Uncovering the Lethal Cocktail

Ric Treble lets us in on the analytical challenges in testing illegal drugs widely marketed under the guise of plant foods and research chemicals

Analysis of the major drugs of abuse such as heroin, cocaine, cannabis and amphetamine is only too familiar to forensic scientists and toxicologists, who spend much of their time examining powders and tablets or samples of blood or urine. The chemistry and metabolism of these commonly encountered drugs are well understood and analysis of the drugs and their metabolites in a wide range of substrates is routinely carried out.

However, a new trend in drug use has recently become apparent, with a wide range of novel materials being offered for sale to those seeking psychoactive effects. This trend first became noticeable when benzylpiperazine and related compounds were promoted as legal stimulant ‘party pills’. This was followed by the appearance of the ‘Spice’ drugs; synthetic cannabis receptor agonists which produce similar effects to cannabis. More recently, cathinones, which are the beta-keto versions of the phenethylamine range of drugs, have appeared as alternatives to stimulants such as amphetamine and cocaine. Websites are now promoting many such exotic chemicals and products, with names like MDAI, MDPV, JWH-018, Benzofury and NRG-1.

Some of these new materials, such as mephedrone and naphyrone, have received wide publicity. Others are less well known but are widely available. The chemicals are believed to be synthesised in Asian and Eastern European laboratories, marketed via internet websites and supplied direct to users by post and courier parcels, all in return for an internet-friendly payment system. There is a major concern that few, if any, of these materials have been subject to toxicological testing, so any associated health risks are unknown.

Controlling this trade is challenging, as many of the new materials are not covered by drug control legislation and, at least some are ‘designer drugs’; that is, their structure has been deliberately designed so as to avoid legal controls. Producers also try to avoid medicines controls and other consumer protection legislation by marketing the materials as ‘plant food’ or ‘research chemicals’, and marking the products as ‘not for human consumption’. In addition, policing internet-led trading presents practical difficulties for law-enforcement agencies, particularly when the trade is international.

The driving force behind the development of the legal high drug market seems to be a combination of factors, including users’ wishes to obtain a psychoactive effect while avoiding using illegal substances, the awareness that traditional drugs of abuse such as amphetamine, ecstasy and cocaine are increasingly of unreliable quality, the easy availability and low cost of these legal alternatives and possibly even a belief that, if something isn’t banned, it must be safe.

Drug testing processes are struggling to keep up with the influx of new materials, so routine drug screening systems, such as those used in workplace and drug-driving tests, may not yet be able to identify the new substances. Even if the new material is known, its metabolic pathways may not yet have been identified, so forensic and clinical toxicologists have to make educated guesses about which analytes they might seek.

The rate at which new materials are appearing has been accelerating. During 2009, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) reported 29 new substances had been brought to their attention via the European Early Warning System. Additional new materials continue to be promoted by websites, of which some are compounds that had only previously been reported in pharmaceutical research literature, some are ‘designer’ variants of existing drugs of abuse, some are pharmaceuticals from foreign pharmacopoeias, while others are ‘designer pharmaceuticals’; or, chemically modified versions of existing pharmaceuticals.

To further complicate the picture, when packaged products have been forensically tested, it is often found that the ingredients are not those declared and, in some cases, the active ingredients are found to change from batch to batch. It is therefore very difficult for users to know what substances they are taking. If they then present themselves at a hospital emergency unit, their self-declaration of what they had been using cannot be relied on.

All this presents a major challenge for LGC and other analytical laboratories, whether faced with an unknown white powder or a biological sample. Many of the new substances are closely-related molecules, including homologues, analogues and structural isomers, so obtaining a precise identification can be difficult. Primary techniques such as nuclear magnetic resonance (NMR) can be required to establish identity and, in the case of traces in biological samples, advanced mass spectrometry (MS) techniques, including accurate mass MS, may be required.

Although laboratories can keep up to date with trends by exchanging information via the Early Warning System and can assist each other by exchanging analytical data such as infra-red spectra and mass spectra, there is a key need for authenticated reference samples of new materials, so that laboratories can establish chromatographic performance on their own systems.

Around the world, reference material producers like LGC Standards are working to provide reference standards for these new substances. Traditionally, production of new reference materials takes many months, or even years, from synthesis and purification through characterisation, stability testing and certification prior to release. We now face an environment in which a previously unknown substance can appear for sale on websites and be in widespread use within weeks, followed by reports of adverse effects, followed closely by the imposition of legal controls. The requirement is therefore to provide laboratories with rapid access to reliable reference materials to support them in their work.

At LGC Standards, production methods are being adapted to meet this new environment. Once new target materials have been identified, synthesis routes are devised or, in some cases, raw materials are being purchased directly from the website suppliers. Materials are then purified and characterised before a reference standard is released. As undertaking long-term stability studies on each new material would defeat the objective of a rapid response, reference materials are issued with interim expiry dates and are then subjected to retests, so that expiry dates can then be extended as stability performance is established.

Development and provision of reference materials is an international activity, involving both national standards organisations, such as the National Measurement Institute of Australia and the US National Institute of Standards and Technology, and private companies, including The Cerilliant Corporation, Toronto Research Chemicals and LGC Standards. By bringing together standards from many such sources, LGC Standards is assembling extensive ranges of reference standards for the new materials.

There is, however, an additional difficulty for laboratories. As the new materials are assessed and, in many cases, become controlled drugs, they become subject to the legal requirements relating to controlled drugs. If the materials are controlled in the end users’ country, licenses are required to possess them. If the reference materials are being sourced from another country, and are controlled in either the source or destination countries, import and/or export licences will be required. Obtaining these licenses takes time, further delaying the process of getting the reference standard into the laboratory. Where possible, LGC Standards is using local inventory warehousing to address this problem.

The development of these new psychoactive materials has aspects of a chemical arms race – as a material appears, is assessed and becomes controlled, a new substance takes it place. While legislative developments can help to address this cycle, forensic and clinical laboratories are faced with the challenge of identifying a stream of new materials. LGC Standards is supporting forensic and clinical laboratories in this work by timely provision of reference materials.