legal high induced illnesses
and an increase in toxicity cases, but lack the methodology required to detect these drugs
(and their metabolites) in biological samples or recognise the symptoms of toxicity.
Prohibition is intended to protect public health by limiting the availability and use of drugs
like substituted cathinones. However, legislation would appear to be failing and is instead
simply displacing drug use. Users continue to consume an array of unknown synthetic
compounds and can easily purchase large amounts (1Kg) of illegal substances despite – and
perhaps entirely unaware of – the unpredictable consequences it may have on their health.
[Insert ‘what this paper adds’’ box]
Authors Contributions.
TA conceptualised the paper and applied for funding to conduct the research. JWB
conducted the chemical analysis of the substances. Both authors contributed to the writing,
argument and structure of the article including any revisions that have been made.
Conflicts of Interest
We have no conflicts of interest to declare.
Competing Interests Statement
We declare that we have no competing financial, professional or personal interests that
might have influenced the work described in this manuscript.
Data Sharing
There is no additional data available.
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Legal Highs or Illegal Highs? The pharmacology of substances freely available over the
internet and their impact on public (ill)health.
15
Role of Funding Source
Funding came from the University of Leicester, College of Social Sciences research grant.
The funding source had no role in the study design, analysis or in the writing up of the
research.
Ethics Committee Approval
This research received ethical approval from the Criminology department’s ethics
committee.
References
1 International Narcotic Control Board. Annual Report. New York: United Nations,
2011.
2 European Monitoring Centre for Drugs and Drug Addiction. Europol 2010 Annual
Report on the Implementation of Council Decision 2005/387/JHA. Lisbon: EMCDDA,
2011.
3 Baron M, Eile M, Eile, L. Analysis of Legal Highs – Do they contain what it says on the
tin? Drug Testing and Analysis, 2011.
4 Brandt SD, Sumnall HR, Measham F, Cole J. Analyses of second-generation 'legal
highs' in the UK: initial findings. Drug Testing and Analysis 2010; 2: 377–82.
5 Dargan PI, Hudson S, Ramsey J, Wood DM. The impact of changes in UK classification
of the synthetic cannabinoid receptor agonists in Spice. International Journal of Drug
Policy 2011; 22: 274-277.
6 Ramsey J, Dargan PI, Smyllie M, Davies S, Button J, Holt DW, Wood DM. Buying legal
recreational drugs does not mean that you are not breaking the law. QJ Med 2010;
103:777-783
7 Smith K, Flately J. Drug Misuse Declared: Findings from the 2010/11 British Crime
Survey (England and Wales). London: Home Office, 2011.
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internet and their impact on public (ill)health.
16
8 Davies S, Wood DM, Smith G, Button J, Ramsey J, Archer R, Holt DW, Dargan PI.
Purchasing legal highs on the internet – Is there consistency in what you get? QJ Med
2010; 103: 489-493.
9 Measham F, Moore K, Newcombe R, Welch Z. Tweaking, bombing dabbing and
stockpiling: The emergence of mephedrone and the perversity of prohibition. Drugs
and Alcohol Today 2010; 10: 14-21.
10 Sheridan J, Butler R. They’re legal so they’re safe right? International Journal of Drug
Policy 2010; 21: 77-81.
11 Advisory Council on the Misuse of Drugs. Consideration of the
Naphthylpyrovalerone Analogues and Related Compounds. London: ACMD, 2010.
12 De Paoli G, Maskell PD, Pounder DJ. Naphyrone: analytical profile of the new "legal
high" substitute for mephedrone. Journal of Forensic and Legal Medicine 2011; 18:
93.
13 Gibbons S, Zloh M. An analysis of the legal high mephedrone. Bioorganic and
Medicinal Chemistry Letters 2010; 20: 4135-4139.
14 Vardakou I, Pistos C, Spiliopoulou C. Drugs for youth via Internet and the example of
mephedrone. Toxicology Letters 2011.
15 EMCDDA. Understanding the Spice phenomenon. Lisbon: EMCDDA, 2009.
16 Wood DM, Looker JJ, Shaikh L, Button J, Puchnaewicz M, Davies S, Lidder S, Ramsey
J, Holt DW, Dargan PI. Seizures associated with recreational use of Bromo-
dragonFLY. Journal of Medical Toxicology 2009; 5: 226-229.
17 Osterweil N. Topical Benzocaine associated with Methemoglobinemia. Medscape
Today 2011.
18 McKinney CD, Postiglione KF, Herold DA. Benzocaine-adulterated Street Cocaine in
association with Methemoglobinemia. Clin. Chem 1992; 38: 596-597.
19 Power JD, McGlynn P, Clarke K, McDermott SD, Kavanagh P, O’Brien J. The analysis of
substituted Cathinones, part 1: chemical analysis of 2-,3-and 4-
methylmethcathinone. Forensic Science Journal 2011; 212: 6-12.
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internet and their impact on public (ill)health.
17
20 SOCA. Drug profits take a hammering as Benzocaine haul is burned. London:
Stationary Office, 2010. http://www.soca.gov.uk/news/260-drug-profits-take-a-
hammering-as-benzocaine-haul-is-burned- (accessed Sept 25, 2011).
21 Smith CPT, Cardile AP, Miller M. Bath salts as a legal high. The American Journal of
Medicine 2011.
22 Salmner EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O’Riordan, JI. A harmless
high? The Lancet 2010; 376: 742.
23 Forensic Magazine. Detecting bath salts. 25 October, 2011.
24 Ayres TC, Wilson A. Why legality matters: The influences making legal highs the
drug of choice. Paper presented at the York Deviance Conference, University of York,
2011.
25 Boyce N. Health warnings for people who use heroin. The Lancet, 2011; 377:193-
194.
26 Nutt D, King L, Phillips L. Drug harms in the UK: A multicriteria decision analysis.
The Lancet 2010; 376: 1558-1565.
27 Rolles S, Measham F. Questioning the method and utility of ranking drug harms in
drug policy. International of Drug Policy 2011; 22: 243-246.
28 Brandt SD, Freeman S, Sumnall HR, Measham F, Cole J. Analysis of NRG Legal Highs
in the UK: Identification and Formation of Novel Cathinones. Drug Testing and
Analysis 2011; 3: 569-575.
29 Brandt SD, Sumnall HR, Measham F, Cole J. The Confusing Case of NRG-1. The Lancet
2010; 341: 62.
30 EMCDDA. Annual Report 2011: The State of the Drugs Problem in Europe. Lisbon:
EMCDDA, 2011.
31 Anita Marshland. Public Health England: A Letter, London: Department of Health,
2011. http://bhamcf.files.wordpress.com/2010/10/nhs-pblchlthltr-11-3.pdf
(accessed December 20, 2011).
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Tables - BMJ
Table 1: Analysis techniques
Fourier Transform Infrared Spectroscopy (FTIR) Fourier Transform Infrared Spectroscopy analyses the composition of a
substance by measuring how much Infrared energy is absorbed by
different molecules, thereby enabling the molecules present to be
determined.
Raman Spectroscopy Raman Spectroscopy uses inelastic scattering of monochromatic light
(usually a laser) to excite vibrational modes of bonds in the sample that
result in a frequency shift of the emitted light, thereby enabling the
composition of the sample to be determined.
Proton Nuclear Magnetic Resonance (1H NMR) Proton Nuclear Magnetic Resonance uses the absorption of
electromagnetic waves by protons (H+ ions) in a magnetic field that
results in a frequency shift of the emitted electromagnetic waves to
enable the composition of the sample to be determined.
Carbon-13 NMR (13C NMR) Carbon-13 NMR employs the same principle as proton NMR but uses
resonance of the C13 atom rather than the proton.
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Table 2: Summary of the 22 legal highs purchased via the internet, including the compounds detected, the accuracy of their description
and their legal status.
Product Compounds Detected As
Described Status
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB) Yes Legal
Jolly Green
Granules
Benzocaine
Did not
specify
contents
Legal
MDAI
5,6-Methylenedioxy-2-aminoindane Yes Legal
Methoxetamine
2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone Yes Legal
MPA
N-methyl-1-(thiophen-2-yl)propan-
2-amine. Yes Legal
NRG-2
4-methylethcathinone (4-MEC).
Contaminant mephedrone. No Illegal
NRG-3
1-benzofuran-6-ylpropan-2-amine
(6-APB). No Legal
Su
pp
lie
r A
5-IAI
5-Iodo-2-aminoindane. Yes Legal
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB). Yes Legal
MDAI
Benzocaine. No Legal
Su
pp
lie
r B
5-IAI
5-Iodo-2-aminoindane. Yes Legal
Su
pp
l
ier
C Benzofury
1-benzofuran-6-ylpropan-2-amine. Yes Legal
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Methoxetamine
2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone. Yes Legal
Jolly Green
Granules
Benzocaine.
Did not
specify
contents
Legal
MDAI Gold
5,6-Methylenedioxy-2-aminoindane. Yes Legal
MPA
N-methyl-1-(thiophen-2-yl) propan-
2-amine. Yes Legal
NRG-2
4-methylethcathinone (4-MEC).
Contaminant mephedrone. No Illegal
NRG-3
1-benzofuran-6-ylpropan-2-amine
(6-APB). No Legal
Su
pp
lie
r D
5-IAI
5-Iodo-2-aminoindane. Yes Legal
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB). Yes Legal
MDAI Gold
5,6-Methylenedioxy-2-aminoindane. Yes Legal
Su
pp
lie
r E
Methoxetemine 2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone. Yes Legal
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross-sectional studies
Section/Topic Item
# Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 2
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 3
Objectives 3 State specific objectives, including any prespecified hypotheses 4-5
Methods
Study design 4 Present key elements of study design early in the paper 5
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection
NA
Participants
6
(a) Give the eligibility criteria, and the sources and methods of selection of participants NA
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
NA
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
5
Bias 9 Describe any efforts to address potential sources of bias 9
Study size 10 Explain how the study size was arrived at NA
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
NA
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 5
(b) Describe any methods used to examine subgroups and interactions NA
(c) Explain how missing data were addressed NA
(d) If applicable, describe analytical methods taking account of sampling strategy NA
(e) Describe any sensitivity analyses NA
Results
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Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed
NA
(b) Give reasons for non-participation at each stage NA
(c) Consider use of a flow diagram NA
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
NA
(b) Indicate number of participants with missing data for each variable of interest NA
Outcome data 15* Report numbers of outcome events or summary measures 6-8
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
NA
(b) Report category boundaries when continuous variables were categorized NA
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period NA
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 6-8
Discussion
Key results 18 Summarise key results with reference to study objectives 8
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
9, 12
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
8-12
Generalisability 21 Discuss the generalisability (external validity) of the study results 8-12
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
15
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet
and their impact on public (ill)health. Legal Highs or Illegal Highs?
Journal: BMJ Open
Manuscript ID: bmjopen-2012-000977.R1
Article Type: Research
Date Submitted by the Author: 01-May-2012
Complete List of Authors: Ayres, Tammy; University of Leicester, Criminology; University of Leicester, Psychology Bond, John; University of Leicester, Chemistry
<b>Primary Subject Heading</b>:
Public health
Secondary Subject Heading: Health policy, Pharmacology and therapeutics, Addiction, Global health
Keywords: EDUCATION & TRAINING (see Medical Education & Training), PUBLIC HEALTH, TOXICOLOGY, MEDICAL EDUCATION & TRAINING
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For peer review only
A chemical analysis examining the pharmacology of novel psychoactive substances freely
available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
1
Article Summary:
Article Focus:
To analyse the chemical composition of substances bought over the internet, including the
legality of the active ingredients and if products differ between retailers.
To consider the medical implications and adverse health risks associated with legal highs
bought over the internet.
Key Messages:
The most recent examination of the composition of ‘legal highs’, conducted six months after
the introduction of the ban, found no presence of banned cathinones.
Our study shows that, eighteen months after the introduction of the ban, illegal cathinone
substitutes are, readily available for purchase in the UK in large (1Kg) quantities with little
known about their clinical effects.
Strengths and Limitations:
The small number of products tested (22 products) and the limited number of retailers
sampled, are both limitations of this study. However, this study does show that despite
being banned, illegal cathinones remain readily available over the internet, despite their
potential harmfulness.
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A chemical analysis examining the pharmacology of novel psychoactive substances freely
available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
2
Abstract:
Objectives: Public Health England aims to improve the nation’s health and acknowledges
that unhealthy lifestyles, which include drug use, undermine society’s health and wellbeing.
Recreational drug use has changed to include a range of substances sold as ‘research
chemicals’ but known by users as ‘legal highs’ (legal alternatives to the most popular illicit
recreational drugs), which are of an unknown toxicity to humans and often include
prohibited substances controlled under the Misuse of Drugs Act (1971). Consequently the
long-term effects on users’ health and inconsistent, often illegal ingredients, means this
group of drugs presents a serious risk to public health both now and in the future.
Therefore, the aim of this study is to ascertain what is in legal highs, their legality and
safety, while considering the potential impact these synthetic substances might be having
on public health.
Design: A total of 22 products were purchased from 5 different internet sites, 18 months
after the UK ban on substituted cathinones, like mephedrone, was introduced in April 2010.
Each substance was screened to determine its active ingredients using accepted analytical
techniques.
Setting: The research was conducted in Leicestershire, but has implications for the
provision of primary and secondary health care throughout the UK.
Results: Two products, both sold as NRG-2 from different internet suppliers, were found
to contain the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-
methylmethcathinone (4-MMC), the latter being present in much smaller quantities.
Although sold as research chemicals and labeled ‘not for human consumption’ they are
thinly disguised ‘legal highs’, available online in quantities that vary from one gram to one
kilogram.
Conclusions: Despite amendments to legislation, prohibited class B substances are still
readily available in large quantities over the internet. Our findings suggest that these
prohibited substances are being manufactured or imported into the UK on a large scale,
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Highs?
3
which has serious implications for public health and clinicians who are ill-equipped to deal
with this newly emerging problem.
Introduction
Public Health is inadvertently connected to wider society and the cultural nuances that
influence individual health and well being, which include drug use. From the public health
implications arising from increased heroin use in the 1980s to the more recent furore
surrounding legal highs, pharmacological leisure has always impacted on public health and
medical practitioners. The noughties are no different, as the culture of recreational drug
use has changed to include a group of substances known by users as ‘legal highs’ but
referred to in the literature as ‘novel psychoactive substances’ (NPS)1 - a range of chemical
and herbal substitutes marketed as legal alternatives to the most popular but illicit
recreational drugs. Although herbal products (i.e. Salvia Divinorum, Damiana and Kratom)
are widely available, this research will focus on synthetic substances since their increased
popularity has caused a furore in the media and problems for the authorities who are
unable to act quickly enough to monitor and legislate on the vast array of new substances
being created in this burgeoning market. According to the International Narcotic Control
Board (INCB) the growth in production and distribution of these new designer drugs is
‘escalating out of control’2 with their availability growing at an unprecedented pace.3
Unlike traditional recreational drugs, little is known about the chemical composition of
these new substances, their toxicity or the long-term effects associated with their use,
meaning they pose a serious challenge to public health agencies and has the potential to
undermine the objectives of Public Health England. Many first generation legal highs (e.g.
mephedrone, piperazines and spice) have been brought under the Misuse of Drugs Act
(1971), the most recent being mephedrone, which was banned in April 2010, when the
Misuse of Drugs Act, 1971 (Amendment) Order categorised mephedrone and other
substituted cathinones as a Class B controlled drug. However, despite introducing
legislative controls over these drugs there is some evidence to suggest little has changed
and banned substances are still being sold online under a new guise. Products are
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A chemical analysis examining the pharmacology of novel psychoactive substances freely
available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
4
frequently given new names and marketed as superior, but legal, alternatives to the banned
substances they purport to replace.4-7 It is not known how many of these new products
contain newly synthesised and legal chemicals and how many continue to contain illegal
substances like mephedrone, which has been linked to a number of deaths.1 In an effort to
protect the public from the harmfulness of NPSs a new temporary class order has been
introduced, which prohibits the manufacture and supply of temporary class drugs for 12
months while the Advisory Council on the Misuse of Drugs (ACMD) assess it for permanent
control under the Misuse of Drugs Act (1971) (e.g. Methoxetamine was temporarily
classified in March 2012).
Despite the rapid growth in the production and sale of these synthesised chemical products
there is a dearth of research in this area. Excluding the recent research on synthetic
cannabinoids6, only three studies have analysed the chemical composition of legal highs;
two5,7 within six weeks of the 2010 ban on substituted cathinones and one conducted six
months later4. The research conducted immediately after cathinones were brought under
the Misuse of Drugs Act in April 2010, found prohibited cathinone derivatives, including
mephedrone in 62∙5%5 and 83%7 of the legal highs tested. The same research also found
that 70% of the new generation of legal highs purporting to contain naphyrone (i.e. NRG-1
and NRG-2) and marketed as a legal alternative to mephedrone, actually contained a
mixture of banned cathinones, including mephedrone; the drug it was claiming to replace.
Only one of the NGR products tested contained naphyrone as advertised,5 illustrating that
although marketed as legal products, many of the substances sold were actually illegal.
Although research conducted immediately after the ban5,7 found cathinones in the products
they tested it is possible these findings merely reflect retailers’ response to the ban and
their attempts to sell off surplus stock containing the prohibited cathinones,5 rather than
their widespread availability. Supporting this supposition and in contrast to the research
conducted immediately after the ban, research conducted six months later by Baron and
colleagues4 found no cathinones in the NRG products tested. Instead the products
contained piperazines (BZP: 1-benzylpiperazine and 3-TFMPP: 3-
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A chemical analysis examining the pharmacology of novel psychoactive substances freely
available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
5
trifluoromethylphenylpiperazine) a substance banned in December 2009. Although, this
provides erudite evidence that illegal substances continue to be mis-sold as legal highs, it
also demonstrates the inconsistent and varied ingredients found in these products.8
Therefore the purpose of this study is to develop previous research and ascertain whether
cathinones, such as mephedrone, are still being sold under the guise of newly labelled legal
highs eighteen months after they were banned. By conducting the research at this time we
overcome the caveats associated with earlier research, as the 2010 legislative controls
prohibiting cathinones should have taken effect and any old stock containing mephedrone
should have been sold during this period. The emergence of forty-one new products in the
last year3 and demands for ‘further characterisation of these products’5 also indicates a
prerequisite for continually analysing these substances to facilitate a better understanding
of these products, particularly their chemical composition, and their potential impact on
public health. Although health professionals are aware of the problems associated with
new drugs, the evidence suggests they are not equipped to deal with these largely unknown
synthetic substances. However, before considering the potential impact legal highs might
be having on public health, our discussion commences with an overview of the research
methods and the chemical analyses employed to ascertain the active ingredients present in
each substance. Subsequently this is followed by a discussion of the results, before
considering the medical implications of mislabelling and selling unknown, often illegal
substances. Although these findings have implications for the criminal justice system and
the prosecution of users under the Misuse of Drugs Act (1971), this is beyond the remit of
this paper, which focuses on the medical implications and adverse health risks associated
with legal highs.
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A chemical analysis examining the pharmacology of novel psychoactive substances freely
available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
6
Methods
The research investigated a range of second and third generation legal highs (products
created after the chemical structure of banned substances was modified to bypass the
legislation), which are available to purchase online. A total of 22 products marketed as
research chemicals, plant food or bath salts were purchased from five different internet
sites. The five internet sites were randomly selected from an online list generated using
the terms ‘buying research chemicals’, ‘buying plant food’ and ‘buying NRG2’; the list was
generated from the first ten results on each page. A list of products available from more
than two of the sites (to facilitate comparisons) was generated and eight products were
randomly chosen for this research. All the products were purchased eighteen months after
the April 2010 UK ban on cathinone substitutes and fifteen months after the July 2010 ban
on naphyrone. The products were handled and tested by an analyst with a Chief Officer of
Police’s delegated authority to be in possession of controlled substances. The substances
were stored in the secure drug store of a local police force and retained by them for
destruction at the conclusion of the experiments.
Information concerning the marketing, packaging, ingredients, method of use, dosage and
warnings over use was noted. Each product was, in turn, analysed qualitatively using a
combination of the techniques outlined in table 1. Each product was analysed with FTIR,
Raman Spectroscopy and Proton NMR. Additionally, where there was an indication from
the spectroscopy that a product contained an illegal substance, that product was analysed
with 13C NMR. For the FTIR and Raman Spectroscopy, the products were analysed in solid
form. Those products supplied as a tablet were ground to a powder, whilst those supplied
as a capsule were emptied. For both NMR, 0∙1 gm of the powder was dissolved in 0∙6 ml of
Deuterated chloroform (CDCl3) for analysis. All instruments were calibrated using
calibration sources and correction software supplied by the manufacturers. No specific
comparison with reference standards for the illegal chemicals identified was undertaken.
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[Insert Table 1]
Results
The results of the analyses were compared with the information provided by the suppliers
and the legality of the active ingredients ascertained. This information is summarized in
Table 2. Although, methoxetamine was legal when the research was conducted, it was
classified as a temporary class drug in March 2012, making its supply illegal.
[Insert Table 2]
Advertised Active Ingredients: Consistency in what you get?
The majority of products purchased (91%) provided information pertaining to the active
ingredients present in each substance (either on the website or packaging, or both),
although products purchased from three of the suppliers (A, B and D) did not adhere to the
advertised ingredients. Out of the twenty-two products supplied and analysed, 9% did not
list the active ingredients (Jolly Green Granules) and 23% did not contain the active
ingredients listed on the website or package. Instead of containing 17-alpha,21-Dihydroxy-
16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione-21-acetate, both of the NRG-3
products contained benzofuran (1-benzofuran-6-ylpropan-2-amine). This suggests that
the benzofuran mixture is being sold as a number of different products (benzofuran and
NRG-3), thus supporting previous research.4 Benzofuran was found in 27% of the products
and although it is chemically similar to amphetamines and MDMA, there is little scientific
information on its toxicity, its psychoactive properties or its effect on humans and their
health. Instead of the advertised ingredients, Benzocaine was found in three of the products
(MDAI and both Jolly Green Granules). Benzocaine is a local anaesthetic and a popular
cutting agent for cocaine. In contrast to earlier research5 there were no traces of
mephedrone in either of the Jolly Green Granules. However, both NRG-2 products
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contained 4-methylethcathinone (4-MEC) with a smaller, trace, amount of 4-
methylmethcathinone (4-MMC) or mephedrone, possibly as an unwanted contaminant,
making them illegal. By measuring the integrated intensities of the Proton NMR9
resonances, the relative concentration of 4-MEC was approximately 35 times that of 4-
MMC. Consistent with the findings of Brandt et al.,5 no other compounds were found in
either NRG-2 samples. Therefore, the product being sold is of a high purity and the amount
of illegal cathinone taken is simply the quantity of powder consumed.
Legal Highs or Illegal Highs?
The majority of products (91%) were identified as containing either the active ingredients
stated on the packet or a chemical that is not controlled in the UK. Of the four NRG
products analysed further by 13C NMR to confirm their contents, only two were found to
contain the illegal compounds 4-methylethcathinone and 4-methylmethcathinone
(mephedrone). 4-methylethcathinone (4-MEC) is classified as a class B controlled
substance in the UK. Even though it is not named specifically on the class B drug list, it is a
substituted cathinone and therefore subject to the 2010 Misuse of Drugs Act (Amendment)
Order. 4-MEC is structurally derived from cathinone by substitution in the phenyl ring
with an alkyl substituent and by substitution at the Nitrogen atom with an alkyl group (see
figures 1 and 2).
[Insert Figure 1]
[Insert Figure 2]
The contaminant 4-methylmethcathinone (mephedrone) in NRG-2 , is also a substituted
cathinone and a class B controlled substance in the UK, subject to the 2010 Misuse of Drugs
Act (Amendment)Order (see figure 3).
[Insert Figure 3]
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These findings show illegal cathinones are still being sold online as legal alternatives to
illegal substances, which was also a marketing tool used by all of the suppliers in this
research. Analogies were made between the substances for sale, and either the recently
banned cathinone, mephedrone, or illegal drugs like amphetamine, ecstasy (MDMA) or
ketamine.
Variation between Retailers
The chemical composition of the products purchased from supplier A and supplier D were
identical, as was the packaging, indicating that either two websites are fronting the same
company, or that both companies purchase goods from the same source. Specifically, the
NRG-2 products tested from supplier A and D and the relative concentration of each
chemical suggested that they originated from the same source. If both suppliers A and D
obtained NRG-2 from the same source this suggests that, given the large quantities
available to purchase (up to one kilogram), the scale of production or importation of these
substances is alarming.
Suppliers varied on the information they provided in terms of contents, instructions on use
and whether the drug was labelled ‘not fit for human consumption’. Out of the twenty-two
products purchased, 68% contained the warning ‘not fit for human consumption’ on the
internet site, but all contained this warning on the packaging. Although 23% had
information on how to use the product, this was of little use if the user intended to ingest it,
as it related to feeding plants or conducting research (see table 2). The information
provided included ‘doses of 0.05g will give your plants incredible growth…to be dissolved
in water’ and ‘very small doses of this research chemical are required for legitimate
research, it is essential that your lab has access to scales that can weigh in increments of
ten milligrams (0∙01g)’. The majority of websites and drug packets contained no safety
information (77%) explaining how to use the substance or the recommended dose, which
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is concerning since many of the substances purchased could be bought in amounts that
varied from one gram to one kilogram.
Discussion
This study has shown that substituted cathinones continue to be freely available for
purchase over the internet, eighteen months after being classified as a class B drug. Two
products, both sold as ‘NRG-2’ from different internet suppliers, were found to contain the
banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-
methylmethcathinone (4-MMC), the latter being present in trace quantities. The physical
appearance, packaging, labeling (not for human consumption) and chemical analysis of
these products suggest they originated from the same source; although neither product
contained the ingredients listed. In contrast to previous research5,7 the majority (68%) of
substances tested in this study contained the stated active ingredients. Of the 22 products
supplied and analyzed, 9% did not list the ingredients and 23% did not contain the
ingredients listed on the website or package, which means consumers are putting their
health at risk. The inconsistent ingredients, varied chemical composition and unknown
subsequent drug interactions are potentially harmful to the user, particularly since these
substances are of a high purity and available to buy in large quantities (up to 1Kg).
Strengths and weaknesses of this study in the wider context
Our study employed a range of recognized analytical techniques to identify the active
ingredients in each of the products purchased. While the analysis carried out here is not in
itself a weakness, a limitation of this study is the relatively small sample size. Our study
purchased and analyzed 22 random products from five internet suppliers and, from the
packaging and chemical analyses, two of these suppliers appeared to be selling products
from the same source. Thus, at best, we have analyzed products from four different
sources and only found banned substances in 2 of the products. However, this is the first
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analysis of the composition and legal classification of substances, sold under the banner of
research chemicals, to be carried out within the last twelve months. Also, the number of
products tested here (22) is far in excess of the number tested in the previous most recent
study (7)4, which failed to find cathinones in any of their products. Our research also
overcomes the caveats associated with previous work carried out within six weeks5,7 or six
months4 of the 2010 amendment. Our findings show that research conducted immediately
after the 2010 ban, which found cathinones in a number of legal highs4,6 was not merely
indicative of the retailers’ attempts to sell off surplus stockpiles of mephedrone. Instead,
this research indicates that despite being brought under the Misuse of Drugs Act (1971),
substituted cathinones are still being sold illegally over the internet. Although the extent to
which substituted cathinones are supplied is still unknown, finding cathinones in the small
sample of products tested here indicates the widespread distribution of cathinones over
the internet is highly probable.
Implications for clinicians and policymakers
Despite the perception that ‘legal’ means ‘safe’ to some users,10,11 novel psychoactive
substances (NPS) appear to be more harmful than many of their more traditional illegal
counterparts. Even though drugs like benzofuran, bromo-dragonFLY and MPA (N-methyl-
1-(thiophen-2-yl)propan-2-amine) are legal to buy, little is known about the safety of these
substances, how they interact with other drugs, their long-term effects (psychologically and
behaviourally) on humans or their toxicity. This also applies to the banned drugs
naphyrone,12-13 synthetic cannabinoids14 and mephedrone.15-17 Users of substituted
cathinones like mephedrone are presenting to hospitals with tachycardia (rapid heart
rate), hypertension, chest pains, myoclunus (muscle contractions), hallucinations, paranoia,
violence and sympathomimetic syndrome.17 Although there is emerging medical research
documenting the harmfulness of NPSs12-18 there is also evidence pertaining to the emergent
health risks associated with legal anaesthetics, like Benzocaine and Lidocaine, which are
being sold in their place.5 Allergic reactions to Benzocaine are common and ingesting more
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than the recommended amount can cause an overdose, particularly in susceptible
individuals, because there is ‘no therapeutic window (between the doses required to
produce a therapeutic effect and those producing toxicity).19 Benzocaine has also been
linked to a toxic blood disorder methemoglobinemia in adults who take small quantities
medicinally20 and unknown quantities illicitly in adulterated cocaine.21 The presence of
Benzocaine in legal highs is well documented.5,22 However, it is never listed as one of the
active ingredients meaning each product contains indefinite quantities, which is disturbing
since research estimates that Benzocaine induced methemoglobinemia only requires a
small amount to cause cyanosis19,23 (a bluish discolouration of the skin caused by a
deficiency of oxygen in the blood). Although, there have been no known deaths from
Benzocaine, the death of a teenager was attributed to cocaine containing four times the
toxic dose of Lidocaine,24 illustrating the potential health risks arising from the varied
composition of these products.
The arbitrariness of the advertised ingredients and mislabelling of products exacerbates
the detrimental consequences for the health of the user. Products do not always contain the
advertised active ingredients,8 even those with the same name. The contents of the NRG
products has varied substantially from one type of cathinone, to a combination of
cathinones, to banned piperazines, to inorganic material or Benzocaine. 4,5,7,25,26 Users are
inadvertently being exposed to unidentified drugs in unknown concentrations, which
increase the risk of toxicity and overdose. Those repeatedly buying the same product and
expecting the same effects may actually be taking a completely different and more potent
substance. The user is also exposed to the risks arising from the potentiating effect of any
drug interactions and their subsequent metabolites produced inside the body. However,
any adverse effects brought on by these drugs are unlikely to be identified by clinicians, as
drug screening does not identify these new and unique compounds27 and despite recent
publications examining specific toxicity case studies,28 their toxicological detection in
biological specimens is challenging.29 Since only a small amount is need to elicit an effect,
and the minimum amount that can be purchased is one gram, users will continue to present
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themselves to A&E departments across the country. Medical practitioners need to be made
more aware of these substances, their effects and potential health risks. The healthcare
professionals who are aware of the problems associated with NPSs are ill-equipped to deal
with them due to the paucity of scientific and medical research in this area. Since Public
Health England recognises the ‘importance of having an effective, highly trained and
professionally skilled Public Health workforce’30 this is an area that needs addressing.
Research and reliable medical data on NPSs are sparse and despite requests there is no
‘centralised system…linking for instance toxicology and forensics across the country to
collate information’.31
The public health risks associated with these drugs are compounded by the lack of safety
guidance (i.e. use and dosage information) provided by websites. All substances are
labelled as not fit for human consumption, with some advocating medical assistance if
swallowed. While this does not seem to deter use, it means NPSs can be sold having
undergone no checks and adhering to no regulations, which means they could contain
anything. Therefore the growth in NPSs poses insurmountable challenges to clinicians
attempting to identify and diagnose the adverse health effects arising from the ingestion of
un-researched, unknown and unidentifiable chemicals.
Unanswered questions and future research
The small sample (22 products) analysed in this study means the question of how many
sites are selling products containing banned substances, how widespread the purchase of
these substituted cathinones actually is and the extent to which they are being taken by
unsuspecting consumers remains unknown. Since there is an estimated 314 online shops,32
about 80 of which are based in the UK, we sampled products from less than 2% of these
online suppliers. Therefore, future research should investigate a much wider range of
internet suppliers and their products to establish not only the chemical composition of
these substances but to help identify which products contain prohibited substances like
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mephedrone. Future research could also usefully investigate low level contaminants in
these substances, not least as a possible means of linking sites of manufacture. There is a
need for more medical research to be conducted in this area examining the potential
impact NPSs have on public health. This article illustrates more training for clinicians is
required and demonstrates the need for a centralised system, which collates and stores
information that medical practitioners can draw on when faced with a suspicious case.
Surprisingly there has been no public health campaign highlighting the risks associated
with NPSs, to raise awareness among the public or the medical profession, despite the
potential risks to health.
Conclusion
Illicit cathinones continue to be sold online under the guise of ‘legal highs’. The imposition
of legislative controls banning certain substances has had little effect on the chemical
composition of novel psychoactive substances or their availability, indicating that bringing
in new laws on drugs as quickly as they emerge is not tackling the problem of supply (or
demand). Instead it displaces the problem and invites chemists to modify the molecular
structure of chemicals to create legal alternatives to the newly banned substances. The
continual evolution of chemical compounds designed to evade the law is potentially
creating more dangerous and unknown synthetic substances than the ones currently being
legislated on. Although, these substances are potentially more harmful than their illegal
counterparts, many remain legal to buy and consume, thus undermining the scientific
calculation of harm that underpins drug legislation; a calculation, which has come under
increasing criticism in recent years.33-34 It also poses an infinite challenge to mainstream
healthcare professionals dealing with the adverse health effects arising from these
substances.
Although new substances are constantly being created to evade the law, illegal ones are
also being sold openly on the internet, indicating that the police are unable to enforce
current legislation and prohibit supply. Unsuspecting buyers are not only breaking the law
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but are buying substances that are potentially harmful. Novel psychoactive substances
(NPS) have the potential to cause serious public health problems to a new generation of
drug users who see them as a safer alternative to their illicit counterparts.10-11 The public
health costs of treating users in the short- and long-term comes at a time of economic
paucity and cut backs in the public health sector. The medical profession are facing a new
genre of NPS induced illnesses and an increase in toxicity cases, but lack the methodology
required to detect these drugs (and their metabolites) in biological samples or recognise
the symptoms of toxicity. Prohibition is intended to protect public health by limiting the
availability and use of drugs like substituted cathinones. However, legislation would appear
to be failing and is simply displacing drug use. Users continue to consume an array of
unknown synthetic compounds and can easily purchase large amounts (1Kg) of illegal
substances despite – and perhaps entirely unaware of – the unpredictable consequences it
may have on their health.
[Insert ‘what this paper adds’ box]
Authors Contributions.
TA conceptualised the paper and applied for funding to conduct the research. JWB
conducted the chemical analysis of the substances. Both authors contributed to the writing,
argument and structure of the article including any revisions that have been made.
Competing Interests Statement
We declare that we have no competing financial, professional or personal interests that
might have influenced the work described in this manuscript.
Data Sharing
There is no additional data available.
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Role of Funding Source
Funding came from the University of Leicester, College of Social Sciences research grant.
The funding source had no role in the study design, analysis or in the writing up of the
research.
Ethics Committee Approval
This research received ethical approval (reference tca2-88995) from the Criminology
department’s ethics committee.
References
1 Advisory Council on the Misuse of Drugs. Consideration of the Novel Psychoactive
Substances (Legal Highs). London: ACMD, 2011.
2 International Narcotic Control Board. Annual Report. New York: United Nations,
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3 European Monitoring Centre for Drugs and Drug Addiction. Europol 2010 Annual
Report on the Implementation of Council Decision 2005/387/JHA. Lisbon: EMCDDA,
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4 Baron M, Eile M, Eile, L. Analysis of Legal Highs – Do they contain what it says on the
tin? Drug Testing and Analysis, 2011.
5 Brandt SD, Sumnall HR, Measham F, et al. Analyses of second-generation 'legal highs'
in the UK: initial findings. Drug Testing and Analysis 2010; 2: 377–82.
6 Dargan PI, Hudson S, Ramsey J, et al. The impact of changes in UK classification of
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7 Ramsey J, Dargan PI, Smyllie M, et al. Buying legal recreational drugs does not mean
that you are not breaking the law. QJ Med 2010; 103:777-783
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Highs?
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8 Davies S, Wood DM, Smith G, et al. Purchasing legal highs on the internet – Is there
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10 Measham F, Moore K, Newcombe R, et al. Tweaking, bombing dabbing and
stockpiling: The emergence of mephedrone and the perversity of prohibition. Drugs
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11 Sheridan J, Butler R. They’re legal so they’re safe right? International Journal of Drug
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12 Advisory Council on the Misuse of Drugs. Consideration of the
Naphthylpyrovalerone Analogues and Related Compounds. London: ACMD, 2010.
13 De Paoli G, Maskell PD, Pounder DJ. Naphyrone: analytical profile of the new "legal
high" substitute for mephedrone. Journal of Forensic and Legal Medicine 2011; 18:
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14 EMCDDA. Understanding the Spice phenomenon. Lisbon: EMCDDA, 2009.
15 Gibbons S, Zloh M. An analysis of the legal high mephedrone. Bioorganic and
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17 Spiller HA, Ryan ML, Weston RG, et al. Clinical experience with and analytical
confirmation of bath salts and legal highs (synthetic cathinones) in the United
States. Clinical Toxicology 2011; 49: 499-505.
18 Wood DM, Looker JJ, Shaikh L, et al. Seizures associated with recreational use of
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19 Guay J. Methemoglobinemia related to local anaesthetics: a summary of 242
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20 Osterweil N. Topical Benzocaine associated with Methemoglobinemia. Medscape
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21 Hunter L, Gordge L, Dargan PI, et al. Methemoglobinemia associated with the use of
cocaine and volatile nitrates in recreational drugs: a review. British Journal of
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22 Power JD, McGlynn P, Clarke K, et al. The analysis of substituted Cathinones, part 1:
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23 McKinney CD, Postiglione KF, Herold DA. Benzocaine-adulterated Street Cocaine in
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24 SOCA. Drug profits take a hammering as Benzocaine haul is burned. London:
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29 Forensic Magazine. Detecting bath salts. 25 October, 2011.
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34 Rolles S, Measham F. Questioning the method and utility of ranking drug harms in
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Article Summary:
Article Focus:
To analyse the chemical composition of substances bought over the internet, including the
legality of the active ingredients and if products differ between retailers.
To consider the medical implications and adverse health risks associated with legal highs
bought over the internet.
Key Messages:
The most recent examination of the composition of ‘legal highs’, conducted six months after
the introduction of the ban, found no presence of banned cathinones.
Our study shows that, eighteen months after the introduction of the ban, illegal cathinone
substitutes are, readily available for purchase in the UK in large (1Kg) quantities with little
known about their clinical effects.
Strengths and Limitations:
The small number sample size of products tested (22 products) and the limited number of
retailers sampled, in this research areare botha limitations of this study. However, this
study does show that despite being banned, illegal cathinones remain readily available over
the internet, despite their potential harmfulness.
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Abstract:
Objectives: Public Health England aims to improve the nation’s health and acknowledges
that health and wellbeing are influenced by wider society, particularly unhealthy lifestyles,
which include both problematic and recreational drug usedrug use, undermine society’s
health and wellbeing. Recreational drug use has changed recently to include a range of
substances sold as ‘research chemicals’ but known by users as ‘legal highs’ (legal
alternatives to the most popular illicit recreational drugs), which are of an unknown
toxicity to humans and often include prohibited substances controlled under the Misuse of
Drugs Act ( 1971). Consequently the long-term effects on users’ health and inconsistent,
often illegal ingredients, means this group of drugs presents a serious risk to public health
both now and in the future. Therefore, the aim of this study is to ascertain what is in legal
highs, their legality and safety, while considering the potential impact these synthetic
substances might be having on public health.
Design: A total of 22 products were purchased from 5 different internet sites, 18 months
after the UK ban on substituted cathinones, like (such as mephedrone, ) was introduced in
April 2010. Each substance was screened to determine its active ingredients using
accepted analytical techniques.
Setting: The research was conducted in Leicestershire, but has implications for the
provision of primary and secondary health care throughout the UK.
Results: Two products, both sold as NRG-2 from different internet suppliers, were found
to contain the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-
methylmethcathinone (4-MMC), the latter being present in much smaller quantities. The
physical appearance, packaging and chemical analysis of both products suggests they
originated from the same source. Although sold as research chemicals and labeled ‘not for
human consumption’ they are thinly disguised ‘legal highs’, available online in quantities
that vary from one gram to one kilogram.
Conclusions: Despite amendments to legislation, prohibited class B substances are still
readily available in large quantities over the internet. Our findings suggest that these
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prohibited substances are being manufactured or imported into the UK on a large scale,
which has serious implications for public health and clinicians who are ill-equipped to deal
with this newly emerging problem.
Introduction
Public Health is inadvertently connected to wider society and the cultural nuances that
influence individual health and well being, which include drug use. From the public health
implications arising from increased heroin use in the 1980s to the more recent furore
surrounding legal highs, pharmacological leisure has always impacted on public health and
medical practitioners. The noughties are no different, as the culture of recreational drug
use has changed to include a group of substances known by users as ‘legal highs’ but
referred to in the literature as ‘novel psychoactive substances’ (NPS)1 - a range of chemical
and herbal substitutes marketed as legal alternatives to the most popular but illicit
recreational drugs. Although herbal products (i.e. Salvia Divinorum, Damiana and Kratom)
are widely available, this research will focus on synthetic substances since their increased
popularity has caused a furore in the media and problems for the authorities who are
unable to act quickly enough to monitor and legislate on the vast array of new substances
being created in this burgeoning market. According to the International Narcotic Control
Board (INCB) the growth in production and distribution of these new designer drugs is
‘escalating out of control’2 with their availability growing at an unprecedented pace.3
Unlike traditional recreational drugs, little is known about the chemical composition of
these new substances, their toxicity or the long-term effects associated with their use,
meaning they pose a serious challenge to public health agencies and has the potential to
undermine the objectives of Public Health England. MAlthough many first generation legal
highs (e.g. mephedrone, piperazines and spice) have been brought under the Misuse of
Drugs Act (1971), the most recent being (e.g. mephedrone, which was banned in April
2010, when the Misuse of Drugs Act, 1971 (Amendment) Order categorised mephedrone
and other substituted cathinones as a Class B controlled drugmephedrone, BZP and spice.
However, despite introducing legislative controls over these drugs ), there is some
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evidence to suggest little has changed and banned substances are still being sold online
under a new guise. Products are frequently given new names and marketed as superior, but
legal, alternatives to the banned substances they purport to replace.4-7 It is not known how
many of these new products contain newly synthesised and legal chemicals and how many
continue to contain illegal substances like mephedrone, which has been linked to a number
of deaths.1 In an effort to protect the public from the harmfulness of NPSs a new temporary
class order has been introduced, which prohibits the manufacture and supply of temporary
class drugs for 12 months while the Advisory Council on the Misuse of Drugs (ACMD)
assess it for permanent control under the Misuse of Drugs Act (1971) (e.g. Methoxetamine
was temporarily classified in March 2012).
Despite the rapid growth in the production and sale of these synthesised chemical products
there is a dearth of research in this area. Excluding the recent research on synthetic
cannabinoids6, only three studies have analysed the chemical composition of legal highs;
two5,7 within six weeks of the 2010 ban on substituted cathinones and one conducted six
months later4. The research conducted immediately after cathinones were brought under
the Misuse of Drugs Act in April 2010, found prohibited cathinone derivatives, including
mephedrone in 62∙5%5 and 83%7 of the legal highs tested. The same research also found
that 70% of the new generation of legal highs purporting to contain naphyrone (i.e. NRG-1
and NRG-2) and marketed as a legal alternative to mephedrone, actually contained a
mixture of banned cathinones, including mephedrone; the drug it was claiming to replace.
Only one of the NGR products tested contained naphyrone as advertised,5 illustrating that
although marketed as legal products, many of the substances sold were actually illegal.
Although research conducted immediately after the ban5,7 found cathinones in the products
they tested However, it is possible these findings merely reflect retailers’ response to the
ban and their attempts to sell off surplus stock containing the prohibited cathinones,5
rather than their widespread availability. Supporting this supposition and in contrast to
the research conducted immediately after the ban, research conducted six months later by
Baron and colleagues4 found no cathinones in the NRG products tested. Instead the
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products contained piperazines (BZP: 1-benzylpiperazine and 3-TFMPP: 3-
trifluoromethylphenylpiperazine) a substance banned in December 2009. Although, this
provides erudite evidence that illegal substances continue to be mis-sold as legal highs, it
also demonstrates the inconsistent and varied ingredients found in these products.8
Therefore the purpose of this study is to develop previous research and ascertain whether
cathinones, such as mephedrone, are still being sold under the guise of newly labelled legal
highs eighteen months after they were banned. By conducting the research at this time we
overcome the caveats associated with earlier research, as the 2010 legislative controls
prohibiting cathinones should can be expected to have taken effect and any old stock
containing mephedrone should have been sold during this period. The emergence of forty-
one new products in the last year3 and demands for ‘further characterisation of these
products’5 also indicates a prerequisite for continually analysing these substances to
facilitate a better understanding of these products, particularly their chemical composition,
and their potential impact on public health. Although health professionals are aware of the
problems associated with new drugs, the evidence suggests they are not equipped to deal
with these largely unknown synthetic substances. However, before considering the
potential impact legal highs might be having on public health, our discussion commences
with an overview of the research methods and the chemical analyses employed to ascertain
the active ingredients present in each substance. Subsequently this is followed by a
discussion of the results, before considering the medical implications of mislabelling and
selling unknown, often illegal substances. Although these findings have implications for the
criminal justice system and the prosecution of users under the Misuse of Drugs Act (1971),
this is beyond the remit of this paper, which focuses on the medical implications and
adverse health risks associated with legal highs.
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Methods
The research investigated a range of second and third generation legal highs (products
created after the chemical structure of banned substances was modified to bypass the
legislation), which are available to purchase online. A total of 22 products marketed as
research chemicals, plant food or bath salts were purchased from five different internet
sites. The five internet sites were randomly selected from an online list generated using
the terms ‘buying research chemicals’, ‘buying plant food’ and ‘buying NRG2’; the list was
generated from the first ten results on each page. A list of products available from more
than two of the sites (to facilitate comparisons) was generated and eight products were
randomly chosen for this research. All the products were purchased eighteen months after
the April 2010 UK ban on cathinone substitutes and fifteen months after the July 2010 ban
on naphyrone. The products were handled and tested by an analyst with a Chief Officer of
Police’s delegated authority to be in possession of controlled substances. The substances
were stored in the secure drug store of a local police force and retained by them for
destruction at the conclusion of the experiments.
Information concerning the marketing, packaging, ingredients, method of use, dosage and
warnings over use was noted. Each product was, in turn, analysed qualitatively using a
combination of the two or more techniques outlined in table 1. Each product was analysed
with FTIR, Raman Spectroscopy and Proton NMR. Additionally, where there was an
indication from the spectroscopy that a product contained an illegal substance, that
product was analysed with 13C NMR. For the FTIR and Raman Spectroscopy, the products
were analysed in solid form. Those products supplied as a tablet were ground to a powder,
whilst those supplied as a capsule were emptied. For both NMR, 0∙1 gm of the powder was
dissolved in 0∙6 ml of Deuterated chloroform (CDCl3) for analysis. All instruments were
calibrated using calibration sources and correction software supplied by the
manufacturers. No specific comparison with reference standards for the illegal chemicals
identified was undertaken.
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[Insert Table 1]
Results
The results of the analyses were compared with the information provided by the suppliers
and the legality of the active ingredients ascertained. This information is summarized in
Table 2. Although, methoxetamine was legal when the research was conducted, it was
classified as a temporary class drug in March 2012, making its supply illegal.
[Insert Table 2]
Advertised Active Ingredients: Consistency in what you get?
The majority of products purchased (91%) provided information pertaining to the active
ingredients present in each substance (either on the website or packaging, or both),
although products purchased from three of the suppliers (A, B and D) did not adhere to the
advertised ingredients. Out of the twenty-two products supplied and analysed, 9% did not
list the active ingredients (Jolly Green Granules) and 23% did not contain the active
ingredients listed on the website or package. Instead of containing 17-alpha,21-Dihydroxy-
16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione-21-acetate, both of the NRG-3
products contained benzofuran (1-benzofuran-6-ylpropan-2-amine). This suggests that
the benzofuran mixture is being sold as a number of different products (benzofuran and
NRG-3), thus supporting previous research.4 Benzofuran was found in 27% of the products
and although it is chemically similar to amphetamines and MDMA, there is little scientific
information on its toxicity, its psychoactive properties or its effect on humans and their
health. Instead of the advertised ingredients, Benzocaine was found in three of the products
(MDAI and both Jolly Green Granules). Benzocaine is a local anaesthetic and a popular
cutting agent for cocaine. In contrast to earlier research5 there were no traces of
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mephedrone in either of the Jolly Green Granules. However, both NRG-2 products
contained 4-methylethcathinone (4-MEC) with a smaller, trace, amount of 4-
methylmethcathinone (4-MMC) or mephedrone, possibly as an unwanted contaminant,
making them illegalicit. By measuring the integrated intensities of the Proton NMR9
resonances, the relative concentration of 4-MEC was approximately 35 times that of 4-
MMC. Consistent with the findings of Brandt et al.,5 no other compounds were found in
either NRG-2 samples. Therefore, the product being sold is of a high purity and the amount
of illegal cathinone taken is simply the quantity of powder consumed.
Legal Highs or Illegal Highs?
The majority of products (91%) were identified as containing either the active ingredients
stated on the packet or a chemical that is not controlled in the UK. Of the four NRG
products analysed further by 13C NMR to confirm their contents, only two were found to
contain the illegalicit compounds 4-methylethcathinone and 4-methylmethcathinone
(mephedrone). 4-methylethcathinone (4-MEC) is classified as a class B controlled
substance in the UK. Even though it is not named specifically on the class B drug list, it is a
substituted cathinone and therefore subject to the 2010 Misuse of Drugs Act (Amendment)
Order. 4-MEC is structurally derived from cathinone by substitution in the phenyl ring
with an alkyl substituent and by substitution at the Nitrogen atom with an alkyl group (see
figures 1 and 2).
[Insert Figure 1]
[Insert Figure 2]
The contaminant 4-methylmethcathinone (mephedrone) in NRG-2 , is also a substituted
cathinone and a class B controlled substance in the UK, subject to the 2010 Misuse of Drugs
Act (Amendment)Order (see figure 3).
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[Insert Figure 3]
These findings show illegalicit cathinones are still being sold online as legal alternatives to
illegalicit substances, which was also a marketing tool used by all of the suppliers in this
research. Analogies were made between the substances for sale, and either the recently
banned cathinone, mephedrone, or illegalicit drugs like amphetamine, ecstasy (MDMA) or
ketamine.
Variation between Retailers
The chemical composition of the products purchased from supplier A and supplier D were
identical, as was the packaging, indicating that either two websites are fronting the same
company, or that both companies purchase goods from the same source. Specifically, the
NRG-2 products tested from supplier A and D and the relative concentration of each
chemical suggested that they originated from the same source. If both suppliers A and D
obtained NRG-2 from the same source this suggests that, given the large quantities
available to purchase (up to one kilogram), the scale of production or importation of these
substances is alarming.
Suppliers varied on the information they provided in terms of contents, instructions on use
and whether the drug was labelled ‘not fit for human consumption’. Out of the twenty-two
products purchased, 68% contained the warning ‘not fit for human consumption’ on the
internet site, but all contained this warning on the packaging. Although 23% had
information on how to use the product, this was of little use if the user intended to ingest it,
as it related to feeding plants or conducting research (see table 2). The information
provided included ‘doses of 0.05g will give your plants incredible growth…to be dissolved
in water’ and ‘very small doses of this research chemical are required for legitimate
research, it is essential that your lab has access to scales that can weigh in increments of
ten milligrams (0∙01g)’. The majority of websites and drug packets contained no safety
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information (77%) explaining how to use the substance or the recommended dose, which
is concerning since many of the substances purchased could be bought in amounts that
varied from one gram to one kilogram.
Discussion
This study has shown that substituted cathinones continue to be freely available for
purchase over the internet, some eighteen months after being classified as a class B drug.
Two products, both sold as ‘NRG-2’ from different internet suppliers, were found to contain
the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-
methylmethcathinone (4-MMC), the latter being present in trace quantities. The physical
appearance, packaging, labeling (not for human consumption) and chemical analysis of
these products suggests they originated from the same source; although . Although sold as
research chemicals and labeled ‘not for human consumption’, neither product contained
the ingredients listed. In contrast to previous research5,7 the majority (68%) of substances
tested in this study contained the stated active ingredients. Of the 22 products supplied
and analyzed in this study, 9% did not list the ingredients and 23% did not contain the
ingredients listed on the website or package, which means consumers are putting their
health at risk. Tsince the inconsistent ingredients, varied are inconsistent the chemical
composition and unknown subsequent drug interactions are unknown and therefore
potentially harmful to the user, particularly since . Disturbingly these substances are of a
high purity and available to buy in large quantities (of up to 1Kg), including those
containing banned cathinones.
Strengths and weaknesses of this study in the wider context
Our study has employed a range of recognized analytical techniques to identify the active
ingredients in each of the products purchased. Whilest the analysis carried out here is not
in itself a weakness, the extent to which substituted cathinones are supplied to, possibly,
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unsuspecting purchasers is still unknown. Thus, a limitation of this study is the relatively
small sample size. Our study purchased and analyzed 22 random products from five
internet suppliers and, from the packaging and chemical analyses, two of these suppliers
appeared to be selling products from the same source. Thus, at best, we have analyzed
products from four different sources and only found banned substances in 2 of the
products. However, this is the first analysis of the composition and legal classification of
substances, sold under the banner of research chemicals, to be carried out within the last
twelve months. Also, the number of products tested here (22) is far in excess of the number
tested in the previous most recent study (7)4, which failed to find cathinones in any of their
products. , which is eighteen months after the April 2010 amendment to the 1971 Misuse
of Drugs Act. Our research also overcomes the caveats associated with previous work was
carried out within six weeks5,7 or six months4 of the 2010 amendment. Also, the number of
products tested here (22) is far in excess of the number tested in the previous most recent
study (7)3. Our findings also show that research conducted immediately after the 2010
ban, which found cathinones in a number of legal highs4,6 that were being sold as ‘NRG’
(particularly NRG-1 and NRG-2) was not merely indicative of the retailers’ attempts to sell
off surplus stockpiles of mephedrone. Instead, this research indicates that despite being
brought under the Misuse of Drugs Act (1971), substituted cathinones are still being sold
illegally over the internet. Although the extent to which substituted cathinones are supplied
is still unknown, finding cathinones in the small sample of products tested here indicates
the widespread distribution of cathinones over the internet is highly probable, which has
serious public health implications. Therefore, the most significant difference between the
previous most recent research and this study is the identification that substituted
cathinones are still freely available in large quantitites.
Implications for clinicians and policymakers
Despite the perception that ‘legal’ means ‘safe’ to some users,10,11 novel psychoactive
substances (NPS) synthetic drugs appear to be more harmful than many of their more
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traditional illegal counterparts. Even though drugs like benzofuran, bromo-dragonFLY and
MPA (N-methyl-1-(thiophen-2-yl)propan-2-amine) are legal to buy, little is known about
the safety of these substances, how they interact with other drugs, their long-term effects
(psychologically and behaviourally) on humans or their toxicity. This also applies to the
banned drugs naphyrone,12-13 mephedrone13-14 and synthetic cannabinoids.14 and
mephedrone.15-17 Users of substituted cathinones like mephedrone are presenting to
hospitals with tachycardia (rapid heart rate), hypertension, chest pains, myoclunus
(muscle contractions), hallucinations, paranoia, violence and sympathomimetic
syndrome.17 Although there is emerging medical research documenting the harmfulness of
NPSthese synthetic substances12-18 there is also evidence pertaining to the emergent health
risks associated with legal anaesthetics, like Benzocaine (which was found in three of the
products tested here) and Lidocaine, which are being sold in their place.5 ADespite being
widely used in pharmaceutical products, allergic reactions to Benzocaine are common and
ingesting more than the recommended amount can cause an overdose, particularly in
susceptible individuals, because there is ‘no therapeutic window (between the doses
required to produce a therapeutic effect and those producing toxicity).19 Benzocaine has
also been linked to a toxic blood disorder methemoglobinemia in adults who take small
quantities medicinally20 and unknown quantities illicitly in adulterated cocaine.21 The
presence of Benzocaine in legal highs is well documented..5,22 However, it However it is
never listed as one of the active ingredients meaning and each product contains indefinite
quantities, which . Consequently the amount of Benzocaine being consumed by the user is
unknown, which is disturbing since because research estimates that Benzocaine induced
methemoglobinemia is dose dependent and only requires a small amount 15-25mg/kg is
needed to cause cyanosis19,23 (a bluish discolouration of the skin caused by a deficiency of
oxygen in the blood). Although, there have been no known deaths from Benzocaine, in
2010 the coroners court in Ireland attributed the death of a teenager was attributed to
cocaine containing four times the toxic dose of Lidocaine,24 further illustrating the potential
health risks arising from the varied composition of these products.
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The arbitrariness of the advertised ingredients and mislabelling of products exacerbates
the detrimental consequences for the health of the user. Products do not This research
found the products purchased did not always contain the advertised active ingredients,
replicating earlier research in this area,8 even those with which has consistently found
different active ingredients in the same nameproducts brought from the internet. The
contents of the NRG products has varied substantially from one type of cathinone, to a
combination of four-five cathinones, to banned piperazines, to inorganic material or
Benzocaine. 4,5,7,25,26 Users are inadvertently being exposed to unidentified drugs in
unknown concentrations, which increases the risk of toxicity and overdose. Those
repeatedly buying the same product and expecting the same effects may actually be taking
a completely different and more potent substance. TThis not only has serious health
implications in terms of pharmacological intoxication and overdose, but also exposes the
user is also exposed to the risks arising from the potentiating effect of any drug
interactions and their subsequent metabolites produced inside the body. However, These
risks are exacerbated further since users suffering from any adverse effects brought on by
these drugs are unlikely to be identified by clinicians, as drug screening does not identify
these new and unique compounds27 and despite recent publications examining specific
toxicity case studies of toxicity,28 little is scientifically known about these drugs, and their
toxicological detection in biological specimens is challenging.29 Since only a small amount
is need to elicit an effect, and the minimum amount that can be purchased is one gram,
users will continue to present themselves to A&E departments across the country. M,
therefore medical practitioners need to be made more aware of these substances, their
effects and potential health risks. TEven the healthcare professionals who are aware of the
problems associated with NPSs this new genre of drugs are not equippedill-equipped to
deal with them problems as they arise due to the paucity of scientific and medical research
in this area. Since Public Health England recognises the ‘importance of having an effective,
highly trained and professionally skilled Public Health workforce’30 this is an area that
needs addressing. Research and reliable medical data on NPSs legal highs areis sparse and
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despite requests there is no ‘centralised system…linking for instance toxicology and
forensics across the country to collate information’ despite requests for such a system.31
The public health risks associated with these drugs are compounded by the lack of safety
guidance (i.e. use and dosage information) provided by websites. All substances are
labelled as not fit for human consumption, with some advocating medical assistance if
swallowed; ‘hazard: not for human consumption, and if ingested consult medical
assistance’. While this does not seem to deter use and is seen by some users as a way of
evading the law and facilitating their sale online,24, in reality it means NPSs these
substances can be sold having undergone no checks and adhering to no regulations, which
means they . If these substances were marketed for human consumption they would be
regulated either as a medicine (after undergoing years of endless trials) or by the Food
Standards Agency to make sure they were safe for humans. As it stands, these substances
could contain anything because the legal highs market remains uncontrolled and
unregulated. Therefore the growth in NPSs . The burgeoning market in synthetic drugs
poses insurmountable challenges to clinicians attempting to identify and diagnose the
adverse health effects arising from the ingestion of un-researched, unknown and
unidentifiable chemicals.
Unanswered questions and future research
The small sample (22 products) analysed in As this study means was limited to analyzing
just 22 products purchased from five different internet suppliers, there remains the
question of how many sites are selling products containing banned substances, how
widespread the purchase of these substituted cathinones actually is and the extent to
which they are being taken by unsuspecting consumers remains unknown. Since there is
an estimated 314 online shops, selling legal highs to ‘at least one EU member state’32, about
80 of which are based in the UK, we sampled products from less than 2% of these online
suppliers. Therefore, future research should investigate a much wider range of internet
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available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
15
suppliers and their products to establish not only the chemical composition of these
substances but to help identify which products contain prohibited substances like
mephedrone. Future research could also usefully investigate low level contaminants in
these substances, not least as a possible means of linking sites of manufacture. There is a
However, this research also highlights the need for more medical research to be conducted
in this area , examining ing the potential impact NPSs legal highs have on public health.
This article illustrates more training for . It also shows that clinicians is required and need
specific training on these unknown chemical substances and demonstrates thea need for a
centralised system, which collates and stores information that medical practitioners can
draw on when faced with a suspicious case. Surprisingly there has been no public health
campaign highlighting the risks associated with NPSsthese widely available synthetic
substances, to raiseing awareness among the public or the medical profession, despite the
potential risks to health.
Conclusion
Illicit cathinones continue to be sold online under the guise of ‘legal highs’. The imposition
of legislative controls banning certain substances has had little effect on the chemical
composition of novel psychoactive substances legal highs or their availability, indicating
that bringing in new laws on drugs as quickly as they emerge is not tackling the problem of
supply (or demand). Instead it displaces the problem and invites chemists to modify the
molecular structure of chemicals to create legal alternatives to the newly banned
substances. The continual evolution of chemical compounds designed to evade the law is
potentially creating more dangerous and unknown synthetic substances than the ones
currently being legislated on. Although, these substances are potentially more harmful
than their illegalicit counterparts, many remain legal to buy and consume, thus
undermining the scientific calculation of harm that underpins drug legislation and
determines whether a substance is made illegal; a calculation, which has come under
increasing criticism in recent years.33-34 It also poses an infinite challenge to mainstream
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16
healthcare professionals dealing with the adverse health effects arising from these
substances.
Although new substances are constantly being created to evade the law, illegal icit ones are
also being sold openly on the internet, indicating that the police are unable to enforce
current legislation and prohibit supply. Unsuspecting buyers are not only breaking the law
but are buying substances that are potentially harmful. NThe genre of ovel psychoactive
substances (NPS) legal highs haves the potential to cause serious public health problems to
a new generation of drug users who see them as a safer alternative to their illicit
counterparts.10-11 The public health costs of treating users in the short- and long-term
comes at a time of economic paucity and cut backs in the public health sector. The medical
profession are facing a new genre of NPS legal high induced illnesses and an increase in
toxicity cases, but lack the methodology required to detect these drugs (and their
metabolites) in biological samples or recognise the symptoms of toxicity. Prohibition is
intended to protect public health by limiting the availability and use of drugs like
substituted cathinones. However, legislation would appear to be failing and is instead
simply displacing drug use. Users continue to consume an array of unknown synthetic
compounds and can easily purchase large amounts (1Kg) of illegal substances despite – and
perhaps entirely unaware of – the unpredictable consequences it may have on their health.
[Insert ‘what this paper adds’ box]
Authors Contributions.
TA conceptualised the paper and applied for funding to conduct the research. JWB
conducted the chemical analysis of the substances. Both authors contributed to the writing,
argument and structure of the article including any revisions that have been made.
Conflicts of Interest
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available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
17
We have no conflicts of interest to declare.
Competing Interests Statement
We declare that we have no competing financial, professional or personal interests that
might have influenced the work described in this manuscript.
Data Sharing
There is no additional data available.
Role of Funding Source
Funding came from the University of Leicester, College of Social Sciences research grant.
The funding source had no role in the study design, analysis or in the writing up of the
research.
Ethics Committee Approval
This research received ethical approval (reference tca2-88995) from the Criminology
department’s ethics committee.
References
1 Advisory Council on the Misuse of Drugs. Consideration of the Novel Psychoactive
Substances (Legal Highs). London: ACMD, 2011.
2 International Narcotic Control Board. Annual Report. New York: United Nations,
2011.
3 European Monitoring Centre for Drugs and Drug Addiction. Europol 2010 Annual
Report on the Implementation of Council Decision 2005/387/JHA. Lisbon: EMCDDA,
2011.
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available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
18
4 Baron M, Eile M, Eile, L. Analysis of Legal Highs – Do they contain what it says on the
tin? Drug Testing and Analysis, 2011.
5 Brandt SD, Sumnall HR, Measham F, Cole J. Analyses of second-generation 'legal
highs' in the UK: initial findings. Drug Testing and Analysis 2010; 2: 377–82.
6 Dargan PI, Hudson S, Ramsey J, Wood DM. The impact of changes in UK classification
of the synthetic cannabinoid receptor agonists in Spice. International Journal of Drug
Policy 2011; 22: 274-277.
7 Ramsey J, Dargan PI, Smyllie M, Davies S, Button J, Holt DW, Wood DM. Buying legal
recreational drugs does not mean that you are not breaking the law. QJ Med 2010;
103:777-783
8 Davies S, Wood DM, Smith G, Button J, Ramsey J, Archer R, Holt DW, Dargan PI.
Purchasing legal highs on the internet – Is there consistency in what you get? QJ Med
2010; 103: 489-493.
9 Pauli GF, Jaki BU, Lankin DC. A routine experimental protocol for qHNMR illustrated
with Taxol. Journal of Natural Products 2007; 70: 589-595.
10 Measham F, Moore K, Newcombe R, Welch Z. Tweaking, bombing dabbing and
stockpiling: The emergence of mephedrone and the perversity of prohibition. Drugs
and Alcohol Today 2010; 10: 14-21.
11 Sheridan J, Butler R. They’re legal so they’re safe right? International Journal of Drug
Policy 2010; 21: 77-81.
12 Advisory Council on the Misuse of Drugs. Consideration of the
Naphthylpyrovalerone Analogues and Related Compounds. London: ACMD, 2010.
13 De Paoli G, Maskell PD, Pounder DJ. Naphyrone: analytical profile of the new "legal
high" substitute for mephedrone. Journal of Forensic and Legal Medicine 2011; 18:
93.
14 EMCDDA. Understanding the Spice phenomenon. Lisbon: EMCDDA, 2009.
15 Gibbons S, Zloh M. An analysis of the legal high mephedrone. Bioorganic and
Medicinal Chemistry Letters 2010; 20: 4135-4139.
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Highs?
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16 Vardakou I, Pistos C, Spiliopoulou C. Drugs for youth via Internet and the example of
mephedrone. Toxicology Letters 2011.
17 Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical
confirmation of bath salts and legal highs (synthetic cathinones) in the United
States. Clinical Toxicology 2011; 49: 499-505.
18 Wood DM, Looker JJ, Shaikh L, Button J, Puchnaewicz M, Davies S, Lidder S, Ramsey
J, Holt DW, Dargan PI. Seizures associated with recreational use of Bromo-
dragonFLY. Journal of Medical Toxicology 2009; 5: 226-229.
19 Guay J. Methemoglobinemia related to local anaesthetics: a summary of 242
episodes. Anesthesia and Analgesia 2009; 108: 837-845.
20 Osterweil N. Topical Benzocaine associated with Methemoglobinemia. Medscape
Today 2011.
21 Hunter L, Gordge L, Dargan PI, Wood DM. Methemoglobinemia associated with the
use of cocaine and volatile nitrates in recreational drugs: a review. British Journal of
Clinical Pharmacology 2011; 72: 18-26.
22 Power JD, McGlynn P, Clarke K, McDermott SD, Kavanagh P, O’Brien J. The analysis of
substituted Cathinones, part 1: chemical analysis of 2-,3-and 4-
methylmethcathinone. Forensic Science Journal 2011; 212: 6-12.
23 McKinney CD, Postiglione KF, Herold DA. Benzocaine-adulterated Street Cocaine in
association with Methemoglobinemia. Clin. Chem 1992; 38: 596-597.
24 SOCA. Drug profits take a hammering as Benzocaine haul is burned. London:
Stationary Office, 2010. http://www.soca.gov.uk/news/260-drug-profits-take-a-
hammering-as-benzocaine-haul-is-burned- (accessed Sept 25, 2011).
25 Brandt SD, Freeman S, Sumnall HR, Measham F, Cole J. Analysis of NRG Legal Highs
in the UK: Identification and Formation of Novel Cathinones. Drug Testing and
Analysis 2011; 3: 569-575.
26 Brandt SD, Sumnall HR, Measham F, Cole J. Second generation mephedrone: the
confusing case of NRG-1. British Medical Journal 2010; 341: 3564.
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available over the internet and their impact on public (ill)health. Legal Highs or Illegal
Highs?
20
27 Smith CPT, Cardile AP, Miller M. Bath salts as a legal high. The American Journal of
Medicine 2011.
28 Salmner EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O’Riordan, JI. A harmless
high? The Lancet 2010; 376: 742.
29 Forensic Magazine. Detecting bath salts. 25 October, 2011.
30 Anita Marshland. Public Health England: A Letter, London: Department of Health,
2011. http://bhamcf.files.wordpress.com/2010/10/nhs-pblchlthltr-11-3.pdf
(accessed December 20, 2011).
31 Boyce N. Health warnings for people who use heroin. The Lancet, 2011; 377:193-
194.
32 EMCDDA. Annual Report 2011: The State of the Drugs Problem in Europe. Lisbon:
EMCDDA, 2011.
33 Nutt D, King L, Phillips L. Drug harms in the UK: a multicriteria decision analysis. The
Lancet 2010; 376: 1558-1565.
34 Rolles S, Measham F. Questioning the method and utility of ranking drug harms in
drug policy. International of Drug Policy 2011; 22: 243-246.
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Tables - BMJ
Table 1: Analysis techniques
Fourier Transform Infrared Spectroscopy (FTIR) Fourier Transform Infrared Spectroscopy analyses the composition of a
substance by measuring how much Infrared energy is absorbed by
different molecules, thereby enabling the molecules present to be
determined.
Raman Spectroscopy Raman Spectroscopy uses inelastic scattering of monochromatic light
(usually a laser) to excite vibrational modes of bonds in the sample that
result in a frequency shift of the emitted light, thereby enabling the
composition of the sample to be determined.
Proton Nuclear Magnetic Resonance (1H NMR) Proton Nuclear Magnetic Resonance uses the absorption of
electromagnetic waves by protons (H+ ions) in a magnetic field that
results in a frequency shift of the emitted electromagnetic waves to
enable the composition of the sample to be determined.
Carbon-13 NMR (13C NMR) Carbon-13 NMR employs the same principle as proton NMR but uses
resonance of the C13 atom rather than the proton.
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Table 2: Summary of the 22 legal highs purchased via the internet, including the compounds detected, the accuracy of their description
and their legal status.
Product Compounds Detected As
Described Status
Su
pp
lie
r A
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB) Yes Legal
Jolly Green
Granules
Benzocaine
Did not
specify
contents
Legal
MDAI
5,6-Methylenedioxy-2-aminoindane Yes Legal
Methoxetamine
2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone Yes *Legal
MPA
N-methyl-1-(thiophen-2-yl)propan-
2-amine. Yes Legal
NRG-2
4-methylethcathinone (4-MEC).
Contaminant mephedrone. No Illegal
NRG-3
1-benzofuran-6-ylpropan-2-amine
(6-APB). No Legal
5-IAI
5-Iodo-2-aminoindane. Yes Legal
Su
pp
lie
r B
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB). Yes Legal
MDAI
Benzocaine. No Legal
5-IAI
5-Iodo-2-aminoindane. Yes Legal
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Su
pp
lie
r
C
Benzofury
1-benzofuran-6-ylpropan-2-amine. Yes Legal
Methoxetamine
2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone. Yes *Legal
Su
pp
lie
r D
Jolly Green
Granules
Benzocaine.
Did not
specify
contents
Legal
MDAI Gold
5,6-Methylenedioxy-2-aminoindane. Yes Legal
MPA
N-methyl-1-(thiophen-2-yl) propan-
2-amine. Yes Legal
NRG-2
4-methylethcathinone (4-MEC).
Contaminant mephedrone. No Illegal
NRG-3
1-benzofuran-6-ylpropan-2-amine
(6-APB). No Legal
5-IAI
5-Iodo-2-aminoindane. Yes Legal
Su
pp
lie
r E
Benzofury
1-benzofuran-6-ylpropan-2-amine
(6-APB). Yes Legal
MDAI Gold
5,6-Methylenedioxy-2-aminoindane. Yes Legal
Methoxetemine 2-(3-methoxyphenyl)-2-
(ethylamino)cyclohexanone. Yes *Legal
Note: *Legal – Methoxetemine was legal when this research was initially conducted,
however it has since (March 2012) been classified as a temporary class drug making its
supply illegal.
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What This Paper Adds
What this paper adds:
Section 1: What is already known on this subject
Partly as a result of identifying substituted cathinones in so-called ‘legal highs’ -
marketed as legal alternatives to the most popular but illicit recreational drugs, these
substances were brought under the Misuse of Drugs Act in 2010. The most recent
examination of the composition of ‘legal highs’, conducted six months after the
introduction of the ban, found no presence of banned cathinone substitutes in the
products they tested.
Section 2: What this study adds
This paper draws the medical literature on novel psychoactive substances together with
the research examining the chemical composition of these substances together, to
illustrate the public health issues arising from this new genre of drugs. Our study shows
that, eighteen months after the introduction of the ban, illegal cathinone substitutes are,
once again, readily available for purchase in the UK in large (1Kg) quantities with little
known about their clinical effects.
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross-sectional studies
Section/Topic Item
# Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 2
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 3
Objectives 3 State specific objectives, including any prespecified hypotheses 4-5
Methods
Study design 4 Present key elements of study design early in the paper 5
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection
NA
Participants
6
(a) Give the eligibility criteria, and the sources and methods of selection of participants NA
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
NA
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
5
Bias 9 Describe any efforts to address potential sources of bias 9
Study size 10 Explain how the study size was arrived at NA
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
NA
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 5
(b) Describe any methods used to examine subgroups and interactions NA
(c) Explain how missing data were addressed NA
(d) If applicable, describe analytical methods taking account of sampling strategy NA
(e) Describe any sensitivity analyses NA
Results
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Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed
NA
(b) Give reasons for non-participation at each stage NA
(c) Consider use of a flow diagram NA
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
NA
(b) Indicate number of participants with missing data for each variable of interest NA
Outcome data 15* Report numbers of outcome events or summary measures 6-8
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
NA
(b) Report category boundaries when continuous variables were categorized NA
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period NA
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 6-8
Discussion
Key results 18 Summarise key results with reference to study objectives 8
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
9, 12
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
8-12
Generalisability 21 Discuss the generalisability (external validity) of the study results 8-12
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
15
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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67x40mm (300 x 300 DPI)
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67x34mm (300 x 300 DPI)
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80x44mm (300 x 300 DPI)
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