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The new drug phenomenon

2014; Wiley; Volume: 6; Issue: 7-8 Linguagem: Inglês

10.1002/dta.1686

1942-7611

Simon D. Brandt, Leslie A. King, Michael Evans‐Brown,

Neurotransmitter Receptor Influence on Behavior

This special issue provides a multidisciplinary snapshot of recent developments of the broader, arguably phenomenal, changes to the drug market that have occurred in the past decade related to the rise of the new drug phenomenon. This change is largely a result of the growing commodification by entrepreneurs, and increasingly, by criminal groups, of a huge range of psychoactive substances not controlled under drug laws and fuelled by their sale on an open market. The issue includes papers that were presented at the Third International Forum on New Drugs, organized by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and held in Lisbon in June 2013. The aim of the forum was to bring together experts from around the world to exchange experiences, identify information gaps and research needs, as well as anticipate future developments and challenges related to the emergence of new drugs. The issue builds on and provides an update to the papers published in the special issue on new psychoactive substances published in Drug Testing and Analysis in 2011 (Vol. 3, issues 7–8). Other issues dedicated to psychoactive substances ('illicit drugs' and 'psychedelic substances') were also published in 2011 (Vol. 3, issue 9) and 2012 (Vol. 4 issues 7–8), respectively. In every issue of the journals in the fields of pharmacology, medicinal chemistry, the botanical sciences, and biochemistry, articles appear that advertise the isolation, synthesis, or evaluation of materials which have some pharmacologic action. Any article describing a new family of compounds ('Potential Centrally Active Stimulants Evaluated in Experimental Animals', for example) will encourage an unknown number of synthetic repetitions by underground researchers and manufacturers (with immediate pharmacologic evaluation in man). These studies follow none of the recognized guidelines for clinical investigation and are not responsible to any regulatory agency. If the results are undesirable or unacceptable, the matter is forgotten. If the results are considered virtuous or marketable, a new product appears briefly, under some popularly recognizable name and achieves, de facto, a broadly based " clinical" evaluation. When the product survives this initial marketing experiment, a new drug problem has made its appearance on the drug-abuse scene. However, if the product proves unacceptable (dysphoric, debilitating, lethal), the inquiry is dropped. Such explorations continue outside of the awareness of the social body politic.7 Keeping Dr Shulgin's observations in mind, one cannot help but think that little has changed. Over the past few years, the new drug phenomenon has become largely defined by both the growing number of substances being detected from increasingly broader chemical and pharmacological families, and the open sale of many of these substances as 'legal highs', 'bath salts', or 'research chemicals' from bricks and mortar and online shops that specialize in the sale of such substances and/or cannabis seeds and drug paraphernalia (so-called head shops or smart shops), but they are also sold by street-level drug dealers.5, 6 Others have emerged as a result of their diversion and misuse as medicines,5, 6, 8 while to a lesser degree, new drugs continue to emerge as a result of their production in either hobbyist or clandestine laboratories. In the latter case, this includes new drugs, which emerge either deliberately or unintentionally as a result of the use of unlisted precursors, such as 4-methylamphetamine synthesized from 4-methylphenyl-2-propanone.9 Most new substances first emerged as a result of chemical curiosity either from formal or informal study, and were commodified by entrepreneurs who saw the potential value of the substance based on initial human experimentation. From a historical point of view, perhaps only a comparatively small number have emerged on the drug market and gained a foothold beyond experimental use by psychonauts and diffused to broader sections of the population. Ketamine, 3,4-methylenedioxymethamphetamine (MDMA) or γ-hydroxybutyrate (GHB) may serve as prominent examples.3, 4, 10 In some cases the diffusion of these substances appeared to be a rather slow process compared to how they may be presented in the media. For example, experimental use of MDMA began, if not in the late 1960s, then certainly by the early 1970s, with broader use only occurring from the 1980s onwards. Of note is that ketamine, MDMA and GHB did not emerge as 'legal' replacements to controlled drugs, although it seems reasonable to assume that their non-controlled status under drug laws in some countries ultimately helped their diffusion: during the early 1980s, MDMA tablets, for example, were sold by entrepreneurs in Texas as 'Sassyfras' in bottles, mislabeled as a health food product while mainstream marketing techniques of mail order using a toll-free phone number and payment by credit card were used as well as sale in bars which were subject to sales tax.3 The appearance of new psychoactive substances (NPS) on the drugs market that are not controlled under international and national drug control laws is not a new phenomenon; many of the substances themselves were first synthesized years ago. The 'cat and mouse game', whereby there is a continuous circumvention of existing legislation as new substances appear, can be traced back to the early years of the twentieth century with international attempts to control esters of morphine.11 In recent years, however, there has been an increasing commodification of the market in new substances. This has been fuelled by entrepreneurs, and increasingly organized crime groups, who have exploited a growing manufacturing capacity in countries such as China and India and globalized trade. Here, the Internet has played a key role in both the advertisement and sale allowing an open market to develop. This is reflected in the rapid rate of appearance of NPS, which in Europe over the past few years has averaged one new substance every 5–6 days. Indeed in 2013, 81 NPS were detected on the European drug market compared to 74 in 2012, 49 in 2011, and 41 in 2010. In the first five months in 2014, 37 were detected.6 Similarly, monitoring of Internet shops typically selling new substances as 'legal highs' and 'research chemicals' to European consumers by the EMCDDA identified 651 shops in 2013, similar to the 693 identified in 2012 and vastly higher than the 314 and 170 shops identified in 2011 and 2010, respectively.6 Though a number of ring-substituted phenethylamines, such as 2,5-dimethoxy-4-methylamphetamine (STP)12, 13 began to appear in the 1960s, a major shift began in the late 1970s, and particularly in the 1980s with the emergence of the proliferation of uncontrolled derivatives of α-prodine and fentanyl (e.g. α-methylfentanyl and 3-methylfentanyl) which were given the nickname 'designer drugs' by Gary Henderson.14 The term was pointing towards analogs of compounds with proven pharmacological activity manufactured by underground chemists for sale on the street which meant, for example, that MDMA and its analogues were originally not considered as such.14 It has been estimated, however, that in 1984 the concept of designer drugs appeared only four times in the US print media while it rose to about 400 times in 1985/1986, which also included increasing association with MDMA.15 Table 1 provides some representative examples of designer drug definitions. Although many substances had been deliberately created to evade drugs legislation, some, such as desmethylprodine or 3,4-methylenedioxypyrovalerone (MDPV), provided examples of what might be termed 'failed pharmaceuticals', namely substances originally developed by the pharmaceutical industry as potential therapeutic agents, but which, largely for unknown reasons, were never commercialized as licensed medicines. Indeed, an increasingly important feature of the new drug phenomenon in more recent years has been the re-discovery of these agents as a potential source for commercial distribution on the drug market. There is little doubt that the publication of PiHKAL in 199116 and TiHKAL in 199717 provided the next stimulus for novel substances. During the 1990s, many new substances on the illicit market were ring-substituted phenethylamines, almost all of which had been described in PiHKAL and have been classified as designer drugs. The impact of TiHKAL was less marked; although many novel tryptamines appeared, they have been of minor significance and never became widespread or were ever seen in large quantities, perhaps reflecting the smaller market for hallucinogens compared to stimulant and entactogenic substances. Throughout this period, illicit drugs were manufactured in clandestine laboratories, mostly located in Europe and the United States, and produced as tablets bearing characteristic logos or as powders. They were sold directly on the illicit drug market, often surreptitiously as amphetamine and MDMA (or more commonly as 'ecstasy') by criminal networks; sometimes they were sold as a 'new type' of ecstasy or as drugs in their own right. In the European Union (EU), concern about new substances was focused on possible health risks and the problems that could arise, particularly in terms of law enforcement and judicial cooperation if such substances were controlled in some member states, but not in others.18 It was agreed that progress could be made by sharing information and by establishing a risk-assessment procedure and a mechanism for their eventual control across the EU. This led, in 1997, to the 'Joint Action concerning the information exchange, risk assessment and control of new synthetic drugs' (NSDs) (Table 1).19 By the early years of the twenty-first century, however, there began a diversification into new drug families; a process that in the past few years has taken on an unprecedented pace.5, 6 Some of these substances fitted the description of designer drugs, some were NSDs, some 'failed pharmaceuticals', while others were plants or plant products. Even a few licensed medicines became drawn into the net. The EU Joint Action of 1997 was replaced in 2005 with a strengthened mechanism based on Council Decision 2005/387/JHA.20 Thus, NSD was replaced with 'new psychoactive substance' (NPS), which encompassed a broader definition (Table 1). The United Nations Office for Drugs and Crime has subsequently adopted an essentially similar definition but also introduced the legally contentious concept of abuse.21 In the UK in 2011, the Home Office Advisory Council on the Misuse of Drugs (ACMD)22 created a definition of what it called 'novel psychoactive substances' which contained a modified definition with reference to 'seeking for intoxicant use' (Table 1). In 2013, the European Commission proposed new legislative measures that would replace the Council Decision with the aim of strengthening the response to new psychoactive substances in the EU; the proposals are currently being examined by the Council of the European Union and the European Parliament.23-25 Alongside these many definitions, many less formal names have been used including 'research chemical' and 'plant food', while synthetic cannabinoids frequently became known and marketed as 'incense' or 'herbal smoking blends', such as 'Spice' and 'K2'.26 In New Zealand, piperazine derivatives were known as 'party pills' and in the United States cathinone derivatives became 'bath salts'. Some of these names were selected as attempts to circumvent regulatory systems by hiding the fact that they were intended for human consumption. Table 2 shows how a selected group of substances may be captured by these various definitions. Although the term 'legal high' had been used since at least the 1950s, it gained more common currency during the 1970s, largely to describe herbal products.27, 28 Since the emergence of substances such as the synthetic cathinone mephedrone in the late 2000s, it has become a widely used term, often by the media and subsequently the public, to refer to the entire group of largely synthetic new substances. Today, a 'legal high' is frequently perceived as a psychoactive substance not covered by existing domestic drugs legislation but this is often not the case, with the media frequently referring to now controlled drugs, such as mephedrone and synthetic cannabinoids, as 'legal highs' which confuses the issue. There is a need to consider this carefully, for example, when collecting data related to public health, which may be destined to inform policymaking, as highlighted by King and Nutt.29, 30 Understandably these developments, particularly those related to the open sale of 'legal highs' and 'research chemicals', have caused concern in policymakers, drug professionals, the media, and general public that society is exposed to hundreds of 'legal' pharmacological replacements for cannabis, MDMA, amphetamine, cocaine, and heroin. While many new substances will not gain a foothold as drugs in their own right and spread to broader groups of users, they may still be capable of causing serious harm. The largely unknown pharmacology, their routes of administration, and their potential potency, can pose serious risks to users. This is compounded by both the growing range of substances and the generally high availability; problems that are especially apparent when they are sold as 'legal highs' with no information provided to the user of the actual substance(s) and dose present, and as a result of an increasing number finding their way to the black market where they are sold as ecstasy, cocaine, ketamine, heroin, or LSD to unsuspecting users.6 The emergence of new drugs has created a need for access to reference material in order to verify their identification. Structural elucidation of newly encountered substances requires the availability of sufficient amounts of material, which is normally not an issue when bulk powders or pellet-type formulations are encountered. A more critical issue is their detection in biological fluids related to serious adverse events, such as deaths,6 as well as for drug testing required by the criminal justice system. Here the concentration values are much smaller and implementation of techniques such as liquid chromatography nuclear magnetic resonance (LC-NMR) is normally not available in routine laboratories. Various forms of mass spectral detection methods are often involved in the analysis of newly emerging substances, which may offer first clues about their identity. It has been increasingly recognized in recent years, however, that the presence of isomers has to be considered as well, which can place obvious limitations on the reliance on mass spectral analysis alone. The time lag between compound identification and its availability from commercial suppliers has decreased, thanks to the increasing speed of dissemination regarding the detection of newly identified substances (e.g. through drug monitoring systems such as the European Union 'Early Warning System on New Psychoactive Substances' (EU Early Warning System),6 publications in scientific journals, and discussions available on the Internet, etc.). Practical difficulties can arise, for example, when the attempt to purchase certified reference material results in exceedingly long delays. In cases where such standards fall under legislative control, commercial suppliers have to comply accordingly, for example in the form of applying for an import licence. One alternative, presumably also used by commercial suppliers of reference material, is the purchase of uncontrolled material from Internet vendors followed by purification and certification. Ideally, compound identification of a suspected new compound is supported by targeted organic synthesis. Clearly, some compounds may be more challenging to prepare than others but a range of advantages are frequently observed: (1) the analyte in question may not be commercially available; (2) a targeted synthesis of its isomers enables unambiguous identification; (3) independence from commercial suppliers; (4) ability to observe synthesis-related impurities which may be relevant when characterizing a newly emerging substance, thus, gaining potential insights into how this substance may have been manufactured; (5) extending the synthesis of a currently emerging substance to a range of analogs and derivatives allows for the ability to disseminate analytical data to the forensic, law enforcement and clinical community at the same time. The preparation of target analytes and impurities can also form an important basis for further studies beyond analytical characterization, such as exploration of pharmacological features and metabolism. The articles presented in this special issue provide examples where a number of these angles have been explored. Dr Albert Hofmann, the famous natural product chemist and discoverer of LSD, psilocybin, and many other biologically relevant substances, had an extraordinary track record in terms of published and patented research when working at Sandoz.31 An important body of work included an extensive exploration of tryptamine chemistry and one example that became relevant in 2012 was 5-(2-aminopropyl)indole (5-IT) which was associated with 24 deaths in Europe that were reported to the EU Early Warning System.32 In 2013, this resulted in a decision by the Council of the European Union to subject the substance to control measures across the EU following a risk assessment conducted by the Scientific Committee of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).33 5-IT, and five of its isomers, including α-methyltryptamine (AMT, 3-IT), which indicated some bioactive properties, had been prepared by Hofmann and Troxler in the early 1960s.34 The need for re-investigating the synthesis of such examples often stems from the fact that a range of analytical data considered important from a contemporary perspective, for example MS and NMR, were often not available in those earlier days. In the present issue, Scott et al. have re-investigated the synthesis and characterization of all six isomers and demonstrated the ability to differentiate between the isomers at the same time.35 An important observation made during the preparation of 2-IT was that the solvent commonly used during the final reduction step (tetrahydrofuran) led to the formation of a tricyclic by-product. The implementation of an HPLC-based method was described by Herraiz and Brandt who demonstrated that 5-IT was a selective, competitive and reversible inhibitor of the monoamine oxidase A isozyme (MAO-A) with IC50 and Ki values of 1.6 μM and 0.25 μM, respectively.36 It was also demonstrated that 5-IT was less potent than clorgyline and harmaline but more potent than toloxatone and moclobemide under the in vitro conditions studied. Another range of psychoactive materials that emerged in recent years was based on the 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) template. In a carefully researched investigation, which included interviews with contributors from online discussion forums, Morris and Wallach trace the history of non-medical use of dissociative agents. The authors skillfully guide the reader from the beginnings of non-medical use of PCP starting to be recognized in the late 1960s to recent inventions made by recreational users themselves as exemplified by methoxetamine and beyond.37 The preparation and full characterization of three PCP derivatives (3-MeO, 4-MeO and 3-Me) and their PCPy counterparts have been provided by Wallach et al. who demonstrated that differentiation between the isomeric candidates was feasible. Interestingly, a GC-MS induced degradation following the analysis of 4-MeO substituted analytes was observed (HCl salts) which led to the detection of 1-(1-cyclohexen-1-yl)-4-methoxybenzene.38 The availability of cathinone-based products has caught the attention of extensive research in recent years and the range of products commercially available tends to differ around the world. Christie et al. provided an exciting example of how non-invasive analysis can be effectively employed when analyzing cathinone products that used to be commercially available. The authors demonstrated the powerful combination of organic synthesis of cathinone isomers with analysis by Raman and infrared spectroscopy.39 The exploration of rigidified conformers based on a range of 2,4,5-trisubstituted phenethylamines, which eventually became known as FLY and DFLY analogues, has yielded potent 5-HT2A receptor agonists40 and a number of them have briefly appeared on the recreational market although it is currently unclear how prevalent these particular analogues are at this stage. As is the case with many other phenethylamines, a commonly used method of synthesis includes the preparation of ketone precursors that are then subject to reductive amination procedures. Following this approach, O'Connor and Keating explored the preparation and characterization of four ketone intermediates to set the scene for their future conversion to 3C-B-FLY and bromo-dragonFLY, respectively. The other two ketones were represented by their dehalogenated counterparts.41 The synthesis and characterization of nitracaine (3-(diethylamino)-2,2-dimethylpropyl 4-nitrobenzoate), methoxypiperamide (4-methoxyphenyl) (4-methylpiperazin-1-yl)methanone) and mephtetramine (2-((methylamino)methyl)-3,4-dihydronaphthalen-1(2H)-one) was described by Power et al. who encountered these substances as 'research chemicals' from online vendors in 2013. The authors extended the work to the incubation with pooled human liver microsomes to assess their transformation by LC-MS.42 The presence of nitracaine was also confirmed in a test purchase. Nitracaine is the 4-nitrobenzoate analogue of dimethocaine (4-aminobenzoate nucleus), which has also appeared on the market. While dimethocaine has been shown to display cocaine-like properties,43 further work is warranted to assess whether nitracaine shows a similar profile. The synthesis of N-methyl-1-(thiophen-2-yl)propan-2-amine (methiopropamine, MPA) was first published in 194244 and represents a thiophene bioisostere of methamphetamine. It appears to be considered as a psychostimulant although detailed studies are unavailable. However, it has been marketed as an individual substance or in combination with others in a range of branded products. The pyrolysis of MPA, i.e., mimicking conditions encountered during smoking, was investigated by Bouso et al. who observed the formation of 13 products. Ten analytes were confirmed by synthesis and the authors could show that the pyrolysis products were formed in analogy to those observed with methamphetamine. In addition, it was also confirmed that β-keto MPA and a bicyclic tetrahydropyridine compound were formed.45 Aminorex (5-phenyl-4,5-dihydrooxazol-2-amine), originally described in the early 1960s as a potential anorexigen, commercialized as such, and later withdrawn from the market as a result of it causing an epidemic of pulmonary hypertension,46, 47 forms a template that can give rise to a range of analogues with anorectic properties in animals.48 One of the analogues described at the time, i.e., 4-methylaminorex (4-MAR), appeared briefly as a recreational psychostimulant in the late 1980s49 but aminorex-type substances have generally not been encountered to a large extent. However, 27 deaths have been reported in Hungary and the United Kingdom to the EU Early Warning System in the past year, which were associated with the detection of the previously unknown analogue para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni'). Brandt et al. describe a comprehensive investigation that included the preparation and analytical characterization of the (±)-cis- and (±)-trans- racemates. A test purchase from an Internet shop confirmed that (±)-cis-4,4'-DMAR was available for sale as a 'research chemical'. Finally, studies with rat brain synaptosomes, which included the comparison with d-amphetamine, aminorex and (±)-cis-4-MAR showed that (±)-cis-4,4'-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 ± 1.1 nM (DAT), 26.9 ± 5.9 nM (NET) and 18.5 ± 2.8 nM (SERT), respectively.50 Non-clinical studies such as that provided by Brandt et al., which characterize the chemical, pharmacological, and toxicological properties of new psychoactive substances provide critical data in our understanding of the potential harms posed by such substances in order to understand the data reported through early warning systems. The impact of degradation on analysis has to be taken into account as well when dealing with the detection of drugs in biofluids as it is not always clear whether the presence of certain analytes is the consequence of degradation or metabolism. External factors of relevance include temperature, pH, exposure to light, type of matrix and duration of storage. Soh and Elliott investigated the stability of 13 new drugs in blood and plasma at room temperature using LC-based UV and Q-TOF methods of detection. Two substances that were shown to suffer particularly from instability under the conditions used were 4-methyl-N-ethylcathinone (4-MEC) and AMT. While the former became undetectable in blood within 14 days, with a corresponding loss of 54% in plasma, the latter was observed to result in a variety of breakdown products. The remaining eleven new drugs remained stable in blood and plasma for at least 21 days. Casework data have also been presented. For example, in the case of 4-MEC, dihydro-4-MEC was detected as a metabolite but also as a degradation product during storage.51 Emilia Fornal reported the electrospray ionization Q-TOF product spectra for thirty-nine substituted cathinones. The high resolution approach enabled the identification of dissociation pathways due to the ability to determine the molecular formulae associated with the particular product ions.52 The nature of immunoassay screening kits requires time for development when new substances appear on the market and a number of challenges have to be overcome if these are to be employed under routine conditions. Swortwood et al.53 and Ellefsen et al.54 have taken on the challenge of evaluating a range of kits and compounds. In the former case, sixteen immunoassay kits were obtained and tested with 24 phenylethylamines (including 8 substituted cathinones), 3 piperazines, and 3 tryptamines. In the latter case, the authors tested commercialized anti-mephedrone and anti-MDPV antibodies, which included method development, validation and analysis of authentic urine samples followed by confirmatory screening by LC-MS, and in both studies, both potential for high-throughput analysis and opportunities for improvements have been highlighted. Given the diverse nature and background of newly emerging substances, available data on their bioactive properties can vary quite dramatically and perhaps in the majority of cases, very little is known without further study. An extra dimension in the debate has been set against the backdrop of the situation in New Zealand where the Psychoactive Substances Act 2013 has been introduced, which has laid the foundation for a pre-marketing regulatory framework associated with new drugs. An important key feature includes the need for establishing low risk of harm, and while exact details remain to be determined in more detail, there is little doubt that the implementation of established rules, guidelines and procedures commonly encountered in the medicine regulatory system will be important.55-58 The recently enacted Psychoactive Substances Amendment Act, offered further clarification that, as a principle, animal tests obtained from experimentation within New Zealand should not form the basis for decisions regarding product approval.59 Whether this might raise occasional deviation from procedures commonly accepted as industrial standards remains to be seen. In any event, the challenges remain in cases where little data may be available about a particular substance, which includes questions about the extent of toxicity and whether a new drug is psychoactive in the first place. The perspective article provided by Andrew Leach touches on a range of methods used in the pharmaceutical industry to assess whether a given substance shows desired (efficacy) and/or undesired effects (toxicity) within the field of central nervous system-targeted development. It is also pointed out that although computational results do not form part of the submission of a regulatory package, a range of both two- and three-dimensional predictive tools are commonly explored to inform drug development. The range of in vitro, in vivo, and supporting experimental and computational approaches is vast and yet, the failure rate of clinical trials is far over 90%, which highlights the difficulties when attempting to evaluate and predict central nervous system (CNS) related properties.60 Major challenges remain for the development of new CNS-targeted medicines based on the knowledge of primary targets alone and the same may apply when attempting to assess abuse potential. There is a tendency to apply some form of post-rationalization of the off-target effects of known compounds when interpreting adverse events associated with new drugs, for example, when pointing towards similarities in binding targets, which also includes the use of computational methods. While the concept of substitution pharmacotherapy has been applied to nicotine or heroin addition, similar principles have been of interest to research for treatment strategies associated with cocaine and amphetamine-type psychostimulant dependence. This gives rise to the idea of evaluating psychostimulant-like substances for thei