New Psychoactive Substances (NPS) remain the fastest growing recreational drug class on the market. With 201 different substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) until December 2019, the class of synthetic cannabinoid receptor agonists (SCRAs) represents the largest subgroup of NPS,1 and SCRAs use has become particularly popular in prisons.2-4There is evidence that synthesis of new compounds and their distribution is driven by chemical companies mainly located in China and possibly also in other countries like India.5 Different national legislative approaches have been applied to impede the spread of NPS. In most countries the common approach is to schedule new drugs under the legislation for narcotic drugs or psychotropic substances. However, a few countries implemented specific NPS laws using generic definitions. These laws are either based on chemical structures (e.g. Germany, Croatia, Turkey and Australia) or on the psychoactive effects of the compounds (e.g. Austria, United Kingdom and Ireland). In 2013, New Zealand implemented the ‘Psychoactive Substances Act’ and created the possibility of a regulated legal market for NPS. Although formally this law remains in force, no product has been approved to date for a number of reasons, one of them being the necessity of animal experiments to show that the products are ‘low‐risk’.6

In Germany, until November 2016 a limited number of NPS was scheduled under the Narcotics Law (BtMG = Betäubungsmittelgesetz). However, the lengthy process of inclusion of new substances into the annexes of the Narcotics Law resulted in a ‘cat and mouse game’ where online shop owners always had the chance to sell NPS without the risk of prosecution. Once a substance was scheduled under the Narcotics Law, new uncontrolled SCRAs were launched on the market, usually by minor modifications of the molecular structure of known, prohibited drugs. In November 2016, the German law on NPS (NpSG = Neue‐psychoaktive‐Stoffe‐Gesetz) entered into force. In contrast to the Narcotics Law, the NpSG covers groups of substances as defined by structural features. In this law, SCRAs were defined by a modular chemical structure based on four characteristic structural elements: core, linker, linked group and sidechain, a system that has been proposed by Kikura‐Hanajiri et al..7 As a consequence, all relevant SCRAs marketed at that time in Germany and 86% of the SCRAs monitored by the EMCDDA were covered by the law. In contrast to the BtMG, the NpSG does not lead to criminal prosecution for acquisition and possession of NPS intended for personal use.

One of the most popular SCRAs in 2016 in Germany was 5F‐MDMB‐PINACA (better known under the name 5F‐ADB), although it had been scheduled under the German Narcotics Law in May 2016. 5F‐ADB features a 5‐fluoropentyl side chain attached to an indazole core and a methyl tert ‐butyl‐leucine linked group connected by a carboxamide linker at C‐3 of the indazole core. The human consumption of this SCRA resulted in severe toxicity as documented by a number of reports on poisonings and deaths.8-10 In August 2018, 32 NPS were banned by law in China. Among these were eight SCRAs including 5F‐ADB.11

In this letter we report on ‘the rise and fall’ of 5F‐ADB (chemical structure in Figure 1) in Germany, as documented by the prevalence of this substance in urine and serum samples analyzed in our laboratory and the prevalence in test purchases in the period from 2016 to 2019. At the same time, the prevalence of the structurally closely related synthetic cannabinoids 5F‐MDMB‐PICA and 4F‐MDMB‐BINACA (chemical structures in Figure 1) will be analyzed. There is a close structural similarity between 5F‐MDMB‐PICA and 5F‐ADB, the former containing an indole instead of an indazole core. 4F‐MDMB‐BINACA can be regarded as a homolog of 5F‐ADB and carries a 4‐fluorobutyl instead of a 5‐fluoropentyl side chain. The restriction of our analysis to these three compounds is based on the assumption that producing laboratories can easily switch between such compounds by exchanging one of the synthesis precursors. The findings will be discussed in the context of changes in the German and Chinese legislation as shown in Figure 2.

Between January 2016 and September 2019, a total of 987 herbal blends containing SCRAs (tested with a method described by Moosmann et al. 12) were purchased online mainly from shops with websites in German language during a market monitoring continually performed in our laboratory. In none of these products the active ingredient was declared. During the study period, 4,291 serum, heart blood or femoral vein blood samples were tested for SCRAs during routine analysis with an LC–MS/MS method regularly updated with all relevant compounds (as reflected by the online monitoring). The method was recently described in detail by Giorgetti et al..13 In total, 575 samples were tested positive for at least one SCRA, resulting in a positivity rate of 13%. Urine samples were analyzed using a validated LC–MS/MS screening method for metabolites of SCRAs based on the method published by Franz et al., 14 additionally covering 4F‐MDMB‐BINACA. During the period under review in this letter, a total number of 24,369 urine samples were analyzed with a positivity rate of 14%. Urine samples were obtained from German prisons, forensic psychiatric hospitals, rehabilitation clinics or private service laboratories, whereas the major proportion of the serum and blood samples was obtained from other German forensic toxicology laboratories (mainly post mortem and ‘driving under the influence of drugs’ samples).

In Figure 2, the positivity rates of herbal blends containing 5F‐ADB, 5F‐MDMB‐PICA or 4F‐MDMB‐BINACA are shown on a quarterly basis. During the first two quarters of 2016, the proportion of herbal blends positive for 5F‐ADB was 30%, falling to 5% in the third quarter after being scheduled under the Narcotics Law in May, and to 0% by the end of the year. Surprisingly, after the introduction of the NpSG the proportion of herbal blends containing 5F‐ADB increased until the third quarter of 2018. Then, the proportion of positive herbal blends containing 5F‐ADB decreased again and reached 0% in the third quarter of 2019. A similar development is reflected by the results of the analysis of biological samples. The decrease starting in the fourth quarter of 2018 could best be explained by the ban of 5F‐ADB in China in August 2018.7 In contrast to the herbal blends, the proportion of positive biological samples never reached zero, regardless of the regulations in Germany or China. This finding might best be explained by ‘stocks’ of 5F‐ADB products kept by users. Apart from that, the relative proportions of 5F‐ADB positive herbal blends generally were in good agreement with the proportions in serum and urine samples. The SCRA 5F‐MDMB‐PICA was first detected in the second half of 2016 and dropped in 2017, possibly due to the introduction of the NpSG. Unexpectedly, it appeared again in the first quarter of 2018 and prevalence in biological samples steadily increased from 3/2018 to 3/2019, reaching a maximum of approx. 60% in serum samples and approx. 50% in urine samples. The latest compound with close structural similarity to 5F‐ADB is 4F‐MDMB‐BINACA which has been detected in serum and urine samples starting in 2019 and quickly reached positivity rates of up to 50%. In test‐purchased herbal blends, 4F‐MDMB‐BINACA was first detected shortly after receiving the first positive biological samples. Interestingly, 4F‐MDMB‐BINACA was mainly identified in products of online shops formerly selling products containing 5F‐ADB, which was not the case for 5F‐MDMB‐PICA. Therefore, this new SCRA can be regarded as a replacement for 5F‐ADB. Human CB₁ in vitro receptor affinity (radioligand binding assay) and receptor activation ([³⁵S]GTPgammaS binding assay) seem to be very similar for 5F‐ADB and 4F‐MDMB‐BINACA (own unpublished data).

The presented example suggests that scheduling SCRAs under German legislation – either the Narcotics Law or the NpSG – had only limited effects on the spectrum of substances offered by NPS online shops and consumed by drug users. In contrast, the prohibition of 5F‐ADB in China clearly had an effect on its availability and led to a shift towards structurally similar SCRAs in 2019. It is likely that available production capacity in the synthesis laboratories that formerly produced 5F‐ADB was used for synthesis of these compounds by simply exchanging a precursor. Although our data is restricted to compounds offered in online shops delivering to German addresses and relative prevalence in a subgroup of German users, similar correlations can be expected in other European countries with specific NPS legislation complementing the national Narcotics Law. Our data also shows that an efficient overall reduction of NPS supply was neither achieved by scheduling NPS under the Narcotics Law nor by the introduction of the NpSG in Germany. Although the internationally accepted logic of scheduling narcotic drugs does imply legal control of NPS, which probably can only be achieved by generic laws in an efficient way, the effectiveness of such regulations has to be questioned. It might be worth having a closer look at countries with decriminalizing drug policies like Portugal and the Netherlands instead, where NPS seem to be underrepresented when compared to other European countries.15, 16

The example of the ‘rise and fall’ of 5F‐ADB shows that product monitoring by test‐purchasing and analyzing NPS products in combination with data from the analysis of human blood and urine samples are helpful tools to shed light on changes in local drug supply, drug demand, and market mechanisms.