Number of Opioids Identified

By April 2019, the EMCDDA European Database on New Drugs (European Database on New Drugs [EDND], 2019) contained 751 entries, with 51 of them being classified as opioids. By February 2019, the UNODC listed a total of 892 substances in their NPS database (Unodc Early Warning Advisory on New Psychoactive Substances [UNODC EWA NPS], 2019), with 61 being NSOs. It could, however, be argued that the NPS scenario is much larger than that outlined by those substances that have been seized and formally identified by the European Union (EU) and the UN databases. Because the online NPS scenario typically predicts the real-life NPS market availability (Corazza et al., 2013; Schifano et al., 2015), identifying what is being discussed online by web-based NPS enthusiasts (e.g., the “e-psychonauts”) may well be of interest (Orsolini et al., 2015; Corkery et al., 2017).

Although data about the clinical, pharmacological, and toxicological characteristics of a number of opioid drugs have already been made available (Suzuki and El-Haddad, 2017; Armenian et al., 2018; Baumann et al., 2018; Beardsley and Zhang, 2018; Tabarra et al., 2019), there is a clear lack of knowledge relating to the number of novel substances offered to online/real-life customers (Kacinko and Papsun, 2019), also owing to the difficulties in detecting them in both interdiction and clinical settings (Abdulrahim and Bowden-Jones, 2018).

Fentanyl Analogs

Most (e.g., 55%) opioids identified here were fentanyl analogs. Although present findings do not necessarily confirm in any possible way these substances’ levels of use, they can still reflect the attention given by psychonauts to these drugs and help in explaining aspects of the current “opioid epidemic” (Kakko et al., 2019; Zhao, 2019). A few fentanyl analogs have been mentioned in the literature (Suzuki and El-Haddad, 2017; Zawilska, 2017; Misailidi et al., 2018; Lipiński et al., 2019), especially in terms of the acute clinical toxicity issues relating to their intake (Abdulrahim and Bowden-Jones, 2018). Vulnerable subjects can access online a large number of these substances (Suzuki and El-Haddad, 2017), without even being aware of what they are taking exactly (Ciccarone et al., 2017; Bardwell et al., 2019; McLean et al., 2019; Stein et al., 2019). Indeed, levels of related clinical toxicological information are sometimes available only postmortem (Giorgetti et al., 2017; Concheiro et al., 2018; D’Errico, 2018; Kraemer et al., 2019).

Apart from a range of some well-known fentanyl-related substances, two ohmefentanyl and seven carfentanyl analogs were here identified. It is of interest that the analgesic activity of ohmefentanyl in mice is 6,300 times more potent than that of morphine (Xu et al., 1985) and that carfentanyl has been reported in association with a number of fatalities (Wilcoxon et al., 2018). Given the wide range of common and street names available for each molecule, even small modifications occurring in the fentanyl family structure can lead to misidentification of the index drug (Akhondi et al., 2015) and potentially provoke clinically unexpected effects. It is also possible that some substances here commented by psychonauts included fentanyl precursors or metabolites (Wilde et al., 2019). Hence, it is particularly relevant, for the vast range of fentanyl analogs, to use unique codes such as those of IUPAC (Gaulton et al., 2017; Hähnke et al., 2018; PiHKAL, 2019).

Miscellaneous: Non-fentanyl Compounds, Prescribing Opioids, Herbals, and Derivatives

The 136 non-fentanyl analog opioids identified in the NPS.Finder^® database belong to a range of pharmacological classes, and some 10.2% were not reported by the EU and UN databases. Several of these substances have been used in the past for research purposes and/or were never marketed. The present findings are consistent with the current “top” and “rising” posts on social networks like Reddit (Reddit, 2019d). Some of these substances, for example, BDPC/bromadol have already been described as being some 500 times more potent than morphine (Reddit, 2019a; Sharma et al., 2019; TripSit Factsheets, 2019a), whereas others, for example, embutramide, have been associated with suicidal intent (Lajtai et al., 2016). A range of remaining substances identified here have received little/no attention in the literature and include acetoxyketobemidone (e.g., an alternative to ketobemidone, a prescription analgesic that is scheduled in different countries; United Nations Office on Drugs and Crime [UNODC], 1954; Drugs-forum, 2007; Bluelight, 2019a; Reddit, 2019c); 6-methylenedihydrodesoxymorphine/6-MDDM (e.g., a semi-synthetic derivative of hydromorphone about 80 times more potent than morphine and associated with euphoriant effects; Bluelight, 2019b; TripSit Factsheets, 2019b; Reddit, 2019e); isopropyl-U-47700 (identified for the first time in 2018 and belonging to N-substituted benzamides and acetamide opioid analgesics, colloquially known as “U-compounds” or “U-drugs;” Krotulski and Logan, 2018; Sharma et al., 2019; Yin, 2019); and piperidylthiambutene (developed in the 1950s and equipotent to morphine; Adamson and Green, 1950).

NPS.Finder^® identified here virtually all the prescription opioids listed in the ATC/DDD Index. The psychonauts’ interest in commenting about these substances may be a reason of concern, because prescription opioid misuse is a challenging issue worldwide, especially so in both North America and Europe (van Amsterdam and van den Brink, 2015; Helmerhorst et al., 2017).

NPS.Finder^® identified as well a range of well-known opioid herbal compounds, including Papaver somniferum and some crude opiate extracts (e.g., granulate, tincture, and poppy seed tea); Mitragyna speciosa/kratom (but not mitragynine and 7-hydroxymitragynine; Fluyau and Revadigar, 2017; Graziano et al., 2017; Coe et al., 2019; Corkery et al., 2019); and Salvia divinorum. Although herkinorin (Ventura et al., 2018) was not identified in the current database, salvinorin B ethoxymethyl ether/“Symmetry” (e.g., an unusually potent synthetic salvinorin compound, potently binding to kappa opioid receptors; Peet and Baker, 2011; Erowid, 2015; Reddit, 2019b), salvinorin B methoxymethyl (a potent semi-synthetic derivative of salvinorin A; Baker et al., 2009; Peet and Baker, 2011; Reddit, 2019f; Zjawiony et al., 2019), and salvinorin A received here the attention of psychonauts. This may be a cause for concern, because salvinorin products’ psychoactive effects include perceptual disturbances, psychosis, irritability, and anxiety (Ventura et al., 2018).

Finally, it is interesting to note that a range of both endogenous (e.g., amphibian opioid peptides such as dermorphins and deltorphins) and food-derived (e.g., derivatives from milk and soya such as soymorphines and β-casomorphins) opioid peptides, possessing low levels of potency (Teschemacher et al., 1997; Negri et al., 2000; Ohinata et al., 2007; Liu and Udenigwe, 2018), were not mentioned in psychonaut fora.

Comparison With European Union and United Nations Novel Psychoactive Substance-Related Databases

A total of 426 opioids (e.g., 234 fentanyl analogs and 192 non-fentanyl analogs) were identified. The number of NPS.Finder^® opioids is indeed higher than that listed by international agencies like the UNODC and the EMCDDA. By May 2019, the INCB identified 115 opioids (International Narcotics Control Board [INCB], 2019a); up to 2019, the UNODC EWA NPS listed 61 different opioids; by June 2018, the INCB listed 93 fentanyl-related substances with no known legitimate use (International Narcotics Control Board [INCB], 2019b); and by April 2019, the EMCDDA reported 51 opioids out a total of 749 EDND substances (European Database on New Drugs [EDND], 2019). There might be different reasons behind these inconsistencies. First, both the UN and EU agencies collect in their databases only those substances that are detected/seized and properly analyzed and most importantly reported, respectively, worldwide or in the European region. Furthermore, the NPS.Finder^® carried out a range of open web crawling identification activities focusing on a large range of psychonaut-based, specialized, multilingual, sources with a specific focus on new/old psychoactive substances of likely recreational interest. From this point of view, one could also argue that discussing a molecule on the web is not, per se, an indication that the index molecule is being/will be ingested by interested individuals. This can explain why the opioids common to all lists (e.g., the fentanyl analogs 4-fluoroisobutyrfentanyl, acetylfentanyl, acrylfentanyl, butyrylfentanyl, furanylfentanyl, ocfentanil, tetrahydrofuranylfentanyl, and the non-fentanyl analogs AH-7921 and U-47700) are only a small proportion of the total.

Pharmacological and Clinical Considerations

Fentanyl, fentanyl analogs, and the remaining opioids here commented present as partial/full agonists, and with different affinity levels, at the mu, delta, and kappa opioid receptors. This may well suggest the existence of a possible vast range of ill-health consequences associated with these substances (Stein, 2016). However, a clear understanding of the clinical toxicity of each compound is at present problematic. In fact, although the in vitro pKi values/binding affinities, potency, and efficacy levels for a number of opioids are already available (World Health Organization [WHO], 2016; Baumann et al., 2018; World Health Organization [WHO], 2018), these may not provide enough information about the relative in vivo potency (Baumann et al., 2018). In fact, there might be variable effects on G-protein-coupled receptors, which could potentially give rise to a great diversity of intracellular consequences following the administration of different analogs with apparently similar pharmacodynamics (Smith et al., 2018). Furthermore, as highlighted using a molecular docking model, some substances are too structurally similar for the scoring function to distinguish between different analogs (Ellis et al., 2018, 2019). For some opioids, larger dosages of naloxone may be required to reverse the opioid toxidrome than needed in case of a typical heroin overdose (Armenian et al., 2018; Lovrecic et al., 2019). The greatest levels of concerns remain related to fentanyl analogs, because of their harmful potential (Schifano et al., 2019a), the continuous high incidence of emerging analogs on the markets over the last years (Schueler, 2017), and the difficulties in identifying them with analytical chemistry techniques (Gerace et al., 2018b; Morrow et al., 2019). Conversely, those substances here identified possessing a full/partial kappa opioid receptor agonist activities (including salvinorin A and its derivatives; tifluadom; and pethidine) are likely to be particularly attractive for opioid and other research chemical consumers prone to a recreational experimentation associated with complex psychoactive effects (Coffeen and Pellicer, 2019).

The authors are grateful to Damicom srl, a small enterprise from Rome (Italy), whose professionals have developed the NPS.Finder^® web crawler and so generously have allowed here the testing of its potential.