New psychoactive substances — Production (EU Drug Markets Report)


The blueprints and recipes for many of the NPS that have been detected on the European drug market, and thousands more, are catalogued in the scientific and patent literature. In fact, many originate from the good intentions of pharma and academia: some were either once used as medicines or are currently used as medicines; while many were intended as new medicines but were never commercialised because they did not work as expected, or they caused adverse effects, or they were not commercially viable; while others were used in studies to get a better understanding of how our bodies work, and in the hope of developing better medicines or diagnostic imaging. In other cases, a totally new substance may emerge having been specifically designed either for curiosity by an amateur chemist or specifically for the new substances market. Often the inspiration for these comes from the original endeavours of pharma and academia. This was the case for methoxetamine, which was sold as a legal replacement for ketamine; 4,4′-dimethylaminorex which, using the brand name Serotoni, was pitched as a legal replacement for MDMA; as well as a range of synthetic cannabinoids (Morris, 2011; EMCDDA–Europol, 2014). Sometimes, new substances also emerge as a result of a switch in the chemical precursors used in illicit laboratories that produce drugs such as amphetamine and MDMA.

Until about a decade ago, only a handful of new substances were seen each year in Europe. Some were produced in small amounts in amateur laboratories or on a commercial scale in clandestine laboratories by OCGs. These were mostly sold on the illicit drug market, where they would be passed off as amphetamine or ecstasy; some were specifically sold and sought after by name; others were sold as a new type of ecstasy. These types of new substances were often called ‘designer drugs’ — a nod to the fact that they appeared to have been specifically designed to circumvent drug control legislation. Sometimes new substances were also sourced from legitimate chemical companies. Another important section of the market at the time was the diversion of medicines from the legitimate supply chain.

Today, the so-called ‘designer drugs’ and medicines remain an important part of Europe’s market in new substances. In the former case, they usually appear as a result of the activities of organised crime. Sometimes this is because a non-controlled precursor chemical may be used during the synthesis of a substance, which results in a new substance being produced either accidentally or deliberately. This issue with precursors has led to recurring problems in Europe. As mentioned briefly in Chapter 6, in some cases, MDMA manufacturers have instead made PMMA, which in 2014 and 2015 caused clusters of deaths across Europe after high-strength tablets were sold as ecstasy to unsuspecting users. Amphetamine production has also been affected; in the late 2000s, there was a shortage of precursors, which led to two new substances being sold as amphetamine on the European drug market: in 2007, 4-FA was detected on the market because of the use of the precursor 4-fluoro-BMK (see Case study 12), which was followed in 2009 by 4-methylamphetamine, which arose from the use of the precursor 4-methyl-BMK (EMCDDA, 2014c). The reason behind a switch to a non-controlled precursor may be the limited availability of a controlled precursor, or a chemical supplier may deliberately substitute a precursor for another — unbeknownst to a producer; in other cases it may be because a non-controlled precursor is cheaper to buy and/or easier to traffic. In the case of both 4-FA and 4-methylamphetamine, the substances were sold as amphetamine and produced by crime groups involved in the supply of amphetamine. At other times, crime groups have sourced new substances from chemical suppliers in Europe as well as China in order to plug a gap in the availability of substances such as MDMA; such substances include mCPP, BZP and mephedrone. There are also increasing signs that crime groups are interested in producing a range of new substances in Europe. These are discussed below.

Notwithstanding the importance of so-called ‘designer drugs’ and medicines to the market, what is responsible for the huge growth in the contemporary market in new psychoactive substances — in terms of the increase in their number, type and availability — is globalisation. The convergence between modern transport networks, the internet, payment systems, low labour costs and the large growth — and increasing dominance — of the Chinese chemical and pharmaceutical industries that has occurred over the last few years has allowed a new market to flourish (Levinson, 2006; Smil, 2010; Morris, 2011; Stearns, 2011; Halford, 2015).

The internet, and particularly the web, is now a part of everyday life, and, coupled with cheap, efficient and reliable shipping, has allowed China to become the chemical and pharmaceutical wholesaler and retailer to the world while, to a lesser extent, companies in India are also important suppliers, particularly with respect to medicines. Many new substances — such as the synthetic cannabinoids, cathinones, opioids and benzodiazepines — are produced by legitimate companies in these countries that appear to be operating lawfully; some not so legitimate companies are also involved. The companies advertise their catalogue of substances on major online business-to-consumer and business-to-business marketplaces and through their own websites. If a particular substance is not in their catalogue, then it can often be made to order. They accept payment by major credit and debit cards, online payment services or direct bank transfers. Escrow services and online reputation systems — similar to those used by ecommerce giants Amazon and eBay — may also be used, which decreases risk and increases trust between buyer and seller, helping secure trade (Masum and Tovey, 2012). Some suppliers also guarantee to replace the substance or issue a refund if the shipment is intercepted by customs agencies. The amounts offered range from a few milligrams to tens or even hundreds of kilograms; the purity is often claimed to be high. The reach of these companies is global.

Once sold, the substances are then shipped to Europe using express mail and delivery companies; the cost can be as little as EUR 50 or less, and the substances discretely delivered directly to the purchaser’s door in as little as two days — an attractive feature for distributors, retailers and consumers alike. The packages easily blend in among the thousands of small packages shipped from China to Europe each day. Larger amounts are shipped by air or sea cargo. Once in Europe they are processed and packaged into a range of products; the other required materials, packaging and equipment can be sourced from lawfully operating suppliers in China as well in Europe. To get an idea of the potential impact of these developments, it costs around EUR 100 to express ship 1 kg of a new substance from a manufacturer in China to Europe. In the case of some of the fentanyls and synthetic cannabinoids that have been detected, this amount could equate to tens of thousands of doses. The low cost of delivery facilitates the importation of the substances into Europe and their movement across Europe, and small letters and packages can easily be disguised. As the number of items transported by express mail, courier, and air and sea cargo increases (express mail increased by 20 % in 2015), the chances of detection are likely to decrease.

Case study 12: 4-Fluoroamphetamine (4-FA)

Of note is that 4-FA is specifically sought after by some party-goers in the Netherlands and Belgium because they perceive its effects to be ‘milder’ and between those of MDMA and amphetamine. One large study of Dutch users was used to investigate the emergence of the new drug and found a prevalence of use similar to that for GHB and ketamine. Interestingly, it has been suggested that some users have also switched to this drug in order to avoid the high-strength MDMA tablets currently present on the European market. Helping drive the use of this substance is the increase in its availability through its open sale in bricks and mortar shops and on the web (Brunt et al., 2011; Goossens et al., 2013; Linsen et al., 2015). 

Given the grey nature of much of the trade in NPS, it appears that suppliers and importers have less need to resort to the high-tech smuggling techniques used to transport controlled drugs. Despite this, investigations by law enforcement have identified some practices designed to conceal the true nature of the substances and businesses. For example, customs agencies report that consignments containing new substances are often misdeclared as common chemical products and/or of a low value in order to conceal their true nature and avoid suspicion by law enforcement. Recent seizures of the potent opioid acetylfentanyl (which was linked to 32 deaths in 2015 in Europe) originating from China were misdeclared as ‘hot melt powder’, the suppliers attempting to conceal the drug as a commonly used adhesive. In addition, suppliers and importers may deliberately route substances to specific European air and sea ports in countries where the substance is not controlled in order to reduce the chance of interception. Once imported, the substances can then be freely moved around much of Europe.

In addition to supplying new substances, chemical companies may also sell the precursor chemicals that are needed to produce new substances. These are offered on the surface web as well as in anonymous marketplaces. Recent seizures by police of illicit laboratories in Europe operated by OCGs suggest that there may be increasing interest in producing NPS closer to home, where the profits may be higher, and, for some, the risks may be lower. This seems to be the case particularly for substances targeting the lucrative stimulant and opioid markets. The analysis of materials seized at these illicit laboratories confirms that in Europe there is both the capability and the capacity to produce a range of new substances — from cathinones, such as mephedrone and α-PVP, to fentanyls such as butyrfentanyl (see Case study 13). It will be important to closely monitor these developments, and to be alert to signals that suggest that the range of substances being produced in Europe has diversified and expanded beyond the illicit substances.
Similar to new substances, shipments of precursors may be misdeclared on custom declaration forms in an attempt to avoid detection by authorities. In 2015, customs seized a multi-kilogram shipment of the precursor 2-bromo-4-methylpropiophenone, which was being imported into Europe and which can be used to produce synthetic cathinones such as mephedrone. The precursor was misdeclared as ‘butadiene acrylonitrile rubber’ — which is an oil-resistant synthetic rubber used to produce a range of components for the automotive and aeronautical industries. Interestingly, also in 2015, the same precursor was seized in two clandestine laboratories in Europe producing mephedrone.

It is unclear if Europe is an important hub either for bulk quantities of new substances or as a supplier of finished products to third countries. Reports from law enforcement in both Europe and the United States suggest that both these activities take place, but, at this time, it is not possible to estimate their overall importance.

Impurities and adulterants

Information on the impurities in new substances and the products that contain them is severely limited. However, based on knowledge of known chemical synthesis pathways and experience, it is clear that some impurities arising from the production of new substances can cause serious health risks to users. Two examples of impurities leading to serious harms are relevant for the markets in cathinones and opioids. They relate to the synthesis of methcathinone and MPPP, impurities in both of which have been linked to brain damage that mimics Parkinson’s disease.

Case study 13: α-PVP production in Europe

α-PVP is a synthetic cathinone that was risk assessed by the EMCDDA in 2015, after signals of serious harms were detected from data reported to the EU Early Warning System. The risk assessment found that most α-PVP originates from companies in China, including a single seizure of almost 260 kg made at a European airport in 2015. In addition, in 2013 and 2014, two illicit production sites were seized in Poland, where multi-kilogram quantities of α-PVP were synthesised. The synthesis was supervised by trained chemists, and the laboratories were supported by suppliers, producers and distributors of chemicals. The companies involved operated their own websites selling and distributing α-PVP across Poland. In addition, Hungary reported two tablet manufacturing sites that were dismantled in 2013 and in 2014, and it appears that the operators of the sites intended to produce α-PVP tablets.

Similarly, there are limited data on the risks posed by other chemicals used in the manufacture of products containing new substances. In the case of some products, the new substance is dissolved in a solvent and then is sprayed on, or mixed with, plant materials. In addition, other substances used as excipients, such as microcrystalline cellulose (refined wood pulp), which is commonly used as an excipient/diluent in tablets, can cause serious injuries if injected. Chemical analysis of products also commonly finds a number of other active substances, not only new substances, but also illicit drugs and ‘cutting agents’, that may themselves pose risks or potentiate risk through interactions.

It appears that in some cases new substances are produced by companies that also produce a range of pharmacologically active substances — including other new substances and medicines — as well as other chemicals. This gives rise to important concerns about quality control with respect to cleaning procedures to prevent cross-contamination or carryover of potentially toxic residues.

Little is currently known about the potential for genotoxicity and carcinogenicity of new substances, or about the impurities and the adulterants they contain.

Given that most NPS are produced by companies outside the EU, it is difficult to gauge the potential impact on the environment. The new substances that are produced in Europe appear to be made by the same OCGs involved in the production of amphetamine and MDMA, so it is likely that the chemical waste is dumped in a similar way.