TYPE Original Research PUBLISHED 03 August 2022 DOI 10.3389/fpsyt.2022.956120 Synthetic cannabinoids use in a OPEN ACCESS sample of opioid-use disorder patients EDITED BY Arianna Giorgetti, University of Bologna, Italy REVIEWED BY Francesco Paolo Busardò, María Alías-Ferri1,2 , Manuela Pellegrini3 , Emilia Marchei3 , Marche Polytechnic University, Italy Guido Pelletti, Roberta Pacifici3 , Maria Concetta Rotolo3 , Simona Pichini3 , University of Bologna, Italy Clara Pérez-Mañá4,5 , Esther Papaseit4,5 , Robert Muga6,7 , *CORRESPONDENCE Magi Farré Francina Fonseca1,8,9 , Magi Farré4,5* and Marta Torrens1,2,8 mfarre.germanstrias@gencat.cat 1 Addiction Research Group, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain, 2 SPECIALTY SECTION Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Cerdanyola del This article was submitted to Vallés, Spain, 3 National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy, Psychopharmacology, 4 Department of Clinical Pharmacology, Hospital Universitari Trias i Pujol and Institut de Recerca a section of the journal Germans Trias i Pujol (HUGTiP-IGTP), Badalona, Spain, 5 Department of Pharmacology, Therapeutics Frontiers in Psychiatry and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain, 6 Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i RECEIVED 29 May 2022 Pujol (HUGTiP-IGTP), Badalona, Spain, 7 Department of Medicine, Universitat Autònoma de ACCEPTED 18 July 2022 Barcelona (UAB), Cerdanyola del Vallès, Spain, 8 Addiction Program, Institute of Neuropsychiatry and PUBLISHED 03 August 2022 Addictions, Hospital del Mar, Barcelona, Spain, 9 Department of Medicine and Life Sciences (MELIS), CITATION Universitat Pompeu Fabra, Barcelona, Spain Alías-Ferri M, Pellegrini M, Marchei E, Pacifici R, Rotolo MC, Pichini S, Pérez-Mañá C, Papaseit E, Muga R, Fonseca F, Farré M and Torrens M Cannabis is the most widely consumed illegal drug in the world and synthetic (2022) Synthetic cannabinoids use in a cannabinoids are increasingly gaining popularity and replacing traditional sample of opioid-use disorder cannabis. These substances are a type of new psychoactive substance that patients. Front. Psychiatry 13:956120. doi: 10.3389/fpsyt.2022.956120 mimics the cannabis effects but often are more severe. Since, people with COPYRIGHT opioids use disorder use widely cannabis, they are a population vulnerable © 2022 Alías-Ferri, Pellegrini, Marchei, to use synthetic cannabinoids. In addition, these substances are not detected Pacifici, Rotolo, Pichini, Pérez-Mañá, by the standard test used in the clinical practice and drug-checking is more Papaseit, Muga, Fonseca, Farré and Torrens. This is an open-access article common in recreational settings. A cross-sectional study with samples of 301 distributed under the terms of the opioid use disorder individuals was carried out at the addiction care services Creative Commons Attribution License (CC BY). The use, distribution or from Barcelona and Badalona. Urinalysis was performed by high-sensitivity gas reproduction in other forums is chromatography-mass spectrometry (GC-MS) and ultra-high-performance permitted, provided the original liquid chromatography-high –resolution mass spectrometry (UHPLC-HRMS). author(s) and the copyright owner(s) are credited and that the original Any synthetic cannabinoid was detected in 4.3% of the individuals and in 23% of publication in this journal is cited, in these samples two or more synthetic cannabinoids were detected. Among the accordance with accepted academic practice. No use, distribution or 8 different synthetic cannabinoids detected, most common were JWH-032 reproduction is permitted which does and JWH-122. Natural cannabis was detected in the 18.6% of the samples not comply with these terms. and only in the 0.7% of them THC was identified. Several different synthetic cannabinoids were detected and a non-negligible percentage of natural cannabis was detected among our sample. Our results suggest that the use of synthetic cannabinoids may be related to the avoidance of detection. In the absence of methods for the detection of these substances in clinical practice, there are insufficient data and knowledge making difficult to understand about this phenomenon among opioid use disorder population. KEYWORDS cannabis, synthetic cannabinoid, opioid use disorder, new psychoactive substances, urine sample analysis Frontiers in Psychiatry 01 frontiersin.org Alías-Ferri et al. 10.3389/fpsyt.2022.956120 Introduction especially those with psychosis (4). The national survey among the Spanish general population shows a prevalence of SC use of Cannabis is the most used illicit drug worldwide, with an the 0.6% and increases to 1.2% in the group aged between 25 and estimated 200 million users (approximately 4% of the world’s 34 years (14). population) between the ages of 15 and 64 in 2019 (1). In Europe, OUD individuals have not been the focus population for it is also the most widely used drug, with a prevalence of daily studying these substances, which are more likely to be present in use of 1.8% in the general population and 10.3% in individuals recreational settings, such as music festivals or raves, or among between 15 and 24 years of age, respectively (2). e-psychonauts. In the present study, we investigated the use In recent years, synthetic cannabinoids (SCs) have emerged of natural and synthetic cannabis in an OUD population from as substitutes for natural cannabis as they are cannabinoid Barcelona through urinalysis. types 1 and 2 receptor agonists similar to tetrahydrocannabinol (THC), the main psychoactive component of cannabis, which is a partial agonist (3). The most common products containing SCs Materials and methods are smoking mixtures, e-liquids, and infused paper (4). Some effects of SCs intoxication are loss of consciousness, respiratory Study design and participants depression, and behavioral alterations such as aggression or self-injury (5). Over the years, different generations of SCs A secondary analysis from a cross-sectional study of have appeared, each time showing a higher potency than THC, 301 OUD individuals was conducted. The samples belong making them attractive to some consumers (3, 6). Recently, to two collections: one from identified patients from whom a fourth generation of SCs has been described, which could sociodemographic and clinical data were collected, and the cause serious damage to health based on its pharmacological other from anonymous patients with no data collected. Patients and toxicological activity (7). The effects experienced may differ were recruited at addiction care facilities at Hospital del Mar between SC users, as in the case of cannabis use, including (Barcelona) and Hospital Universitari Germans Trias i Pujol feelings of euphoria, relaxation, or even paranoia (5); however, (Badalona) in Spain, from February 2019 to March 2020 and they are usually more intense than those experienced with from July to October 2020, respectively. Due to the impact and natural cannabis (8). changes in the functioning of addiction care services during the SCs were first synthesized in 1970 in an attempt to find COVID-19 pandemic, no samples were collected from March new analgesics for pain treatment, but it was not until the 13th until July 6th , 2020. 2000s that they appeared in the market (9). The popularity of Participation in the study was voluntary, and urine samples these compounds was boosted in 2004 by the emergence of a were collected from each participant. All participants, as an new product called “Spice” (4). A few years later, in 2008, the inclusion criterion, have been diagnosed with OUD by a first cases of poisoning related to SCs use were reported (4), psychiatrist/psychologist according to the fifth edition of the some of which resulted in fatal overdoses (10). Since 2008 to Diagnostic and Statistical Manual of Mental Disorders (15), date, the European Union Early Warning System controls 209 participation in an opioid agonist treatment program, and >18 different SCs; thus, SCs are the largest group of new psychoactive years of age. None of the eligible participants were excluded from substances (NPS) monitored (2, 4). the study. Cannabis is commonly used by patients with opioid use The study was approved by the local Ethical Committee disorder (OUD) (11), which points to this population as a of Clinical Research of the Parc de Salut MAR (CEIC-PSMAR potential consumer of SCs. Other SC users include regular number: 2018/8138/I) and the Hospital Universitari Germans cannabis users, people who experiment with new drugs (e- Trias i Pujol (CEIC-HUGTiP number: PI-18-126). psychonauts), increasingly vulnerable groups, such as high-risk Other details of the participants and methods can be found users (4, 12), and men aged between 13 and 59 with a history of in previous publications that did not focus on SCs (16, 17). polydrug use who consider SCs a good alternative to cannabis (13). Since SCs are not detected in the standard toxicological urine tests used in clinical practice, they can be easily used by Urine analysis individuals for pleasure and enjoyment (13). Notably, the prevalence of SC use is <1% in the Urine samples (9 ml) from recruited individuals were European general population, but this is higher if we focus on collected and stored at −20 ◦ C (in Nunc CryoTubesTM) subpopulations such as young adults or psychiatric patients, until analysis. Sample preparation involved a liquid-liquid extraction and urinalysis was performed using two different validated methodologies. Ultra-high-performance liquid Abbreviations: NPS, new psychoactive substance; OUD, opioid use chromatography high-resolution mass spectrometry (the disorder; SC, synthetic cannabinoid; THC, tetrahydrocannabinol. full scan MS and fragmentation data-dependent MS/MS) Frontiers in Psychiatry 02 frontiersin.org Alías-Ferri et al. 10.3389/fpsyt.2022.956120 was processed by Thermo Scientific TraceFinderTM TABLE 1 Cannabis-related substances and metabolites detected among opioid use disorder urine samples (N = 301). software. The built-in database, mass spectral library of over 1,000 compounds of which more than fifty SCs Substances and metabolites detected N (%) (naphthoylindoles, phenylacetylindoles, indazole carboxamides, tetramethylcyclopropylindoles), retention times, isotope pattern Samples positive to SCs* 13 (4.3) matching, elemental composition determinations are used to JWH-018 1 (0.3) identify and confirm drugs and metabolites in the analyzed JWH-032 4 (1.3) samples. The matching threshold to establish LOIs (limit JWH-122 or JWH-122 N-4-hydroxypentyl / 4 (1.3) of identification) was set at 80%. Moreover, mzCloud Mass JWH-122 N-5- hydroxypentyl Spectral Library was also used as mass spectra international JWH-200 2 (0.7) library for peak identification (Advanced Mass Spectral JWH-209 2 (0.7) Database; www.mzcloud.org). In gas chromatography, the JWH-210 or JWH-210 N-4-hydroxypentyl / 2 (0.7) full scan data files were processed by an AgilentWorkstation JWH-210 N-5- hydroxypentyl (Agilent Technologies). The mass spectra international library RCS-8 1 (0.3) (NIST, National Institute of Standards and Technology research UR-144 or UR-144 N-5-hydroxypentyl 1 (0.3) library) was used for peaks identification (18). Samples positive to natural cannabinoids* 56 (18.6) Cannabidiol - Cannabinol - Data analysis THC 2 (0.7) 11-Nor-9-carboxy-THC (THC-COOH), 56 (18.6) Frequency-based descriptive analysis was carried out using cannabidiol, or cannabinol SPSS (version 22.0; SPSS Inc., Chicago, IL, USA). * Samples can contain more than one SCs o natural cannabinoid. Results populations. While some show a similar, although somewhat A total of 301 urine samples were collected and analyzed. lower prevalence of 15% in positive urine samples (21), other Although more than 50% of the samples were collected studies show a higher prevalence of e.g., 58% (20) and 63% (22). anonymously, subjects were part of an opioid agonist treatment Differences in the prevalence of cannabis use in this population program, the sociodemographic characteristics of patients in this could be explained by characteristics of the sample such as the program indicate that 68% of the patients were men and the country where the studies were conducted. mean age was 52 years (range: 22–77 years old). This study highlights the importance of investigating the The SCs and cannabis derivatives detected in these samples consumption of SCs in this population, as there are limited are shown in Table 1. studies on this topic. Along with this lack of knowledge, Some SCs were detected in 13 (4.3%) urine samples, and 8 we found that polydrug use in the OUD population is different substances of this type were identified. Among these, widespread and often includes cannabis and cannabinoids two or more SCs were found in three (23.07%) samples. The among other substances (17, 23). Polydrug use is associated most detected NPS cannabinoid types were JWH-032 and JWH- with an increased risk of relapse, fatal overdose, and suicidal 122 in four (1.3%) cases each. JWH-018, RCS-8, and UR-144 ideation and attempts (23). Of note, SCs are one of were less common, present in only one (0.3) case each. the groups of NPS with the highest number of reported Natural cannabis was detected in 56 (18.6%) samples. In all intoxications (24). cases, carboxy-THC, cannabidiol, or cannabinol were identified. Human studies for the investigation of the clinical aspects THC was identified in only two (0.7%) of the samples. of SCs are currently limited and usually focused on cases of intoxication or fatalities (25). Although, these are some reports Discussion of observational studies focused on pharmacological effects and fewer on the detection of these substances in addicted We detected the use of SCs in individuals with OUD populations, such as OUD individuals, as is the case of the who were attending addiction care facilities in Barcelona and present study (26–28). Badalona. Notably, cannabis use was widespread among the We hypothesized that there are several factors that could study participants with a Contrary to our results, previous explain the increased use of cannabis and SCs, in recent years. studies in Finland and Germany did not find the presence of SCs First, the legalization of this substance in several countries has in a similar population (19, 20). Furthermore, previous studies contributed to a lower perception of the risk of consumption have investigated the prevalence of natural cannabis use in OUD in the population than the risk perception pre-legalization Frontiers in Psychiatry 03 frontiersin.org Alías-Ferri et al. 10.3389/fpsyt.2022.956120 (1, 29). Another reason is the increase in the consumption of Author contributions cannabinoids for therapeutic or medical purposes, which can lead to misuse and even abuse of these substances (5). Finally, MA-F, MT, and MF: formal analysis. MT, MF, RP, and the view that SCs are safer than other drugs and are a good SP: conceptualization, study design, funding acquisition, and alternative to natural cannabis indicates that these substances are supervision. MA-F, MP, EM, MR, RP, SP, CP-M, RM, EP, FF, potentially abused (30). MT, and MF: investigation. MA-F, MP, RP, SP, MT, and MF: methodology. RP, MT, and MF: project administration. MA-F, SP, MT, and MF: writing–original draft. All authors writing– Conclusion review and editing and read and agreed to the published version of the manuscript. We detected several types of SCs in patients with OUD in Barcelona and Badalona. Additionally, a non-negligible percentage of cannabis use was detected in our sample. Funding These findings suggest that cannabis use is prevalent among patients with OUD and may be substituted by cannabinoid- This work was supported by: European Union’s Justice like NPS to avoid detection in clinical tests. Since we do Programme—Drugs Policy Initiatives (number 806996— not have the instruments and protocols for NPS detection JUSTSO—JUST-2017-AG-DRUG) (GRANT AGREEMENT in clinical practice, knowledge about this phenomenon is NUMBER: 806996-JUSTSO); Instituto de Salud Carlos very limited in this population. It would be interesting III (ISCIII, Fondo de Investigación en Salud (FIS)-Fondo to continue this line of research to have more updated Europeo de Desarrollo Regional (FEDER), Grant Numbers: knowledge about the use of SCs. Importantly, this study FIS PI17/01962 and FIS PI20/00804; Grants RD21/0009/0001 had limitations: first, the samples analyzed were provided by and RD21/0009/0004 funded by Instituto de Salud Carlos III voluntary participants; therefore, random sampling was not (ISCIII-FIS-FEDER Red de Investigación en Atención Primaria exercised. Second, the possibility of detecting substances is de Adicciones-RIAPAd-RICORS), and by the European Union linked to the time of use, dose, and elimination half-life in NextGenerationEU, Mecanismo para la Recuperación y la urine before elimination; these factors were not analyzed in Resiliencia (MRR), Gencat Suport Grups de Recerca, Grant this study. Numbers: 2017 SGR 316 and 2017 SGR 530; The Presidency of the Ministers Council, Department of Antidrug Policies in Italy. Data availability statement Conflict of interest The original contributions presented in the study are included in the article/supplementary material, further inquiries The authors declare that the research was conducted in the can be directed to the corresponding author/s. absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics statement Publisher’s note The studies involving human participants were reviewed and approved by Ethical Committee of Clinical Research of All claims expressed in this article are solely those of the the Parc de Salut MAR (CEIC-PSMAR Number: 2018/8138/I) authors and do not necessarily represent those of their affiliated and Hospital Universitari Germans Trias i Pujol (CEIC- organizations, or those of the publisher, the editors and the HUGTiP Number: PI-18-126). 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