JMIR RESEARCH PROTOCOLS Grifell et al Protocol Self-reported Subjective Effects of Analytically Confirmed New Psychoactive Substances Consumed by e-Psychonauts: Protocol for a Longitudinal Study Using a New Internet-Based Methodology Marc Grifell1,2,3,4,5*, MD; Guillem Mir Fuster4*, BSc; Mireia Ventura Vilamala4, PhD; Liliana Galindo Guarín1,6,7, PhD, MD; Xoán Carbón Mallol4, BA; Carl L Hart3,8, PhD; Víctor Pérez Sola1,2,5,9, PhD, MD; Francesc Colom Victoriano1,5,9,10, PhD 1 Mental Health Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain 2 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Laboratory of Neuropsychopharmacology, Department of psychology, Columbia University, New York, NY, United States 4 Energy Control, Asociació Benestar i Desenvolupament, Barcelona, Spain 5 Institute of Neuropsychiatry and Addiction, Parc de Salut Mar, Premia De Mar, Spain 6 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom 7 Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom 8 Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States 9 Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain 10 Departament of Basic, Evolutive and Education Psychology, Universitat Autònoma de Barcelona, Barcelona, Spain * these authors contributed equally Corresponding Author: Marc Grifell, MD Mental Health Research Group Hospital del Mar Medical Research Institute Dr Aiguader, 88 Barcelona, 08003 Spain Phone: 34 933160400 ext 129 Fax: 34 93 316 04 10 Email: marcgrifellguardia@gmail.com Abstract Background: During the last few years, the continuous emergence of new psychoactive substances (NPS) has become an important public health challenge. The use of NPS has been rising in two different ways: buying and consuming NPS knowingly and the presence of NPS in traditional drugs as adulterants. The rise of NPS use is increasing the number of different substances in the market to an extent impossible to study with current scientific methodologies. This has caused a remarkable absence of necessary information about newer drug effects on people who use drugs, mental health professionals, and policy makers. Current scientific methodologies have failed to provide enough data in the timeframe when critical decisions must be made, being not only too slow but also too square. Last but not least, they dramatically lack the high resolution of phenomenological details. Objective: This study aims to characterize a population of e-psychonauts and the subjective effects of the NPS they used during the study period using a new, internet-based, fast, and inexpensive methodology. This will allow bridging an evidence gap between online surveys, which do not provide substance confirmation, and clinical trials, which are too slow and expensive to keep up with the new substances appearing every week. Methods: To cover this purpose, we designed a highly personalized, observational longitudinal study methodology. Participants will be recruited from online communities of people who use NPS, and they will be followed online by means of a continuous objective and qualitative evaluation lasting for at least 1 year. In addition, participants will send samples of the substances they intend to use during that period, so they can be analyzed and matched with the effects they report on the questionnaires. https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 1 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Results: The research protocol was approved by the Institutional Review Board of the Hospital del Mar Research Institute on December 11, 2018. Data collection started in August 2019 and was still ongoing when the protocol was submitted (September 2020). The first data collection period of the study ended in October 2020. Data analysis began in November 2020, and it is still ongoing. The authors expect to submit the first results for publication by the end of 2021. A preliminary analysis was conducted when the manuscript was submitted and was reviewed after it was accepted in February 2021. Conclusions: It is possible to conduct an institutional review board–approved study using this new methodology and collect the expected data. However, the meaning and usefulness of these data are still unknown. International Registered Report Identifier (IRRID): DERR1-10.2196/24433 (JMIR Res Protoc 2021;10(7):e24433) doi: 10.2196/24433 KEYWORDS psychotropic; psychoactive; psychonautic; longitudinal; observational; pharmacology; psychopharmacology; subjective effects; sentinel; mental health; public health; internet; eHealth; cathinones; drugs of abuse; psychedelics; mobile phone; smart phone; online recruitment; online forums well-known legal or illegal drugs, such as opioids, ecstasy, or Introduction stimulants [5]. Importance of New Psychoactive Substances Between 2009 and 2017, 803 NPS were reported in 111 To date, new psychoactive substances (NPS) still represent a countries or territories [2,6]. In the European Union, by the end very important challenge to legislate, monitor, study, and of 2017, the number of NPS was over 670, of which 632 were develop health interventions. The understanding of use patterns notified after 2004 [2,7]. However, evidence suggests that the remains poor, with most information being based on populations NPS scenario could be much larger than that formally identified and settings where problems have already occurred [1]. by international agencies. In a recent publication, Schifano et al [2] used a web search engine to identify NPS discussed online The ever-increasing number of psychoactive substances used by NPS enthusiasts. Using this methodology, they identified a nowadays represents a new challenge for psychiatry, as the few thousand NPS, a number which is about 4-fold higher than pharmacodynamics and pharmacokinetics of many NPS are not the figures suggested by European and international drug yet thoroughly understood [2]. In addition, NPS consumption agencies. rarely occurs in isolation from other habits but, on the contrary, is placed within a kaleidoscopic range of poly drug use There is an ongoing debate on the scale of challenges posed by trajectories. There seems to be no differential risk for NPS use NPS, as the evidence on the prevalence of NPS use is scarce. compared with the use of traditional psychoactive substances For example, general population surveys suggest that the such as alcohol, cannabis, or cocaine [1]. prevalence of NPS use is relatively low, with the best estimates found in the scientific literature being between 1% and 2% in This new phenomenon represents an unprecedented challenge the United Kingdom. However, the speed of technological in the field of drug use as well as a fast-growing problem from innovation and the ease of synthesizing NPS present substantial social, cultural, legal, and political perspectives [3]. challenges to regulatory authorities, researchers, and clinicians NPS: Definition [5,8]. NPS are substances of abuse, either in a pure form or a NPS: Challenges preparation, that are not controlled by the 1961 Single NPS may now pose a big challenge due to several factors: Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances but which may pose a public health 1. NPS consist of several different classes of substances, which threat. It is important to note that different authors have vary in their psychological and physiological effects. previously referred to them as designer drugs, legal highs, Treatment is often difficult because of the young age of herbal highs, bath salts and research chemicals. Moreover, the most users and the possibility of concurrent polysubstance term new does not necessarily refer to new inventions but to use. The pattern of use is often intermittent in social substances that have recently emerged on the market [4]. Hence, settings, so it may be perceived as less of a problem [9]. new can include a failed pharmaceutical or an old patent that 2. NPS appear into—and sometimes disappear from—the has been rediscovered for recreational substance [2]. market very quickly, and as such, they are not significantly impacted by regulatory efforts. Currently, new substances Another distinction being made is between NPS and emerging are identified in Europe at a rate of one or more per week psychoactive substances, where the latter term captures all NPS [10]. Several key studies have shown the continued use and as well as drugs that may not be newly invented but have popularity of mephedrone, a popular NPS, among specific recently experienced a resurgence of, or increase in, use [2]. drug-using populations after it was brought under control. However, to simplify this work, only the term NPS will be used, The scheduling of new substances could even increase the also including all emerging psychoactive substances. Most NPS speed at which manufacturers innovate, to bypass the law are the result of minor changes to the molecular structure of [11]. https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 2 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al 3. NPS are mainly distributed through the internet in a The same authors also reported that sentinel populations are transnational market without solid information about their likely to be at a greater risk of NPS use. However, it remains effects and risks [11]. During recent years, the widespread mostly limited to attendees of nightclubs where different sexual availability of internet access has led to a gradual, although orientations are accepted. Other authors have also remarked only partial, shift from a street to a web market [12]. The that only a handful of studies have moved beyond prevalence increased web-based distribution has been seen in both the to explore subjective user experiences and motivations [11]. surface web and dark net [13]. 4. Currently, the potential data sources that can provide some NPS can substitute traditional drugs in times when their information on the acute effects of NPS consumption are as availability is restricted [8]. This could be problematic, as follows: (1) user self-reports on internet discussion forums, (2) this substitution happens both by introducing new surveys answered by users, and (3) fatal and nonfatal case substances in the market as well as by selling NPS as reports. traditional drugs, exposing large populations, unknowingly, to the effects of a new unstudied substance without previous Self-reports and surveys are mostly based on self-reported use experiences. This is especially dangerous, combined with rather than the analytical confirmation of the substances used. the rapid turnover of NPS, as they change before we can In contrast, case reports are usually generated from hospital obtain research data using conventional methodologies [5]. settings in the context of an intoxication or overdose with 5. There is a concerted effort to grapple with the challenges multiple substances involved, so there is analytical confirmation of researching NPS, as traditional methodologies are too of the substance but no self-reported effects. Unsurprisingly, slow and expensive to generate relevant and timely data on the literature is dominated by studies investigating the problems the effects of NPS [5]. associated with NPS (773/995, 77.7% of records). Therefore, 6. Clinicians are not usually able to identify a potential NPS caution is required when interpreting these data because of the user, and NPS usually produce negative results to traditional following limitations: drug tests, which are designed to assess a very limited • Users will report what they believe they have used, rather number of traditional substances [6]. On the other hand, than whatever substance is actually taken [10]. NPS users rarely search for professional help linked • Intoxications with multiple substances in hospital settings exclusively to this problem, and clinicians are not trained do not target the information on psychopharmacological to screen or identify NPS use. effects of a particular NPS [5,8]. What Has Been Done and What Is Needed in NPS In their empirical and conceptual review to produce research Research? recommendations, Mdege et al [8] provide the following advice Despite the high number of publications about NPS during the for research, among others: last 20 years, especially after a sharp increase in 2010, there are 1. The need to be aware of innovation opportunities, such as still concerning gaps in our understanding of the phenomena. testing emerging NPS brands online as they become From the evidence map about the NPS research performed by available. Mdege et al [8], 2 things appear quite striking: 2. Using cohort study designs to better understand the • First, most of the studies were performed in a general determinants of NPS use and related physical and mental hospital population (118/294, 40.1%) or specialist settings health, psychosocial problems, and how patterns of (24/134, 18.2%), with relatively low rates of studies coming involvement and consequences change over time. from the internet population (5/59, 8%). In addition, these 3. What are the prevalence and patterns of NPS use in the studies mainly reported severe intoxication or other acute general UK population and do they differ between NPS-related problems. subgroups of the population? • Second, the most frequent study design reported in the 4. Are there sentinel populations capable of being monitored indexed peer-reviewed literature was case series and/or to provide early warnings of new trends? reports (n=367), followed by the literature review (n=243), 5. Which acute intoxication problems are associated with NPS the survey (n=130), and the secondary quantitative data use? analysis (n=99), with only 13 existing randomized 6. Which promising approaches are currently available or can controlled trials, 6 prospective cohort studies, and 1 be made available in the United Kingdom for intervening case-control study [5,8]. with NPS use? There are also some specific limitations to the research Finally, they concluded that there is a need for a major research performed till date. Although the most robust and representative effort to be directed at NPS, which should address NPS together data on NPS use are for mephedrone (surveys have been with other forms of licit and illicit drug use [5,8]. conducted in the United Kingdom since 2010), Mdege et al [8] acknowledge important limitations to this most robust research. The e-Psychonaut Population For example, although participants may report using a substance, Both the limitations and recommendations stated above lead to the names of NPS are sometimes used interchangeably, and the necessity of conducting a longitudinal study in a specific there is no analytical confirmation of the true compound that and potential sentinel population, such as internet was taken. Therefore, there is inherent uncertainty in the NPS–consuming communities. This would allow for early reported use of a particular NPS. assessments of the effects of recently emerged drugs and to https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 3 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al study the patterns of consumption, harm reduction strategies, mephedrone users. Mdege et al [8] also found that NPS users and long-term drug-related problems. often report substance use disorder symptoms, especially craving. Available data on sentinel populations are growing. For example, several studies of attendees of gay-friendly night clubs This community may have some other distinct characteristics. suggest that the trend in reduction of mephedrone witnessed A minority of the sample reported that an NPS was the first nationally may also occur in this subgroup. However, the study drug that they had ever taken. Of those who ceased using NPS, of this sentinel population has failed to predict future harms and majority found it either easy or very easy to stop. Most trends in the global NPS market [5]. commonly, cessation was due to the side effects of NPS [17]. They also perceived internet forums as an important channel Conversely, data on another sentinel population, namely, through which to communicate information on new drugs, and e-psychonauts, have been able to predict future NPS-related retailers reported monitoring forums to determine which drugs harms occurring in more general settings [2]. to stock in their store [8]. These users also tend to post online In fact, the sentinel population of e-psychonauts has been warnings based on first-hand experiences about the potential considered by several authors as potentially useful in identifying harms of the substances consumed and are willing to avoid harm NPS availability, market, and diffusion in advance. This to their peers. Orsolini et al [13] even stated that posting online population is believed to be responsible for shaping and the on drug experience report is arguably the trait d’union of influencing the drug scenarios of the future [13]. In addition, all e-psychonauts, considering the intention behind using a Corazza et al [3] provided evidence supporting the claim that substance is the most significant difference between a the online NPS scenario predicts the real-life NPS scenario. psychonaut and a typical drug user. O’Brien et al [11] also identified the role of e-psychonauts in disseminating emerging The term psychonaut was first described by Newcombe [14] as information about NPS-related harm and considered them well an adult user of psychoactive drugs who takes these substances equipped to make a valuable contribution to NPS policy debates in normal, everyday settings with the intention of subjectively in general, and e-psychonauts are ideally placed to report on exploring their effects. the effects of recent policy changes on NPS-related harms in Some years later, O’Brien et al [11] coined the term particular. cyber-psychonauts to refer to their sample composed Several authors have tried to engage cyber-psychonauts as predominantly of NPS consumers. Cyber-psychonauts are research participants. Mdege et al [8] found difficulties in further defined by their commitment to harm reduction, to using involving NPS users throughout the project due to a lack of NPS safely and responsibly, and to purchasing chemicals online willingness on the part of NPS users to be contacted in ways [8]. other than email. In addition, working with this population has Tackett-Gibson [15] also documents the existence of online inherent sampling problems: internet research participants are, communities populated by self-defined experts in using NPS, by definition, a nonrandom and self-selecting sample, and it is providing a contrasting narrative around drug use and risk to very difficult to know the characteristics of the overall pool that established by the scientific community. A brief perusal of from which the sample is drawn [18,19]. relevant websites confirms the existence of a great number of Different authors believe that these internet communities are a NPS-related discussion threads, suggesting the existence of an huge opportunity for researchers. The qualitative analysis of online community of more discerning NPS users [15]. how different groups interact with online communities may Orsolini et al [13] also refer to this population in their more help to systematize and codify needs, values, and preferences recent study, identifying educated and informed users within that are relevant to the group [20]. In internet communities, web-based drug forum communities, who can provide reliable researchers can simply recruit participants or even go further information on psychoactive compounds. They refer to these and engage drug users more fully in dialog [21]. Some authors users as e-psychonauts, providing the best characterization of even state that the lack of physical presence and separate the population to date [13]. The e-psychonauts appear to be physical settings all reduce researcher control and power, mainly young and unmarried White males, presenting good or thereby potentially leading to a more balanced relationship excellent employment conditions and with a set of key skills, between researchers and participants [22,23]. In any case, including awareness to their inner soul; high standards of e-psychonauts are a hidden, hard-to-reach population that may knowledge about drugs’ chemical and pharmacological issues; have a significant influence on future drug trends. and high levels of both technology-related skills. They are meant Some authors even consider cyber-psychonauts to be ideally to have a wide vocabulary to define their own on drug placed to become involved in the actual implementation of experiences in the most subtle and precise way possible. innovative responses to the increasing prominence of NPS Among this population, the frequency of NPS use is high, with markets, as it is difficult to imagine a more efficient method for one-third of the participants reporting its use in the last week. the rapid dissemination of new information about things such They view themselves as knowledgeable consumers who use as the adverse effects of new products to consumers [24]. the internet to accumulate information about NPS and share The recent alarm related to the growth of the NPS market and their own experiences, informing fellow users of potential the gradual shift from the street to the cyber-drug market may harms. However, other studies [16] reported possible stimulant call for the implementation of preventive tools and practices dependence (3 or more dependence symptoms) in 30% of tailored to these new drug users’ characteristics [13]. https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 4 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Finally, in their empirical and conceptual revision of the NPS 3. Is it possible to collect reliable data to answer these research field, Mdege et al [8] concluded that there was a clear questions using a low-budget internet platform and the need to move beyond an expert-driven discourse on NPS and design used in this study? involve people who use NPS as active and valuable research The researchers’ initial hypotheses are as follows: collaborators and stakeholders instead of passive research participants. 1. The population of e-psychonauts will be made up of functional and educated people who use drugs mainly in a It is clear then that this sentinel population might be difficult recreational way. to reach and retain in a highly structured study protocol 2. During the study period, we will be able to identify a wide [5,8,18,21,25]. However, the collaboration of the Energy Control variety of different substances, some of which have never (EC) International Drug Checking Service might provide a been reported before in the scientific literature or by the critical opportunity for recruitment, offering a free chemical organizations aimed at controlling illicit drug supply. analysis of the substance they want to consume. This service is 3. The study design and implementation will attract enough already being used by this population in the main internet research participants with sufficient commitment to provide communities of psychonauts, and it has a well-regarded valuable, reliable, and meaningful data to generate quality institutional presence in most of them [26,27]. evidence. Relevance and Goals of This Study In summary, NPS pose a public health threat at different levels, Methods and there is a lack of research on the effects of the emerging Overview substances as well as on which ones are appearing now. In addition, the research conducted to date has been unable to cover This study aims to discover the characteristics of the important gaps, such as studying relevant sentinel populations e-psychonaut population and the effects of the NPS they use, of e-psychonauts using new technologies, involving them in with a longitudinal design and no control group. The study is the research, and obtaining confirmatory analytical data of the conducted online, recruiting participants using an innovative substances studied. Old methodologies repeatedly fail to reach and specifically developed platform as part of the study project: the skyrocketing turnover pace of newer NPS in the e-market. Global Research and Analysis of New Substances Project By the time old trials recruit the necessary drug X study (GRASP). participants and engage them in the old trial machinery, drug The study has been designed and will be reported using the X has already become obsolete and has been replaced by Y Checklist for Reporting Results of Internet E-Surveys [28] and and—possibly—even Z drugs. the STROBE (Strengthening the Reporting of Observational This study aims to bridge the abovementioned evidence gaps. Studies in Epidemiology) statement checklist for observational To do so, a naturalistic, observational, and longitudinal design studies [29], with the support of the SPIRIT (Standard Protocol has been adopted, recruiting e-psychonauts to gather information Items: Recommendations for Interventional Trials) statement on their characteristics and the substances that they might be checklist of 2013 [30]. using before their popularization. This has been possible thanks The study protocol was submitted in October 2018 and was to the development of a new online ad hoc tool designed for approved by the Clinical Research Ethics Committee (Parc de this project: an online platform thought to enhance Salut Mar, Barcelona, Spain, ref. 2018/8283/I) in January 2019. communication with the e-psychonauts and allow community The study was conducted according to the Declaration of building. In addition, subjective effects on these substances Helsinki recommendations and the emerging recommendations have been studied, allowing the participants to send samples to for online research on sensible topics [21,25]. All data collected a partner laboratory with gas chromatography (GC)/mass online on the participants were encrypted according to the spectrometry (MS) in Barcelona and administering drug effect European and Spanish data protection regulations (2016/679 questionnaires in the most resembling way possible to the drug European Parliament and 27/4/16 reglamento general de laboratory studies. protección de datos [general law about data protection] Spanish This design has resulted in the first internet-based, multinational Royal Decree). study on a key sentinel population with laboratory confirmation Study Setting on the composition of the reported samples. The study is conducted mainly though internet, using 3 main Study Objectives and Hypothesis tools: The study has been designed to answer 3 main research 1. The specifically designed GRASP platform questions: 2. The Qualtrics survey service licensed though Columbia 1. Who are the people who first try the new substances when University they emerge in the market? 3. The Google Suite platform as an email service to contact 2. What are the substances emerging right now and their candidates and attend to the private questions and concerns subjective effects? of the study participants. In addition, the samples were received through traditional mail in the EC Headquarters in Barcelona, where they were initially https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 5 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al processed and identified. The samples were then transported to information received. All participants indicated their agreement the EC laboratory at the Hospital del Mar Research Institute to participate and signed an informed consent (IC) form (IMIM), second floor, to be analyzed using the techniques (Multimedia Appendix 2) that was sent to the project email described below. The research team worked at both the EC address and checked by the principal investigator before headquarters and the IMIM laboratories. During the inclusion. It was not possible for candidates or participants to COVID-related lockdown that was established in Spain in March answer any online questionnaires without previously receiving 2020, the laboratory analysis was interrupted for 3 months. the specific link, which was sent by the research team only when the participant met the criteria to fill the questionnaire. The usability of the platform and the multiple automated Participants were asked to sign with their online usernames to processes, such as sending an email with a specific link to a further protect their physical identity, as recommended by questionnaire, and the logic pathways (adaptive questioning) Barratt et al [21,25]. Participants received no monetary and validation requirements used in the Qualtrics questionnaires compensation for their participation, but instead, they were were systematically tested by the research team. A checklist of offered the possibility to get the NPS they reported on all possible scenarios was devised, and they were all executed analytically tested for free in the EC laboratory, located in the by a blind research team member and the principal investigator. IMIM, Barcelona. The cost of this service is US $110 if Once errors were identified, they were corrected, and the process contracted independently through the EC International Drug was repeated from the beginning. In addition, participants were Checking Service. encouraged to report any problems or ideas to improve the procedures, so changes could be implemented when needed This study included e-psychonauts, who have been defined as during the study. people with the following characteristics: Participants 1. Previous experience with at least three NPS 12 months All the participants were correctly and fully informed by writing before the study inclusion 2. Activity on online communities where NPS consumption (refer to the participant information sheet in Multimedia Appendix 1) and prompted to ask any questions by email. In is discussed. that case, answers were provided until the candidate confirmed The inclusion and exclusion criteria for participants are provided that they had no more questions and were satisfied with the in Textbox 1. Textbox 1. Inclusion and exclusion criteria for participants. Inclusion Criteria • Meeting the operational definition of e-psychonaut • Being 18 years or older at the time of recruitment • Self-reported plans of maintaining the use of new psychoactive substances for the following 18 months Exclusion Criteria • Difficulties in communicating in English • Difficulties in using new technologies to participate in the study • Potentially pregnant women • Potential presence of severe psychopathological symptomatology Note that there is no restriction on the geographical location of 3. Difficulties in communicating in English and the presence the participants, as the study will not collect such data to further of potential psychopathological impairments have also been protect the participants’ physical identity. Therefore, participants evaluated by the principal investigator, assessing the from around the globe could participate in the study. Both answers to long and elaborate open questions in the inclusion and exclusion criteria have been mainly assessed by screening questionnaire (Q0) and in the written direct self-reporting in an initial screening questionnaire (Q0), introductions to the online platform. except the following: 4. The potential of being pregnant was assessed by indirect 1. questioning using the same screening questionnaire (Q0) Previous participation in forums has been assessed by questionnaire. self-report and exclusive advertisement of the study on these forums. Recruitment 2. Difficulties in using new technologies have been assessed Recruitment ads were sent to the moderators of the selected by the steps required to complete the screening process, online communities after establishing bilateral communication such as sending an IC form in a particular format, with them, mainly to ask permission and explain the goals of registering to the platform, and following the instructions the project. To maximize interest in participating in the study, there to introduce themselves to the research team and other the only focus was on establishing rapport with community participants. leaders, as if they share their interest in the study, they will be https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 6 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al able to transfer it to the rest of the community [31]. Each 5. Dimethyltriptamine-nexus: excluded because of the lack of community moderator posted the research ad in the most a specific NPS subsection. appropriate way in their community after discussing it with the 6. Ecstasy data: excluded because of the lack of an active research team. Research ads were posted on all communities forum and the lack of a specific NPS subsection. during the summer of 2019 (refer to Multimedia Appendix 3 7. Shroomery: Excluded because of the lack of a specific NPS for details). The recruitment was designed to be sequential until subsection. the designed sample size was reached or the study reached its To the best of the authors’ knowledge, the selected communities duration limit. were the main ones at the moment when the selection occurred The operational definition for online communities of people (October 2018), although it has to be acknowledged that this is who use NPS has been adapted from the study by Barratt [21]: a rapidly changing scenario; in a few years, this same process 1. might produce different outcomes. At that moment, the authors Surface websites with at least 5 years of existence 2. were unable to find any contradicting information with that Presence of participation forums dedicated to discussing assumption. Soussan et al [35] referred to bluelight, the use of NPS 3. drugs-forum, and legal-highs forum as the top 3 communities. At least weekly activity on the community forum 4. However, they did not consider collaboration with drug checking The use of pseudo-anonymity by community members to organizations to be a relevant factor. Moreover, as stated above, identify themselves 5. these rankings are expected to change over relatively short The presence of official and analytical drug checking periods [35]. services in the community. The GRASP platform, which allowed for interaction among When the study design was completed (October 2018), there participants themselves and with the research team, was the were 4 communities meeting the previously stated criteria [21]: main tool to promote participant engagement and minimize 1. Bluelight [32]: Established in 1997, bluelight is probably dropout rates. the most prominent community of people who take illicit drugs, with approximately 250,000 members. Within the Sample Size community, there is a subdivision in which the use of NPS In the most recent review consulted by the authors, the sample is exclusively discussed. The community is known for its sizes reached with web-based questionnaires in people who use commitment to promoting risk management and harm illicit drugs ranged from 80 to 9867 [36]. The expected losses reduction strategies among its participants as well as its while filling these types of questionnaires are about 50% of the formidable contributions to similar research projects [28]. sample, but the authors have not found other online longitudinal Registration is required to access the content. studies including questionnaires like this one. According to the 2. Reddit [33]: Established in 2010, this subreddit community aforementioned review, the authors expected 80 candidates as allows almost any type of discussion regarding NPS. The the best possible estimate to achieve 40 final participants. community has approximately 90,000 members, but it is Assuming that each participant takes one NPS every month part of a broader community of people who use illicit drugs during the duration of the study, the expected number of (not only NPS), with over 700,000 members. Both of these registered self-administration trials of NPS would be 480. As are part of the global reddit community, where all types of the study has been designed as exploratory, the sample size topics are discussed. The platform does not require could not be determined based on the needs to perform specific registration to access the content. statistical tests. 3. Drugs-forum [34]: Established in 2003, this community Study Procedures and Timeline also seems to have approximately 250,000 members. Registration is required to access the content. The study’s internal timeline and workflow are graphically 4. DNstarsVIP: Established after discussing about NPS sources represented in Multimedia Appendix 4. The first recruitment was banned on the reddit community, DNstars is a strongly effort consisted of online discussions with forum moderators emerging community with approximately 2000 users. and posting the institutional review board (IRB)–approved Registration is required to access the content. announcement for candidates (displayed in its entirety in Multimedia Appendix 3) in those forums. In the announcement, The main communities that were assessed and excluded were potential candidates were instructed to send an email from a as follows: secure and nonidentifiable address to the research team 1. Legal-highs forum: excluded because of the lack of weekly (admin@grasp.pw). Candidates were then informed more interactions, technical website problems, and impossibility broadly about the study. Candidates were informed to contact community managers. homogeneously by sending the IRB-approved information for 2. Erowid: excluded because of the lack of an active forum. candidates’sheet to their email (the sheet used in this study can 3. Psychonaut wiki: excluded because of the lack of an active be found in Multimedia Appendix 1). The principal investigator forum. then offered the candidates to answer any questions that might 4. Tripsit: excluded because of the lack of an active forum, have arisen after reading the participant information sheet. When although there was an internet relay chat–supported the participants had read and discussed the given information chatroom. about the study with the principal investigator, they were asked to register on the GRASP platform and send the IRB-approved https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 7 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al IC form, completed with the registered username to the study information only available to each participant, such as the email. In Multimedia Appendix 2, the IC form is available for sample code of the reported sample. consultation. Finally, the candidates were asked to complete Study recruitment began in August 2019 and is still ongoing. the screening questionnaire (Q0) and introduce themselves on In August 2020, the first participant concluded the 1-year the platform without providing information that might reveal follow-up. their real-world identities. When all these processes were complete, the principal investigator checked the IC form, the IRB-Approved Protocol Changes During the Study screening questionnaire, and the platform introduction to assess The protocol has been subjected to amendments twice, both if the participant met the inclusion or exclusion criteria. approved by the IRB of the institution (Clinical Research Ethics Candidates were then informed by email about the results of Committee-IMIM). the assessment, thus either being rejected or accepted as participants. The first amendment, submitted in January 2019, reported the following changes in the protocol: Once participants were accepted, they could interact with other participants on the online platform and received detailed 1. Minor changes in the study advertisement sheet, participant instructions on how to conduct the study. However, NPS information sheet, and IC form sourcing and the effects of the substances included in the study 2. The assessment of inclusion criteria was no longer done by were not allowed. In case of a severe protocol violation such as the community moderators and was entirely assessed by this one, participants were immediately removed from the study self-reporting on online questionnaires and their information was deleted. In case of minor protocol 3. An increase in the required sample quantity to be sent to violations, participants were notified and given the opportunity, the laboratory from 30 to 50 mg by default, accepting if applicable, to amend their noncompliant behavior. exceptions depending on the substance potency 4. Addition of a key measurement timepoint at baseline before The first mandatory step was to fill a sociodemographic and ingesting the substance. drug use history questionnaire (Q1). This questionnaire was available to each participant through a participant-specific link, The second amendment, submitted in November 2019, reported which was sent by email once they were accepted. After that, the following changes in the protocol: participants were asked to fill the sample submission 1. Unblinding of the research team to the participant behavior questionnaire (Q2), where information about the sample they and participation intended to consume was asked. This questionnaire was then 2. Addition of an optional timepoint for data collection in the reviewed by the principal investigator and approved if the reporting of the subjective effects of the reported substances substance met the study criteria of being a new psychoactive 3. Extension of the duration of the study from 6 months to 1 substance. The samples that did not meet the inclusion criteria year for each participant were not accepted, and the participant was notified by email. 4. Reduction of the required age for inclusion from 21 to 18 The sample submission questionnaire (Q2) was available to all years. accepted participants as a link on the platform. All the questionnaire answers were reviewed weekly by a member of Outcomes the research team to communicate to the participant the The domains and measurements used in the study are based on acceptance of the sample and to mark them as valid or invalid previous laboratory studies, to maximize consistency in data for later analysis. methodology and to eventually develop a validation study for If the sample was approved, the participant received a this methodology. Multiple studies have shown that web-based specifically generated sample code with the instructions to send data collection and traditional methods (eg, paper and pencil) a small amount of the sample (approximately 30 mg, usually result in equivalent conclusions, demonstrating the validity and below the psychoactive threshold) via traditional mail to the reliability of online data collection for research [37,38]. laboratory at the IMIM. The sample was analyzed there, and Certain studies have been used as model references to select the result was sent back to the user, along with harm reduction the measured outcomes [39-52]. However, new outcomes advice when appropriate. regarding the subjective effects of psychoactive substances have Meanwhile, the users could consume the substance whenever been added to balance the amount of positive and negative they decided, as the study was intended to be observational. effects reported. The order of the questions was kept the same However, most of the participants waited until they had the to facilitate reports to those participants who completed the result of the laboratory analysis to proceed with the same questionnaire multiple times. However, 3 questions to self-administration trial. The self-administration trial started assess validity were present in both the Q3a and Q3b. More with the users filling the drug effect baseline questionnaire information about study outcomes, including assessed domains, (Q3a), and then, they consumed the reported substance and chosen measurements, metrics, and time points, can be found filled the drug effect questionnaire (Q3b) 24 hours after filling in Multimedia Appendix 5. the baseline questionnaire (Q3a). The links to these questionnaires were available for all participants in the forum, and the veracity of the information was ensured by asking https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 8 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Data Collection the screen size used to answer. The possibility to answer the questionnaires comfortably from the smartphone was assessed Questionnaires as an essential by the research team. The study data were collected using a Columbia University Qualtrics license, a well-known questionnaire platform Laboratory Analysis compliant with the guidelines to store sensible information about Preliminary sample identification was performed by GC coupled the research participants. The screening questionnaire (Q0) and to MS using an Agilent 7890B gas chromatograph coupled to the sociodemographic questionnaire (Q1) collected self-reported a 5977A quadrupole mass spectrometer detector (Agilent). The information about the participants’ medical and drug history, gas chromatograph was fitted with a G4513A auto-sampler psychosocial situation, and beliefs and behaviors related to injector. Insert liners packed with salinized glasswool were drugs. used, and the injector and interface were operated at 280 °C. Samples were injected in split mode into a 0.25 mm film The subjective effects of drugs were assessed via visual analog thickness (5% phenylmethylsilicone) column (HP-5MS, Agilent scales, using the same parameters used in most laboratory Technologies). Helium was used as the carrier gas at a flow rate studies to determine the subjective effects of drugs. The main of 1 mL/min. The oven temperature was initially maintained at outcome was the difference in mm from the drug effect 90 °C for 2 minutes and programmed to reach 320 °C at 20 questionnaire (Q3b) at 24 hours (referring to the peak °C/min. It was finally maintained at 320 °C for 9.5 minutes experience) and the baseline questionnaire (Q3a). (total run time was 21.5 min). The mass spectrometer was Each questionnaire also had at least one validity entry to be operated in the electron impact ionization mode at 70 eV. To filled by the researcher directly using the Qualtrics database. confirm the mass spectra, 4 libraries were used: the There were no automated consistency or completeness checks NIST/EPA/NIH Mass Spectral Library, Data Version: NIST before the questionnaire was submitted, other than the validation 14; Searchable Mass Spectral Library Version 2.3 [59]; criteria for certain questions. For example, the question sample Searchable Mass Spectral Library Cayman Spectral Library code reported could not be submitted if the answer was not a [60]; and EC’s internal mass spectral library. Confirmation 5-digit number. (when needed) was performed by liquid chromatography (LC) coupled to tandem MS (LC/MS/MS) using an Agilent 1100 The participants could go back through the questionnaire, but series HPLC (high performance liquid chromatography) once submitted, they could not change their answers. A summary chromatograph (Agilent Technologies) and an Esquire 3000 of the answers was not displayed either before or after plus mass spectrometer MRM (Bruker Daltonic GmbH). submission. Two options were available to change the Chromatography was performed using a Poroshell 120 EC-C18 participants’ answers if they were incorrect according to the column (100 mm length×2.1 mm internal diameter; 2.7 mm participant or not valid according to the researcher. If the change particle size) at 30 °C. The mobile phases consisted of 1% was small, the researcher could just edit the participant response formic acid and 1% formic acid in methanol. The following in the Qualtrics database according to the correct response gradient elution was used: at time 0 minute, 15% B was changed provided by the participant using email or the platform’s private to 90% B in 7 minutes, held for 1 minute, and changed back to messaging system. If the changes were relevant, the researcher the initial conditions in 1 minute. Before injection of the next could mark the questionnaire as invalid and provide another sample, the column was re-equilibrated for 7 minutes. The flow link to the participant. rate was 0.35 mL/min. The electrospray source was operated Public links to copies of the used questionnaires can be found in the positive ionization mode. Product ions that were obtained in the references cited below: by collision-induced dissociation allowed the MS/MS to be operated in the multiple reaction monitoring mode. The dwell 1. Q0, screening questionnaire [53]: contained a total of 37 time was set at 0.25 seconds. The desolvation gas was nitrogen questions set at 365 °C and delivered at a flow rate of 9 L/min. The 2. Q1, sociodemographic questionnaire [54]: contained a capillary voltage was 3.90 kV, and the collision gas was helium. maximum of 351 questions, with an expected average per The Bruker Compass Hystar system software Version 3.2-SR2 participant of 50, due to adaptive questioning and was used for instrument control and identification. questionnaire logic 3. Q2, sample submission questionnaire [55]: contained a total GRASP Forum of 21 questions Secondary data about the participants’ discussions on the study 4. Q3a, baseline drug effect questionnaire [56]: contained a platform were supported by a licensed discourse (Civilized total of 12 questions Discourse Construction Kit, Inc) account and the software used 5. Q3b, drug effect questionnaire given 24 hours after drug to build the platform. Qualtrics (SAP Global Corporate Affairs) administration [57]: contained a total of 39 questions data were downloaded for analysis, which was conducted using 6. Q4, 1-year follow-up questionnaire [58]: contained a the institutionally licensed Microsoft Excel from the IMIM and maximum of 351 questions, with an expected average per R (R Core Team), which is a free software environment for participant of 50, due to adaptive questioning and statistical computing and graphics that does not require a license. questionnaire logic. The number of pages and items on each page were optimized automatically by Qualtrics software and varied according to https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 9 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Data Management and Statistical Analysis with all the current regulations that apply, including institutional, Data will be stored in Qualtrics software and will only be used local, national, and international regulations. according to the goals of the study described in the protocol. All information is being handled confidentially according to Most of the data will be entered directly by the participants, and the organic Spanish law 15/1999 and the European regulation a researcher will screen every questionnaire filled for 2016/679. The IRB has always granted access to any study consistency and ask the participants for clarifications in case of information required. suspected errors in data entry or reporting. The principal investigator (MG) and 3 more researchers (GMF, XCM, and All participants will receive the participant information sheet JGC) will have access to the complete data sets. Data on and will be required to read and fill the IC form, which will be participant performance will be entered manually by one sent to admin@grasp.pw. The principal investigator will be researcher in an internal Excel database. No personal responsible for reviewing all candidates’ IC forms and screening information will be stored other than the safe email address questionnaires for inclusion and exclusion criteria. All asked in the study advertisement and the nickname the candidates and participants will have the opportunity to ask as participant choses to use in the forum. This ensures the many questions as needed before proceeding to any part of the maintenance of pseudo-anonymity, as information about the study, both through the forum and through contacting the leading online persona will be stored, but the link between the online researcher email (admin@grasp.pw). identity and the real identity will not be impossible to establish Participants will not be required to sign IC forms to protect their with the collected information. anonymity and avoid sharing data that could be used to track Data will be managed and processed using Qualtrics software their physical identity. The identity that will be protected by and initially analyzed using Excel by the research team. At the the researchers will be the online one, as no other information same time, an independent statistician will use the same data relatable to the real identities will be given. This procedure is from Qualtrics to perform a partially blind analysis using R. consistent with the methodology of previous studies [61]. Only fully completed and valid questionnaires will be analyzed. The researchers will try their best to limit the influence of their The validity of the questionnaires will be assessed by a research interactions on the participants’ behavior, especially the ones team member based only on the consistency and completeness targeted in the study. However, as recommended by previous of the participants’ answers. research, the participants will be involved in discussing the As it is an exploratory study, the data analysis procedures will study design and incentivized to share their opinions on how be mainly descriptive statistics, to maximize an adequate the study could be improved [8,21]. visualization of the data collected within the minimum space. Protocol changes will be communicated to the participants In addition, as there is no control group, statistical tests will be through the online platform once they are approved. limited to potential comparisons to assess bias on the results, such as comparing data from participants who complete the A more extensive ethical analysis by principles can be found study with participants who drop out or are excluded. However, in Multimedia Appendix 6 [26,27,39-52,62-64]. no statistical corrections will be applied to adjust the Dissemination Policy representativeness of the sample, as this validation will be done All individual and collective data, as well as all the results by comparing the sociodemographics of the study sample with derived from the study, will be strictly protected and will only the characteristics of the population of psychonauts widely be published with the authorization of the principal investigator reported in the literature. Statistical tests might also be used to and the affected participants. All relevant findings will be sent compare information from the initial questionnaire Q1 and the for publication in suitable journals and submitted for data from the follow-up questionnaire Q4. The nonparametric presentation at relevant scientific meetings. The funding Wilcoxon signed-rank analysis will be used to perform a mean organizations will have no role in the publication process. In comparison of the quantitative data and the chi-square test for addition, data without identifiable information will be shared qualitative data. In addition, factor analysis will be attempted with study participants after assessment and approval by the to study the relationship between all the visual analog scales research team. Finally, all results published in the scientific used to assess the subjective drug effects. literature will also be made available in lay language to the The data analysis will focus on the outcomes of the participants communities of origin of the participants. Authorships in the who completed the study. Data entries containing evident errors publications will be determined by the amount of scientific and or inconsistent information will be discarded, and the extent to academic contributions of the members of the research team, which this might have impacted the results will be reported. including external collaborators. There are no plans to make the data sets publicly available. Ethical Considerations This study was approved by the IRB of IMIM on December 11, Results 2018, after the first submission in October 2018, when clarifications were asked and delivered in November 2018. The research protocol was approved by the IRB of the IMIM on December 11, 2018. Data collection started in August 2019 The study has been designed and is being executed according and was still ongoing when the protocol was submitted to the basic principles of rights and dignity of the human being, (September 2020), finalizing in October 2020. as stated in the Helsinki declaration, and this study complies https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 10 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Data analysis began in November 2020, and it is still ongoing. The authors expect to submit the first manuscript with Discussion preliminary results by the end of 2021. It is possible to conduct an IRB-approved study using this new From a total of 182 screened candidates, only 17 (9.3%) methodology and collect the expected data. However, the completed at least one self-administration trial, resulting in a meaning and usefulness of these data are still unknown. total number of 64 self-administration trials. From these, 40 different substances were analyzed. Acknowledgments The authors want to thank the ACC1Ó (Agency for technological Competitiveness) program for recognizing the potential of the project and supporting the idea at an early stage. MG also wants to thank the Instituto de Salud Carlos III and the IMIM for making his contribution possible through a Rio Hortega grant (CM18/00168) ISCIII/FSE. EC volunteers and dedicated staff made the study possible thanks to their technical skills and dedication. The authors would like to thank Iván Fornís and Cristina Gil for performing the challenging laboratory analyses, which was only possible because of their accumulated training and experience using both LC/MS and GC coupled with MS to identify new and rare substances. This research was also supported by and advertised through Bluelight. Bluelight is a nonprofit online community dedicated to reducing drug-related harm. The content is solely the responsibility of the authors and does not necessarily represent the official views of Bluelight. The authors want to specifically thank Monica Barrat for her aid in the recruitment process and her useful insights in the study design. The moderators of the research chemicals subreddit also supported the research; the authors would also like to thank Borat for her aid in recruitment. Finally, MG would like to acknowledge the support and collaboration of their junior research colleagues who helped with informal discussions and provided general support in the design and development of the study: Guy Jones, Alba Toll, Matilde Elices, Kate O’Malley, Tiesha T Gregory, and Christopher Medina. The authors would like to specially thank Josep Guilanyà Casas, who came up with creative solutions when the research team was stuck in technical or conceptual challenges. Most of the study funding has been obtained from public grants and institutions with no conflict of interest in the study design or execution. A minority of the funding has come from a publicly funded nongovernmental organization EC–ABD (Energy Control–Associació Benestar i Desenvolupament), whose laboratory manager has been involved as a scientific supervisor in the study. The Group of Mental Health Research at the IMIM is partly funded by an unrestricted grant from the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya Government of Catalonia (2017_SGR_134). The management of the study and the decision to publish has been exclusively exerted by the principal investigator, with no interference from the funding sources. Conflicts of Interest None declared. Multimedia Appendix 1 Participant information sheet. [DOC File , 50 KB-Multimedia Appendix 1] Multimedia Appendix 2 Informed consent form. [DOC File , 33 KB-Multimedia Appendix 2] Multimedia Appendix 3 Announcement for candidates. [DOC File , 33 KB-Multimedia Appendix 3] Multimedia Appendix 4 Summary of study procedures. [DOC File , 192 KB-Multimedia Appendix 4] Multimedia Appendix 5 Main study outcomes. [DOC File , 78 KB-Multimedia Appendix 5] https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 11 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Multimedia Appendix 6 Ethical analysis by principles. [DOC File , 34 KB-Multimedia Appendix 6] References 1. Higgins K, O’Neill N, O’Hara L, Jordan J, McCann M, O’Neill T, et al. Evidence for public health on novel psychoactive substance use: a mixed-methods study. Public Health Res 2019 Aug;7(14):1-150 [FREE Full text] [doi: 10.3310/phr07140] [Medline: 31408297] 2. Schifano F, Napoletano F, Chiappini S, Guirguis A, Corkery JM, Bonaccorso S, et al. New/emerging psychoactive substances and associated psychopathological consequences – corrigendum. Psychol Med 2019 Sep 12;51(1):43. [doi: 10.1017/s003329171900254x] 3. Corazza O, Assi S, Simonato P, Corkery J, Bersani FS, Demetrovics Z, et al. Promoting innovation and excellence to face the rapid diffusion of novel psychoactive substances in the EU: the outcomes of the ReDNet project. Hum Psychopharmacol 2013 Jul 23;28(4):317-323. [doi: 10.1002/hup.2299] [Medline: 23881879] 4. World Drug Report 2017. United Nations Office on Drugs and Crime. URL: https://www.unodc.org/wdr2017/field/ Booklet_1_EXSUM.pdf [accessed 2021-05-17] 5. Meader N, Mdege N, McCambridge J. The public health evidence-base on novel psychoactive substance use: scoping review with narrative synthesis of selected bodies of evidence. J Public Health (Oxf) 2018 Sep 01;40(3):303-319. [doi: 10.1093/pubmed/fdy016] [Medline: 29409048] 6. Davidson C. New psychoactive substances. Prog Neuropsychopharmacol Biol Psychiatry 2012 Dec 03;39(2):219-220. [doi: 10.1016/j.pnpbp.2012.08.010] [Medline: 23026141] 7. European Monitoring Centre for Drugs and Drug Addiction. Monitoring Drug Use in Recreational Settings Across Europe: Conceptual Challenges and Methodological Innovations, Technical Report. Luxembourg: Publications Office of the European Union; 2018. 8. Mdege ND, Meader N, Lloyd C, Parrott S, McCambridge J. The novel psychoactive substances in the UK project: empirical and conceptual review work to produce research recommendations. Public Health Res 2017 Jun;5(4):1-138. [doi: 10.3310/phr05040] [Medline: 28678463] 9. Weaver MF, Hopper JA, Gunderson EW. Designer drugs 2015: assessment and management. Addict Sci Clin Pract 2015 Mar 25;10(1):8 [FREE Full text] [doi: 10.1186/s13722-015-0024-7] [Medline: 25928069] 10. Wood DM, Heyerdahl F, Yates CB, Dines AM, Giraudon I, Hovda KE, et al. The European Drug Emergencies Network (Euro-DEN). Clin Toxicol (Phila) 2014 Apr 21;52(4):239-241. [doi: 10.3109/15563650.2014.898771] [Medline: 24654801] 11. O'Brien K, Chatwin C, Jenkins C, Measham F. New psychoactive substances and British drug policy: a view from the cyber-psychonauts. Drugs Educ Prev Policy 2014 Dec 09;22(3):217-223. [doi: 10.3109/09687637.2014.989959] 12. Corkery JM, Orsolini L, Papanti D, Schifano F. From concept(ion) to life after death/the grave: The 'natural' history and life cycle(s) of novel psychoactive substances (NPS). Hum Psychopharmacol 2017 May 28;32(3):e2566. [doi: 10.1002/hup.2566] [Medline: 28657188] 13. Orsolini L, Papanti GD, Francesconi G, Schifano F. Mind navigators of chemicals' experimenters? A web-based description of e-psychonauts. Cyberpsychol Behav Soc Netw 2015 May;18(5):296-300. [doi: 10.1089/cyber.2014.0486] [Medline: 25965863] 14. Newcombe R, Johnson M. Psychonautics: A model and method for exploring the subjective effects of psychoactive drugs. In: Proceedings of the Club Health 2000 – First International Conference on Nightlife and Substance Use. 1999 Presented at: Club Health 2000 – First International Conference on Nightlife and Substance Use; November 1999; Amsterdam p. A. 15. Tackett-Gibson M. Constructions of risk and harm in online discussions of ketamine use. Addict Res Theory 2009 Jul 11;16(3):245-257. [doi: 10.1080/16066350801983699] 16. Winstock A, Mitcheson L, Ramsey J, Davies S, Puchnarewicz M, Marsden J. Mephedrone: use, subjective effects and health risks. Addiction 2011 Nov;106(11):1991-1996. [doi: 10.1111/j.1360-0443.2011.03502.x] [Medline: 21592252] 17. Fletcher E, Tasker S, Easton P, Denvir L. Improving the help and support provided to people who take new psychoactive substances ('legal highs'). J Public Health (Oxf) 2016 Dec 02;38(4):489-495. [doi: 10.1093/pubmed/fdv191] [Medline: 28158593] 18. Andrews D, Nonnecke B, Preece J. Electronic survey methodology: a case study in reaching hard-to-involve internet users. Int J Hum Comput Interact 2003 Oct;16(2):185-210. [doi: 10.1207/s15327590ijhc1602_04] 19. Eysenbach G, Wyatt J. Using the internet for surveys and health research. J Med Internet Res 2002 Nov;4(2):E13 [FREE Full text] [doi: 10.2196/jmir.4.2.e13] [Medline: 12554560] 20. Tonks A, Smith R. Information in practice. Br Med J 1996 Aug 24;313(7055):438 [FREE Full text] [doi: 10.1136/bmj.313.7055.438] [Medline: 8776301] 21. Barratt M, Lenton S. Beyond recruitment? Participatory online research with people who use drugs. Int J Internet Res Ethics. 2010. URL: https://espace.curtin.edu.au/handle/20.500.11937/23339 [accessed 2021-05-18] https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 12 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al 22. Hewson C. Gathering data on the internet: qualitative approaches and possibilities for mixed methods research. In: Joinson A, McKenna K, Postmes T, Reips UD, editors. Oxford Handbook of Internet Psychology. Oxford, United Kingdom: Oxford University Press; 2009:405-428. 23. Illingworth N. The internet matters: exploring the use of the internet as a research tool. Sociol Res Online 2017 Nov 07;6(2):79-90. [doi: 10.5153/sro.600] 24. Seddon T. Drug policy and global regulatory capitalism: the case of new psychoactive substances (NPS). Int J Drug Policy 2014 Sep;25(5):1019-1024. [doi: 10.1016/j.drugpo.2014.03.009] [Medline: 24768473] 25. Barratt M. Discussing illicit drugs in public internet forums: visibility, stigma, and pseudonymity. In: Proceedings of the 5th International Conference on Communities and Technologies. 2011 Presented at: C&T '11: Communities and Technologies; June 29 - July 2, 2011; Brisbane Australia p. 159-168. [doi: 10.1145/2103354.2103376] 26. Brunt TM, Nagy C, Bücheli A, Martins D, Ugarte M, Beduwe C, et al. Drug testing in Europe: monitoring results of the Trans European Drug Information (TEDI) project. Drug Test Anal 2017 Feb 17;9(2):188-198. [doi: 10.1002/dta.1954] [Medline: 26888408] 27. Measham FC. Drug safety testing, disposals and dealing in an English field: exploring the operational and behavioural outcomes of the UK's first onsite 'drug checking' service. Int J Drug Policy 2019 May;67:102-107. [doi: 10.1016/j.drugpo.2018.11.001] [Medline: 30541674] 28. Eysenbach G. Improving the quality of web surveys: the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). J Med Internet Res 2004 Sep 29;6(3):e34 [FREE Full text] [doi: 10.2196/jmir.6.3.e34] [Medline: 15471760] 29. Cuschieri S. The STROBE guidelines. Saudi J Anaesth 2019;13(5):31. [doi: 10.4103/sja.sja_543_18] 30. Chan A, Tetzlaff J, Altman D, Laupacis A, Gøtzsche P, Krleža-Jerić K, et al. Spirit 2013 statement: defining standard protocol items for clinical trials. Chinese J Evidence-Based Med 2013;13(12):1501-1507 [FREE Full text] [doi: 10.7507/1672-2531.20130256] 31. Ip EJ, Barnett MJ, Tenerowicz MJ, Perry PJ. The touro 12-step: a systematic guide to optimizing survey research with online discussion boards. J Med Internet Res 2010 May 27;12(2):e16 [FREE Full text] [doi: 10.2196/jmir.1314] [Medline: 20507843] 32. Bluelight.org. URL: https://www.bluelight.org/xf/ [accessed 2021-02-15] 33. Research chemicals discussion - strictly no sourcing. URL: https://www.reddit.com/r/researchchemicals/ [accessed 2021-02-15] 34. Drugs-Forum. URL: https://drugs-forum.com/ [accessed 2021-02-15] 35. Soussan C, Kjellgren A. Harm reduction and knowledge exchange-a qualitative analysis of drug-related internet discussion forums. Harm Reduct J 2014 Sep 08;11:25 [FREE Full text] [doi: 10.1186/1477-7517-11-25] [Medline: 25200686] 36. Miller PG, Sønderlund AL. Using the internet to research hidden populations of illicit drug users: a review. Addiction 2010 Sep;105(9):1557-1567. [doi: 10.1111/j.1360-0443.2010.02992.x] [Medline: 20626378] 37. McCabe SE. Comparison of web and mail surveys in collecting illicit drug use data: a randomized experiment. J Drug Educ 2016 Jul 21;34(1):61-72. [doi: 10.2190/4hey-vwxl-dvr3-hakv] 38. Buchanan T, Smith JL. Research on the Internet: validation of a World-Wide Web mediated personality scale. Behav Res Methods Instrum Comput 1999 Nov;31(4):565-571. [doi: 10.3758/bf03200736] [Medline: 10633975] 39. Martin W, Sloan J, Sapira J, Jasinski D. Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 1971;12(2):245-258. [doi: 10.1002/cpt1971122part1245] [Medline: 5554941] 40. Folstein MF, Luria R. Reliability, validity, and clinical application of the Visual Analogue Mood Scale. Psychol Med 1973 Nov 09;3(4):479-486. [doi: 10.1017/s0033291700054283] [Medline: 4762224] 41. Bozarth MA, editor. Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer; 1987:1-658. 42. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther 2003 Jul 26;306(1):73-83. [doi: 10.1124/jpet.103.049882] [Medline: 12660312] 43. Kleinloog D, Roozen F, De Winter W, Freijer J, Van Gerven J. Profiling the subjective effects of Δ -tetrahydrocannabinol using visual analogue scales. Int J Methods Psychiatr Res 2014 Jun;23(2):245-256 [FREE Full text] [doi: 10.1002/mpr.1424] [Medline: 24496889] 44. Papaseit E, Farré M, Pérez-Mañá C, Torrens M, Ventura M, Pujadas M, et al. Acute pharmacological effects of 2C-B in humans: an observational study. Front Pharmacol 2018 Mar 13;9:206 [FREE Full text] [doi: 10.3389/fphar.2018.00206] [Medline: 29593537] 45. González D, Torrens M, Farré M. Acute effects of the novel psychoactive drug 2C-B on emotions. Biomed Res Int 2015;2015:643878 [FREE Full text] [doi: 10.1155/2015/643878] [Medline: 26543863] 46. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence symptoms following oral THC administration to humans. Psychopharmacology (Berl) 1999 Feb 1;141(4):385-394. [doi: 10.1007/s002130050848] [Medline: 10090646] 47. Bouso JC, Pedrero-Pérez EJ, Gandy S, Alcázar-Córcoles MÁ. Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens. Hum Psychopharmacol 2016 Sep 29;31(5):356-372. [doi: 10.1002/hup.2545] [Medline: 27470427] https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 13 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al 48. Hart CL, Ward AS, Haney M, Nasser J, Foltin RW. Methamphetamine attenuates disruptions in performance and mood during simulated night-shift work. Psychopharmacology (Berl) 2003 Aug 1;169(1):42-51. [doi: 10.1007/s00213-003-1464-4] [Medline: 12734635] 49. Cami J, Farré M, Mas M, Roset PN, Poudevida S, Mas A, et al. Human pharmacology of 3,4-methylenedioxymethamphetamine ("ecstasy"): psychomotor performance and subjective effects. J Clin Psychopharmacol 2000 Aug;20(4):455-466. [doi: 10.1097/00004714-200008000-00010] [Medline: 10917407] 50. Farré M, de la Torre R, Llorente M, Lamas X, Ugena B, Segura J, et al. Alcohol and cocaine interactions in humans. J Pharmacol Exp Ther 1993 Sep;266(3):1364-1373. [Medline: 8371143] 51. Farré M, Terán MT, Roset PN, Mas M, Torrens M, Camí J. Abuse liability of flunitrazepam among methadone-maintained patients. Psychopharmacology (Berl) 1998 Dec 7;140(4):486-495. [doi: 10.1007/s002130050793] [Medline: 9888625] 52. Hart C, Ward A, Haney M, Foltin R, Fischman M. Methamphetamine self-administration by humans. Psychopharmacology (Berl) 2001 Aug 1;157(1):75-81. [doi: 10.1007/s002130100738] [Medline: 11512046] 53. Q0 Screening questionnaire. URL: https://columbiauniversity.qualtrics.com/jfe/form/SV_2iszxYzwI5axeMB [accessed 2021-02-15] 54. Q1 Sociodemographic and drug use questionnaire. URL: https://columbiauniversity.qualtrics.com/jfe/form/ SV_ePBBkRSEIhjrpyt [accessed 2021-02-15] 55. Q2 Sample characteristics. URL: https://columbiauniversity.qualtrics.com/jfe/form/SV_emQoIrAwBYpqkcZ [accessed 2021-02-15] 56. Q3a Experience report baseline. URL: https://columbiauniversity.qualtrics.com/jfe/form/SV_79sKcReAA1zb54N [accessed 2021-02-15] 57. Q3b Drug effects assessment. URL: https://columbiauniversity.qualtrics.com/jfe/form/SV_25njStxWRh1YbTD [accessed 2021-02-15] 58. Q4 Follow up questionnaire. URL: https://columbiauniversity.qualtrics.com/jfe/form/SV_bwNe0bAI2o2E9a5 [accessed 2021-02-15] 59. SWGDRUG mass spectral library. URL: https://www.swgdrug.org/ms.htm [accessed 2021-02-15] 60. Cayman Chemical. URL: https://www.caymanchem.com/ [accessed 2021-02-15] 61. Barratt MJ, Ferris JA, Lenton S. Hidden populations, online purposive sampling, and external validity. Field Methods 2014 Apr 14;27(1):3-21. [doi: 10.1177/1525822x14526838] 62. Fry C, Treloar C, Maher L. Ethical challenges and responses in harm reduction research: promoting applied communitarian ethics. Drug Alcohol Rev 2005 Sep;24(5):449-459. [doi: 10.1080/09595230500263905] [Medline: 16298840] 63. Karamouzian M, Dohoo C, Forsting S, McNeil R, Kerr T, Lysyshyn M. Evaluation of a fentanyl drug checking service for clients of a supervised injection facility, Vancouver, Canada. Harm Reduct J 2018 Sep 10;15(1):46 [FREE Full text] [doi: 10.1186/s12954-018-0252-8] [Medline: 30200991] 64. Saleemi S, Pennybaker SJ, Wooldridge M, Johnson MW. Who is 'Molly'? MDMA adulterants by product name and the impact of harm-reduction services at raves. J Psychopharmacol 2017 Aug 10;31(8):1056-1060. [doi: 10.1177/0269881117715596] [Medline: 28693371] Abbreviations EC: Energy Control EC–ABD: Energy Control–Associació Benestar i Desenvolupament GC: gas chromatography GRASP: Global Research and Analysis of New Substances Project HPLC: high performance liquid chromatography IMIM: Hospital del Mar Research Institute IC: informed consent IRB: institutional review board LC: liquid chromatography MS: mass spectrometry NPS: new psychoactive substances SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials STROBE: Strengthening the Reporting of Observational Studies in Epidemiology https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 14 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Grifell et al Edited by G Eysenbach; submitted 25.09.20; peer-reviewed by A Hidki,Dr, C Reis; comments to author 12.02.21; revised version received 24.02.21; accepted 12.04.21; published 02.07.21 Please cite as: Grifell M, Mir Fuster G, Ventura Vilamala M, Galindo Guarín L, Carbón Mallol X, Hart CL, Pérez Sola V, Colom Victoriano F Self-reported Subjective Effects of Analytically Confirmed New Psychoactive Substances Consumed by e-Psychonauts: Protocol for a Longitudinal Study Using a New Internet-Based Methodology JMIR Res Protoc 2021;10(7):e24433 URL: https://www.researchprotocols.org/2021/7/e24433 doi: 10.2196/24433 PMID: 34255715 ©Marc Grifell, Guillem Mir Fuster, Mireia Ventura Vilamala, Liliana Galindo Guarín, Xoán Carbón Mallol, Carl L Hart, Víctor Pérez Sola, Francesc Colom Victoriano. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.07.2021. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included. https://www.researchprotocols.org/2021/7/e24433 JMIR Res Protoc 2021 | vol. 10 | iss. 7 | e24433 | p. 15 (page number not for citation purposes) XSL• FO RenderX