The first non-fentanil novel synthetic opioid to appear on illicit markets was the opioid analgesic, AH-7921 around 2012–13 (Fig. 4a), subsequently controlled internationally in 2014 and in the UK in 2015 as a Class A drug under the Misuse of Drugs Act [40,41,42]. A structurally unrelated compound, MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine, Fig. 4b), originally synthesized and studied in Japan in the 1970s as a candidate opioid analgesic, emerged and was controlled under the same legislation soon after [43,44,45]. A fluorinated analogue, 2F-MT-45 (1-cyclohexyl-4-(1-(2-fluorophenyl)-2-phenylethyl)piperazine) has recently been detected in the UK, however there is no evidence that the substance is available on vendor sites, possibly due to the unpopularity of MT-45 (and it’s recorded side effects) amongst users [46]. U-47700 (Fig. 2d), a structural isomer of AH-7921, was first detected in Europe in Sweden in late 2014. AH-7921, MT-45 and U-47700 have already been the subject of a number of detailed reviews and risk assessments [4, 5, 41, 44, 47,48,49,50,51,52,53,54] and all have now been internationally controlled. U-47700 was made a Schedule 1 substance in the United States in November 2016 [55] and the UK controlled it as a Class A Schedule 1 substance under the Misuse of Drugs Act 1971 and Misuse of Drugs Regulations 2001 in June 2017 [56]. China, widely agreed to be the main production site, banned its manufacture and export, along with MT-45, in July 2017 [27].

Fig. 4 Internationally controlled non-fentanil novel synthetic opioids a AH-7921 and b MT-45 Full size image

Since its appearance on the illicit drug market, U-47700 has become one of the most prevalent non-fentanil NSOs, particularly in the United States, and case reports referring to the substance in drug seizures and toxicology cases continue to be published [57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. In Europe, U-47700 was reported to the EMCDDA EWS in January 2015 [77]. The reporting of the presence of U-47700 in products that users may naturally believe to contain a different class of drug is of particular concern. U-47700 was recently detected in plant/incense-like products in Belgium, which would normally be expected to contain synthetic cannabinoid receptor agonists (SCRAs), colloquially known as “spice” [78]. In early 2016, U-47700 was detected in approximately 3000 illicit tablets of at least four visually distinct types in Scotland, one of which was visually identical to those known to normally contain the benzodiazepine etizolam and two of which would likely be described as “street diazepam” by users, illicit tablets with a high prevalence in the illicit drug market in Scotland [79].

As a result of the international control of U-47700 and the ban on its manufacture in, and export from, China [27], it is perhaps predictable that U-47700 prevalence will in the future, or will have already, started to decline as has been previously observed for many, but not all, substances in the same situation. U-47700 analogues originating from, or adapted from compounds reported in the early literature, have started to appear on illicit drug market and a high state of vigilance and information sharing is maintained through international early warning systems. Summary structural information on the compounds emerging on to the illicit market is provided in Table 2.

U-49900 (3,4-dichloro-N-[2-(diethylamino)cyclohexyl]-N-methyl-benzamide) is a novel structural analogue of U-47700 (Table 2), first noted on “research chemical vendors” websites and on online drug user fora in November 2016 [80]. A test purchase and analytical characterization study was carried out by the European Union (EU) co-funded RESPONSE project, run by the Slovenian National Forensic Laboratory in November 2016 [81], and soon after an alert was published by the EMCDDA EWS [82]. Unlike U-47700, for which at least limited early (and now updated) pharmacological data exist, no such data for this analogue are currently available. The chemical structure retains the majority of the key features that were identified by Loew et al. [14] as promoting MOR agonist mediated effects (3,4-dichloro on the phenyl ring, the lack of a methylene spacer and an N-methyl group adjacent to the carbonyl), but with N-diethyl substitution on the cyclohexyl moiety instead of the N-dimethyl substitution of U-47700 (Table 2). Fabregat-Safont et al. [83] identified and analytically characterized U-49900 in great detail using a drug sample seized in Spain. In addition, a monograph on U-49900 was recently published by the Scientific Working Group on Drugs (SWGDRUG) [84]. U-49900 has since been reported in seizures and toxicological samples in the United States. Krotulski et al. [85] describe the identification of U-49900 in post-mortem blood and urine specimens collected after an apparent drug overdose and U-49900 detection has also been reported in seized drug samples by the United States Drug Enforcement Administration (DEA) [86].

U-51754 was described in the original Upjohn Company patents and related studies [12,13,14] and has recently appeared on illicit drug vendor sites listed as both methene-U-47700 (most likely named as such due to the presence of the methylene spacer and to illustrate its relationship to U-47700 for marketing purposes) and U-51754 (see Table 2). U-51754 was first detected in Europe via a test purchased sample received by the RESPONSE project in October 2016. The sample was analysed and reported in January 2017 [87] and the data shared via the EMCDDA EWS [88]. U-48800 (2-(2,4-dichlorophenyl)-N-(2-(dimethylamino)cyclohexyl)-N-methyl-acetamide), differing from U-51754 only in the positions of one of the chlorine atoms on the phenyl moiety (Table 2), was not included in the original Upjohn Company patents or any of the related pharmacological studies. U-48800 was detected in Germany in a sample received for testing in October 2017 by the ADEBAR project, a project co-funded by the Internal Security Fund of the EU, the German Federal Criminal Police Office, the German Federal Customs Service and a number of State Bureaus of Criminal Investigations. The data was reported to the RESPONSE project in February 2018 [89] and detection of U-48800 in seized samples was also notified by the DEA in the last quarter of 2017 [86].

In early animal studies U-51754, was reported to be approximately ten times less potent as a MOR agonist (and therefore approximately 0.75 times the analgesic potency of morphine) than U-47700. It is likely to have more pronounced KOR mediated effects [13] than U-47700 due to the presence of a methylene bridge in the molecular structure [14], a feature shared by U-48800 for which no in vitro or in vivo data are currently available.

U-77891 (Table 2) started to appear on user discussion fora in early 2016 [90] continuing into 2017 [91] although there are no available reports of users actually receiving or taking the substance. It has appeared on clearweb vendor sites, although there is no confirmation that it is actually being sold and to the best of the author’s knowledge no seizures of this compound have been reported.

U-50488 (Table 2) has been commercially available from specialist chemical suppliers for some time and many research studies have utilised this model KOR agonist in experimental studies. The first reported illicit seizure in Europe was in Sweden in November 2017 and was reported to the EMCDDA EWS [92]. Analysis was carried out by the National Forensic Centre, Sweden and U-50488 was identified by comparison with a commercially available (±) trans isomer reference standard, although no determination of the stereochemistry of the U-50488 in the seized sample was carried out (Simon Dunne, National Forensic Centre, Linköping, Sweden, personal communication). As mentioned in the previous sections, the (−) trans-(1S,2S) isomer is a selective KOR agonist, whilst the (+) trans-(1R,2R) isomer is a non-selective opioid receptor agonist with relatively poor affinity for both the MOR and KOR receptors [15].

U-47931E/bromadoline (trans-4-Bromo-N-[2-(dimethylamino)cyclohexyl]-benzamide; Table 2) is a MOR agonist referred to in the original 1978 Upjohn Company patent [12] as example 10, with the name bromadoline being registered by the company in 1983 [93]. A 1985 study referred to bromadoline as a compound undergoing “clinical testings in humans for safety and efficiency” [94]. The paper refers to further studies being carried out on the disposition kinetics of bromadoline in humans and canines; however, apart from being included in a further study by Glaxo Group Research Ltd in 1987, the authors have been unable to find any further published studies on this compound [95]. Around September 2017, U-47931E/bromadoline appears to have started to be sold on web vendor sites and was identified for the first time in Europe by the RESPONSE project via a test purchased sample received in October 2017 from a web vendor [96]. The analytical data for the substance was reported in November 2017 and an EMCDDA EWS notification was communicated soon after [97]. The stereochemistry of the sample was not determined and, as far as the authors are aware, no seizures have yet been reported in the professional or peer-reviewed literature. A reference standard has been produced for the U47931E/bromadoline analogue N-methyl-U-47931 and is now commercially available [98], however, to the authors’ knowledge there is currently no indication that this compound has yet appeared on the illicit drugs market.

Isopropyl-U47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methyl-benzamide; Table 2) is one of the most recent U-drug analogues to appear on web vendor sites and was identified by the RESPONSE project via a test purchased sample, received in January 2018 [99]. To date the stereochemistry of the sample has not been determined and no European seizures have been reported in the open literature. Isopropyl-U47700 has been reported in toxicological samples from two cases submitted in March 2018 in the United States in which 3,4-methylenedioxy-U-47700 was also detected [9] and was reported for the first time in seizures in the DEA emerging threat report for the 2nd quarter of 2018 [100].

3,4-Methylenedioxy-U-47700 (trans-N-2-(dimethylamino)cyclohexyl)-N-methylbenzo[d] [1, 3] dioxole-5-carboxamide; Table 2) is the latest compound of this series to be reported to the EMCDDA EWS having been detected in a single sample seized in Poland in April 2018 [101]. The stereochemistry of the sample was not determined. The two chlorines in the 3, 4-position of the benzene ring have been replaced by a 3,4-methylenedioxy ring system, similar to that seen in a large number of psychoactive substances including substituted phenethylamines and cathinones. In early structure activity relationship studies for the N-substituted benzamides and acetamides, the removal of the chlorine atoms in the 3,4-positions of the benzene ring led to a complete removal of MOR mediated effects however there is no information available on the effect on the pharmacological profile of such a structural alteration. There is no information on the pharmacological effects of this substance although the substance has been detected in five cases submitted from January 2018 in the United States, and in two of these, isopropyl-U47700 was also detected [9, 10].

BDPC/bromadol To the best of the authors’ knowledge, at the time of writing there has only been one report of a drug seizure involving BDPC/bromadol. The seizure was reported in Montreal, Canada in 2013, although analytical data confirming the presence of the drug or details of the amounts seized is not currently publicly available and therefore the report cannot be confirmed [102]. There are no publicly available reports of any seizures in Europe.

Online discussion forum based discussions of emerging U-drugs and BDPC/bromadol

There are a number of drug-related internet fora and online drug user communities. The benefits and risks of the use of data from such fora for novel illicit drug research purposes have been discussed previously [103, 104]. When using such sites, users are generally seeking reports of drug use and experiential information and will also post self-reports on the characteristics of novel drugs and their subjective experiences with them. Previous studies have identified four main themes of the discussion threads on such fora where users sought (1) reliable information on novel and emerging substances, (2) dosage and administration information, (3) information on subjectively experienced effects of novel and emerging substances, and (4) support and safety information from other users [103]. Online communities such as this have been previously described as having a self-regulating approach to novel drugs appearing on the illicit market, rapidly sharing information on either harms associated with novel substances or if subjective effects are positive or negative. Researchers seeking information from such fora must acknowledge that the motivation for users to post information about new substances cannot be verified and the actual substance taken by the user can also not be verified—a user may not have been sold the substance they believe they have been sold by a web vendor. In addition, researchers must be aware of the placebo effect with regards to a self-reported subjective experience; the fact that users may have used other substances before, during or after the substance under test; and as regular drug users, they are likely to have built up tolerances to, in this case, opioids which will affect their response to a particular substance. Nevertheless, some useful information can be obtained on the timeline of the appearance of new drugs on the market and users subjective experience of them. The information provided below gives examples of online discussion fora threads only and is not an exhaustive list of such discussions available online.

Online discussions on U-49900 have already been reported previously [83] and are not discussed in detail here. Postings referencing either U-51754 or its alternative name, methene-U-47700, began to appear between May and September 2016 indicating that the drug had appeared on web vendor sites. One user referred to U-51754 as an alternative to U-47700 after the latter had “become illegal” and predicted that it might be dysphoric rather than euphoric [105]. Another user reported taking the drug rectally and claimed the effects were strong, dysphoric and dissociative and with a relatively short duration of around 45 min [106]. Forum posts in another discussion thread, discuss the original research published by the Upjohn Company [107]. Other users reported unpleasant dissociative experiences with no euphoria [108]. The reaction from forum users is generally negative and advice to avoid the substance has been communicated. Postings referencing U-48800 began to appear in April 2017 [109, 110]. In general, the response to this drug by users of online fora has been, as for U-51754, generally negative, although some posts have indicated a more positive, but mild experience [110]. User fora discussions of U-47931E/bromadoline started to appear around September 2017 and appear to identify variability in the products sold as U-47931E/bromadoline on vendor websites and also indicate that vendors were providing samples for testing with other purchases. In early posts, at least two distinct batches of the drug were discussed, one white in colour and one brown/tan. Detailed user reports for both batches describe distinct subjective user experience differences between the two [111, 112]. Insufflation of the brown/tan sample allegedly produced a rush and euphoria whilst another user states that the subjective effects of U-47931e/bromadoline are milder than for U-47700, but last longer [113, 114].

Discussions relating to 3-4-methylenedioxy-U47700 appeared in May and June 2017 [115, 116] and for isopropyl-U-47700 appear to start around November and December 2017 with users stating the latter drug had been offered for sale on vendor sites [117, 118]. The user response to these substances appears almost uniformly negative.

BDPC/bromadol has been discussed on online user fora for many years [e.g. 119, 120]; however, substances purporting to be BDPC/bromadol seem to have recently increased in prevalence on vendor sites (early to mid 2017). Since then a number of experiential reports have been posted and a common theme of such user reports is the lack of the sought after euphoric effects [8, 121]. Some users posting on a German language forum have reported buying BDPC/bromadol as a purported 10 mg/mL solution [121]. Due to its reported analgesic potency in animal studies, its reported MOR affinity, its appearance on vendor sites in a number of forms and the potential for harm, the prevalence of this compound in drug seizures and toxicological samples should be closely monitored.

It seems clear, at least from the limited information provided from drug user forum posts, that novel U-drug analogues and BDPC/bromadol are appearing on web vendor sites, although they may appear and disappear over relatively short time periods based on availability and user demand or response. Their actual prevalence in casework and appearance in biological samples is mostly unknown, but would be expected, at this time, to be very low. In general, the majority of these compounds, in the reports available, have been viewed negatively relative to the user experiences relating to U-47700. Given an understanding of the structure activity relationships and known pharmacology of those U-drug analogues that have been studied, this may be seen as not overly surprising. It will be interesting to observe if users will grow tired of trying these subjectively unpopular analogues or if they will continue to experiment with new analogues as they enter the market in the hope of a more subjectively positive user experience.