Send Orders for Reprints to [email protected] 966 Current Neuropharmacology, 2020, 18, 966-1051 REVIEW ARTICLE The e-Psychonauts’ ‘Spiced’ World; Assessment of the Synthetic Cannabinoids’ Information Available Online Caroline Zangani1, Fabrizio Schifano2,* , Flavia Napoletano3, Davide Arillotta4, Liam Gilgar5, Amira Guirguis6, John M. Corkery7, Orsola Gambini8 and Alessandro Vento9 1Department of Health Sciences, University of Milan, Milan, Italy, Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 2Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 3East London Foundation Trust (ELFT), Homerton University Hospital, London, UK; 4Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Catania, Italy; 5Gabalfa Clinic, Cardiff and Vale NHS Health Board, Cardiff, UK; 6Swansea University Medical School, Institute of Life Sciences, Swansea, UK; 7Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 8Department of Health Sciences, University of Milan, Milan, Italy; 9Department of Mental Health, School of psychology, G. Marconi, Telematic University, Rome, Italy. ASL Roma 2, Rome, Italy. Addictions' Observatory (ODDPSS), Rome, Italy Abstract: Background: A wide range of novel psychoactive substances (NPS) is regularly searched and discussed online by web-based drug enthusiasts (i.e. the e-psychonauts). Among NPS, the range of synthetic cannabinoids (SC; ‘Spice’) currently represents a challenge for governments and clinicians. Methods: Using a web crawler (i.e. the NPS.Finder®), the present study aimed at assessing psy- A R T I C L E H I S T O R Y chonauts’ fora/platforms to better understand the online mentions of SC. Results: The open-web crawling/navigating software identified here some 1,103 synthetic cannabi- Received: December 13, 2019 Revised: February 10, 2020 noids. Of these, 863 molecules were not listed in either the international or the European NPS databases. Accepted: February 28, 2020 Conclusion: A web crawling approach helped here in identifying a large range of unknown SC DOI: likely to possess a misuse potential. Most of these novel/emerging molecules are still relatively 10.2174/1570159X18666200302125146 unknown. This is a reason for concern; each of these analogues potentially presents different toxi- codynamic profiles and there is a lack of docking, preclinical, and clinical observations. Strengthen- ing multidisciplinary collaboration between clinicians and bioinformatics may prove useful in better assessing SC-associated public health risks. Keywords: Psychonauts, NPS, new psychoactive substances, synthetic cannabinoids, web crawling. 1. INTRODUCTION Within this scenario, synthetic cannabinoids (SC), known also as synthetic cannabimimetics or synthetic cannabinoid 1.1. Background receptor agonists (SCRAs), constitute one of the main The web may play a pivotal role in the ‘life cycle’ of classes of new/novel psychoactive substances (NPS). De- NPS [1]. After being synthesized in illegal chemical labora- spite the term ‘novel’, the first products were synthesized by tories, NPS are then made available through e-commerce to pharmaceutical industries between the '70s and '80s, after interested customers. These customers include the e- noticing the potential analgesic, antiemetic and narcotic ef- psychonauts [2], whose primary aim is discovering and ex- fects of the endocannabinoid system [7]. periencing the effects of new chemical compounds [3, 4]. e- Since the first SC identification in the drug market in Psychonauts share their experiences on a range of multilin- 2008, the number of cannabinoids available has grown stead- gual, specialized, dedicated web fora/blogs [5, 6], hence ily. According to both the European Monitoring Centre for facilitating information spreading to other consumers of the Drugs and Drug Addiction (EMCDDA) and the United Na- index new psychoactive molecule [2, 3]. tions Office on Drugs and Crime (UNODC), SC are the most typically seized NPS reported in Europe and elsewhere [8-12]. *Address correspondence to this author at the Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life Whilst being labelled as ‘not for human consumption’ or and Medical Sciences, University of Hertfordshire, Hatfield, UK; as ‘laboratory products’ [13-15], SC are usually made avail- E-mail: [email protected] able in colourful packages with different names (e.g. ‘Spice’, 1570-159X/20 $65.00+.00 ©2020 Bentham Science Publishers The e-Psychonauts’ ‘Spiced’ World Current Neuropharmacology, 2020, Vol. 18, No. 10 967 ‘K2’, ‘Kronic’, ‘Voodoo’). SC use has been associated with virtual storage area and then in an MYSQL database which vulnerable subjects, including inmates and homeless people presented with an SSL security protocol. All data were en- [16]. crypted with asymmetric cryptographic procedures. Because of their activity on CB1 receptors, over the last 2.2. Data Collection decade, SC have at times been interpreted as the ‘legal sub- stitutes’ of cannabis [8]. Indeed, they show higher CB1 bind- NPS.Finder® extracted a range of NPS-related informa- ing affinity levels than (–)-trans-Δ9-tetrahydrocannabinol tion, including chemical and street names; chemical formula; (THC) [8], though multiple interactions with remaining three-dimensional images; and anecdotally reported clini- classes of receptors have also been commented [14]. Hence, cal/psychoactive effects. These data were automatically SC present with a range of unpredictable clinical effects, stored in an online, restricted access/password-controlled which have included severe ill-health events [17] and fatali- database located within firewall-protected, highly secure, ties [9, 10, 18]. and consistently performing servers. Clinicians and health professionals typically perceive 2.3. Data Screening and Duplication Check their NPS-, including SC-, related knowledge levels as in- adequate [19]. Indeed, the pace at which scientific evidence With the help of an ‘ad hoc’ check control panel, all data is updated cannot withstand the constant and rapid entry into were manually and carefully analyzed by 4 medi- the market of further NPS molecules. cally/psychiatrically trained professionals (i.e. FN; DA; CZ; and LG). In the case of data interpretation issues, these were 1.2. Aim resolved by consultation with FS, AG, JC and AV. The aim of the current research was to: (a) identify and The web crawler-identified SC molecules’ denominations categorise the number of SC molecules collected by a dedi- were first searched in Medline/PubMed [20] and in Goo- cated web crawler (i.e. the NPS.Finder®) from a range of gle®/Google® Scholar [21, 22]. A further screening was psychonaut, NPS-related, online sources; and (b) compare carried out with the help of Pubchem; [23] ChemSpider®; the NPS.Finder® SC list with related findings from the [24] and ChEMBL [25-27]. To avoid duplications, the Inter- UNODC and the EMCDDA. national Union of Pure and Applied Chemistry (IUPAC) denomination was used for each molecule. In this way, a 2. METHODS full assessment and editing of each NPS.Finder® data entry was carried out and the range of unique SC molecules 2.1. Search Strategy commented here was identified (please note that the To facilitate the process of early recognition of emerging complete and regularly updated list of NPS identified psychoactive molecules, a crawling/navigating software (i.e. by the web-crawler activities is freely available at the ‘NPS.Finder®’) was designed to automatically scan the https://npsfinder.com/home.php). open/surface web for new/novel/emerging NPS (for a thor- ough description of both web crawling and data cleaning 3. RESULTS activities please refer to recently published studies) [5, 6]. With the help of the web crawler activities, some 5922 This software was designed to map on a 24/7 basis the large substances were here identified. After proper data screening variety of psychoactive molecules mentioned within a range and duplication check completion, some 4204 unique NPS of popular online psychonauts websites/fora (Appendix 1). molecules were included in the database and 1718/5922 Firstly, a number of proper piloting searches were per- (29.01%) remaining molecules were found to be false posi- formed using a range of keywords, including: NPS; novel tives or duplicates. Of these, 1103 SC were collected, repre- psychoactive substances; new psychoactive substances; senting 26.2% (CI 95%: 25.9-27.6%) of the total number of emerging psychoactive substances; drugs online; buy new molecules, and the second largest group after psychedelic substances; psychonauts, drug forums; psychoactive prod- phenethylamines (30.1%; CI 95%: 28.7-31.5%). ucts; synthetic cannabinoids; synthetic cathinones; psyche- Conversely, by 13th June 2019, the UNODC listed 286 delic phenethylamines; novel stimulants; synthetic opioids; SC and, by 1st April 2019, and the EMCDDA database in- tryptamine derivatives; phencyclidine-like dissociatives; cluded 193 different SC. Some 863 SC (78.2%; CI 95%: piperazines; GABA-A/B receptor agonists; prescribed medi- 75.1-80.6%) were identified only by the NPS.Finder® and cations; psychoactive plants; psychoactive herbs; and image- 182 SC (16.5%;