Legal Highs or Illegal Highs? The pharmacology of …...designer drugs is ‘escalating out of control’1 with their availability growing at an unprecedented pace. 2 Unlike traditional

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open


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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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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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,

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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

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6 Ramsey J, Dargan PI, Smyllie M, Davies S, Button J, Holt DW, Wood DM. Buying legal

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Purchasing legal highs on the internet – Is there consistency in what you get? QJ Med

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9 Measham F, Moore K, Newcombe R, Welch Z. Tweaking, bombing dabbing and

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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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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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Legal Highs or Illegal Highs? The pharmacology of substances freely available over the internet and their impact on public (ill)health.

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


(6-APB). No Legal

Su

pp

lie

r A

5-IAI

5-Iodo-2-aminoindane. Yes Legal

Benzofury


(6-APB). Yes Legal

MDAI

Benzocaine. No Legal

Su

pp

lie

r B

5-IAI


Su

pp

l

ier

C Benzofury

1-benzofuran-6-ylpropan-2-amine. Yes Legal

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Methoxetamine


(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



NRG-3


(6-APB). No Legal

Su

pp

lie

r D

5-IAI


Benzofury


(6-APB). Yes Legal

MDAI Gold


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


BMJ Open


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



bought over the internet.

Key Messages:


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




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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Highs?

2

Abstract:


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.


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.



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.




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Highs?

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which has serious implications for public health and clinicians who are ill-equipped to deal


Introduction






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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Highs?

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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).













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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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



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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6

Methods





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.



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



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]


















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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.





contain the illegal compounds 4-methylethcathinone and 4-methylmethcathinone



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]



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


banned cathinone, mephedrone, or illegal drugs like amphetamine, ecstasy (MDMA) or

ketamine.





















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Discussion


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).


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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11

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.


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




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.


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



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]








Data Sharing


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research.


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.


2011.



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

the synthetic cannabinoid receptor agonists in Spice. International Journal of Drug

Policy 2011; 22: 274-277.

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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8 Davies S, Wood DM, Smith G, et al. 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, et al. Tweaking, bombing dabbing and




Policy 2010; 21: 77-81.





93.






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

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.


Today 2011.

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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

Clinical Pharmacology 2011; 72: 18-26.

22 Power JD, McGlynn P, Clarke K, et al. The analysis of substituted Cathinones, part 1:

chemical analysis of 2-,3-and 4-methylmethcathinone. Forensic Science Journal

2011; 212: 6-12.






25 Brandt SD, Freeman S, Sumnall HR, et al. 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, et al. Second generation mephedrone: the

confusing case of NRG-1. British Medical Journal 2010; 341: 3564.


Medicine 2011.

28 Salmner EM, Foley PL, Lauder GD, et al. A harmless high? The Lancet 2010; 376: 742.






194.


EMCDDA, 2011.

33 Nutt D, King L, Phillips L. Drug harms in the UK: a multicriteria decision analysis. The

Lancet 2010; 376: 1558-1565.

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Article Summary:

Article Focus:

To analyse the chemical composition of substances bought over the internet, including the



bought over the internet.

Key Messages:


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




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:


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.


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.



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.



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which has serious implications for public health and clinicians who are ill-equipped to deal


Introduction






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).













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



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





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.



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



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]

















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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.





contain the illegalicit compounds 4-methylethcathinone and 4-methylmethcathinone



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]



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


banned cathinone, mephedrone, or illegalicit drugs like amphetamine, ecstasy (MDMA) or

ketamine.




















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Discussion


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.


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.


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




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.


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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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



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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Highs?

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]





Conflicts of Interest

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Highs?

17

We have no conflicts of interest to declare.




Data Sharing





research.


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.


2011.



2011.

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Highs?

18



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




Policy 2010; 21: 77-81.





93.




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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.


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.






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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Medicine 2011.

28 Salmner EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O’Riordan, JI. A harmless

high? The Lancet 2010; 376: 742.






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Lancet 2010; 376: 1558-1565.



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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?

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


(6-APB) Yes Legal

Jolly Green

Granules

Benzocaine

Did not

specify

contents

Legal

MDAI

5,6-Methylenedioxy-2-aminoindane Yes Legal

Methoxetamine


(ethylamino)cyclohexanone Yes *Legal

MPA

N-methyl-1-(thiophen-2-yl)propan-

2-amine. Yes Legal

NRG-2



NRG-3


(6-APB). No Legal

5-IAI


Su

pp

lie

r B

Benzofury


(6-APB). Yes Legal

MDAI

Benzocaine. No Legal

5-IAI


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Su

pp

lie

r

C

Benzofury

1-benzofuran-6-ylpropan-2-amine. Yes Legal

Methoxetamine


(ethylamino)cyclohexanone. Yes *Legal

Su

pp

lie

r D

Jolly Green

Granules

Benzocaine.

Did not

specify

contents

Legal

MDAI Gold


MPA

N-methyl-1-(thiophen-2-yl) propan-

2-amine. Yes Legal

NRG-2



NRG-3


(6-APB). No Legal

5-IAI


Su

pp

lie

r E

Benzofury


(6-APB). Yes Legal

MDAI Gold


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


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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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Documents

Legal Highs or Illegal Highs? The pharmacology of …...designer drugs is ‘escalating out of control’1 with their availability growing at an unprecedented pace. 2 Unlike traditional