ORIGINAL RESEARCH published: 18 March 2020 doi: 10.3389/fphar.2020.00233 Acute Effects of 2C-E in Humans: An Observational Study Esther Papaseit 1,2† , Eulalia Olesti 3,4† , Clara Pérez-Mañá 1,2* , Marta Torrens 2,5 , Marc Grifell 2,5,6† , Mireia Ventura 6 , Oscar J. Pozo 3† , Elizabeth B. de Sousa Fernandes Perna 7 , Johannes G. Ramaekers 7‡ , Rafael de la Torre 3,4‡ and Magí Farré 1,2‡ 1 Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol-Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Badalona, Spain, 2 Department of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3 Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, Hospital del Mar Medical Edited by: Research Institute (IMIM), Barcelona, Spain, 4 Universitat Pompeu Fabra, Departament de Ciències Experimentals i de la Liana Fattore, Salut (CEXS-UPF), Barcelona, Spain, 5 Drug Addiction Program, Institut de Neuropsiquiatria i Adiccions (INAD), Barcelona, Italian National Research Council, Italy Spain, 6 Energy Control, Associació Benestar i Desenvolupament, Barcelona, Spain, 7 Department of Neuropsychology Reviewed by: and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands Matthias E. Liechti, University Hospital of Basel, Switzerland 2,5-Dimethoxy-4-ethylphenethylamine (2C-E) is psychedelic phenylethylamine, with Styliani (Stella) Vlachou, a chemical structure similar to mescaline, used as new psychoactive substance Dublin City University, Ireland (NPS). It inhibits norepinephrine and serotonin uptake and, more relevant, acts as a *Correspondence: Clara Pérez-Mañá partial agonist of the serotonin 2A (5-HT2A ), 2B (5-HT2B ), and (5-HT2C ) receptors. cperezm.mn.ics@gencat.cat Consumers have reported that 2C-E induces mild-moderate psychedelic effects, but † These authors share first authorship its pharmacology in humans, including pharmacological effects and pharmacokinetics, ‡ These authors share senior have not yet studied. To assess the acute effects of 2C-E on physiological and authorship subjective effects and evaluate its pharmacokinetics, an observational study was Specialty section: carried-out. Ten recreational users of psychedelics self-administered a single oral This article was submitted to dose of 2C-E (6.5, 8, 10, 15, or 25 mg). Blood pressure and heart rate were Neuropharmacology, evaluated at baseline, 2, 4, and 6 h post-administration. Three rating scales were a section of the journal Frontiers in Pharmacology administered to evaluate subjective effects: a set of Visual Analog Scales (VAS), the Received: 17 August 2019 49-item short form version of the Addiction Research Centre Inventory (ARCI), and the Accepted: 20 February 2020 Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) Published: 18 March 2020 at baseline, 2, 4, and 6 h after self-administration. To assess 2C-E concentrations Citation: Papaseit E, Olesti E, oral fluid (saliva) was collected during 6 h. 2C-E induced primarily alterations in Pérez-Mañá C, Torrens M, Grifell M, perceptions, hallucinations, and euphoric-mood. Saliva maximal concentrations were Ventura M, Pozo OJ, achieved 2 h after self-administration. Administration of oral 2C-E at recreational de Sousa Fernandes Perna EB, Ramaekers JG, de la Torre R and doses produces a group of psychedelic-like effects such to 2C-B and other Farré M (2020) Acute Effects of 2C-E serotonin-acting drugs. in Humans: An Observational Study. Front. Pharmacol. 11:233. Keywords: 2C-E (2,5-Dimethoxy-4-ethylphenethylamine), novel psychoactive substances (NPS), psychedelic, doi: 10.3389/fphar.2020.00233 phenylethylamines, psychostimulants Frontiers in Pharmacology | www.frontiersin.org 1 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E INTRODUCTION Among the psychedelic phenethylamines, consumption of 2C- compounds was the most commonly reported (21.7%), and Classical psychedelics (serotonergic psychedelics) have 8.55% admitted taking 2C-E (n = 195) (Palamar et al., 2016). In traditionally been defined as a class of psychoactive substances the latest Global Drug Survey there are no specific data regarding that induce in humans a wide range of complex physiological, the prevalence of 2C-E (Global Drug Survey [GDS], 2018). behavioral and psychological effects through serotonin 5-HT2A In Australia, national cross-sectional surveys among regular receptors stimulation (Nichols, 2016). In the past few years, ecstasy users (n = 693, year 2010) and regular psychostimulant however, phenethylamine psychedelics have emerged as a class of users (n = 1260, years 2012/2013) reported a 2 and 3% prevalence new psychoactive substances (NPS) able to induce similar effects of 2C-E use in the previous 6 months, respectively (Bruno et al., to those of controlled psychedelic substances (Vollenweider, 2012; Matthews et al., 2016). In 2014, a sample of Australian NPS 2001; Aarde and Taffe, 2017). 2C-compounds (2C-s) are ring- users (n = 800) described a 5.9% use in the previous 6 months substituted phenylethylamines derived from the modification (Sutherland et al., 2017). of the mescaline structure with two methoxy groups on the In a survey done in Spain among 230 research chemical users benzene ring (2nd and 5th positions) (Tracy et al., 2017). a 25.7% had taken 2C-E in the previous year. It was the fifth most Although they are widely considered a family of substances frequent substance consumed, and rarely used in combination with hallucinogenic/psychedelic and psychostimulant properties, with other psychostimulants or psychedelics (2C-E + MDMA information available on their pharmacology and toxicology in 1.8%, 2C-E + amphetamine 0.9%, 2C-E + mephedrone 0.9%, humans is very limited. and 2C-E + psilocybin 0.4%) (González et al., 2013). In a 2,5-Dimethoxy-4-ethylphenethylamine [2C-E, or 2-(4- recent study in the United States, including 356,413 respondents ethyl-2,5-dimethoxyphenyl) ethanamine] is colloquially known to the 2008–2016 National Survey on Drug Use and Health, as “Aquarust,” “Eternity,” “Europe,” and “Hummingbird” 0.12% reported lifetime novel psychedelic use. Of these, 30.1, (Sutherland et al., 2016). Synthesized in 1977 by Alexander 14.8, and 23.9%, reported lifetime use of 2C-B (2,5-dimethoxy- Shulgin it is one of the most potent 2C-compounds (Shulgin and 4-bromophenethylamine), 2C-E and 2C-I (2,5-dimethoxy-4- Shulgin, 1990). 2C-E is structurally very closely related to other iodophenethylamine), respectively (Sexton et al., 2019). 2C-s and to other well-studied phenethylamine substitutes such The first description of 2C-E effects was published in as mescaline and MDMA (ecstasy). It first came out the club PiHKAL: A Chemical Love Story, which considered the drug scene in the mid-1980s as a quick replacement for MDMA which to be one of the “magical half-dozen” or more intense had been banned in the United States. 2C-E then remerged on psychedelic phenethylamines (Shulgin and Shulgin, 1990). In the psychedelic scene and lately has been present as part of the recent years, 2C-E recreational users have reported its effects NPS phenomenon. In fact, 2C-E has been documented as being as being a combination of hallucinogenic and stimulating contained in pills sold as ecstasy in America and Europe (United ones, like those of ecstasy and LSD. Like other psychedelics Nations Office on Drugs and Crime [UNODC], 2014), and more drugs and 2C compounds, 2C-E at low doses usually produces recently in Colombia and other Latin American countries, where stimulant effects and increased auditory, visual and tactile it is considered an NPS due to its new presence on the drug sensations. At moderate doses it leads to mild hallucinations, market (Observatorio de Drogas de Colombia [ODC], 2017). and at high ones can cause the user to experience unpleasant Pharmacologically, 2C-E, in a similar manner to other 2C- hallucinations and sympathomimetic effects. In general, effects compounds, inhibits the uptake of serotonin and norepinephrine from 2C-E are reportedly more intense in comparison to 2C-B by membrane transporters (SERT and NET, respectively), (Dean et al., 2013). although with very low activity in relation to amphetamine An average dose of 2C-E ranges from 10 to 20 mg (medium (Nagai et al., 2007; Van Vrancken et al., 2013; Eshleman et al., dose 15–25 mg, high dose 25–40 mg) although exceptionally 2014). 2C-E mainly acts as a partial agonist at the 5-HT2A , 5- elevated doses up to 100 mg have been reported (Dean et al., HT2B , and 5HT2C receptors (related to its psychedelic effects) 2013)2 . Recommendations for an initial dose are between 6 and (Rickli et al., 2015). Also it binds mostly at the adrenergic α-2 20 mg depending on the user’s previous experience with similar receptor (Rickli et al., 2015). drugs, whilst 3 mg is considerate a “microdose” which produces Relatively little information is available regarding human 2C- intense effects on cognitive processes and well-being without the E metabolism. Nevertheless, research has suggested that it follows typical ones on consciousness (Polito and Stevenson, 2019). As similar metabolic pathways to 2C-Bwhich are carried out by with most psychedelics, the effects of 2C-E are long-acting, lasting O-demethylation and N-acetylation (Theobald et al., 2007). typically for 6–12 h, depending on the dose and individual. With respect to epidemiological data on 2C consumption, To date, a dozen cases of acute intoxication (tachycardia, the information available from web-based questionnaires and hypertension, agitation, delirium, and hallucinations) have been population-based surveys is particularly infrequent. In a self reported (Van Vrancken et al., 2013; Iwersen-Bergmann et al., selected sample from the 2013 Global Drug Survey1 , including 2019) and, although very rare, some deaths have been linked 2,282 participants in the United States, reporting attendance to to 2C-E (Topeff et al., 2011; Sacks et al., 2012). Alarmingly, nightclubs in the previous year, 46.4% described lifetime use of no human research has been conducted with 2C-E in spite of at least one of the 58 NPS assessed (age range 16–60 years). the relatively long history of its recreational use and the recent 1 2 https://www.globaldrugsurvey.com/ https://www.erowid.org/ Frontiers in Pharmacology | www.frontiersin.org 2 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E resurgence of interest in psychedelic drugs. The aim of our study examination. They received training with respect to was to evaluate the pharmacological effects and pharmacokinetics questionnaires and procedures employed in the study. Upon of 2C-E in recreational users. arrival, they were questioned about any event that could affect their participation. They were asked to refrain from any drug use 2 days prior to the session. Participants were not allowed to MATERIALS AND METHODS consume alcohol or beverages containing caffeine the previous 24 h. Sessions took place on two different days (5 participants Participants each day and administration were separated by various minutes Ten healthy subjects were selected (4 females and 6 males). among participants) at a private club with ambient music and Volunteers were recreative drug users who had experienced a 2C- participants could talk, read, or play table games during the series compound at least once in a lifetime. Exclusion criteria session and interact in exception to the evaluation times. Also, were a history of any serious medical or psychopathological they were instructed not to talk about the effects of the substance disorder including substance use disorder (except nicotine), during the session. Assessments were performed by at baseline a previous serious adverse reaction with 2C-series, and (pre-dose) and 2, 4, and 6 h after 2C-E self-administration. The chronic medicines use. experiment was conducted from 15:00 to 22:00 h. Urine spot Participants were recruited by word-of-mouth and snowball samples were collected prior administration to exclude prior sampling through the harm reduction, non-governmental substance drug use (benzodiazepines, barbiturates, morphine, organization, Energy Control (ABD). The study protocol was cocaine, amphetamines, methamphetamine, MDMA, marijuana, submitted and approved by the Clinical Research Ethics phencyclidine) with Instant-View, Multipanel 10 Test Drug Committee (CEIC Parc de Salut Mar, Barcelona, Spain, ref. Screen Alfa Scientific Designs Inc., Poway, CA, United States. 2016/6700/I). It was conducted according to the Declaration of Self-administration of 2C-E took place around 16.00 h. The Helsinki recommendations. All the participants were correctly sequence of procedures at each time point of the session was: and fully informed, both orally and in writing, of the purpose, physiological measures, oral fluid collection, and subjective methods and means of the study. All of them indicated their effects questionnaires. A psychiatry was present during the entire agreement to participate and signed an informed consent prior session. Adverse effects were assessed during study session. inclusion. Participants received monetary compensation for their participation. Physiological Effects Design and Treatments Non-invasive systolic and diastolic blood pressure (SBP and The design was a non-controlled prospective observational study DBP), and heart rate (HR) were determined with an Omron R with minimal intervention in subjects who self-administrated monitor at baseline and 2, 4, and 6 h after administration. Oral 2C-E orally. Most evaluations and procedures were similar to a temperature was measured simultaneously. previous naturalistic observational study evaluating acute effects of 2C-B (Papaseit et al., 2018). Each participant participated in Subjective Effects one session. Treatment consisted of oral self-administration of Subjective effects of 2C-E were reported at baseline and at 2, 4, one 2C-E capsule, that they brought to the testing site themselves, and 6 h after self-administration. They were measured using a set which they had obtained from an unknown source. Although no of Visual Analog Scales (VAS), the 49-item Addiction Research information was available about the synthesis of the drug, similar Centre Inventory (ARCI) short form, and the Evaluation capsules tested by Energy Control, a harm reduction organization of the Subjective Effects of Substances with Abuse Potential that provides a Drug Checking Service for users, showed that the (VESSPA-SSE) questionnaires. VAS (100 mm, from “not at all” capsules contained 2C-E at 95% purity with no toxic adulterants. to “extremely”) were used to rate intensity; stimulated; high; The 2C-B pill content was previously analyzed by means of gas good effects; liking; content; changes in colors; changes in chromatography associated with mass spectrometry (GC/MS). shapes; changes in lights; hallucinations-seeing of lights or spots; The method used permits to check for most common drugs of hallucinations-seeing animals, things, insects or people; changes abuse including most of the NPSs and to know the exact purity in hearing; hallucinations-hearings of sounds or voices; different of 2C-E in the powder to prepare dosing by a precision scale body feeling; unreal body feeling; changes in distances; different (Papaseit et al., 2018). The dose of 2C-E self-administrated was surroundings; unreal surroundings; confusion; fear; depression selected by the participants based presumably on their previous or sadness; drowsiness; dizziness; bad effects; headache; nausea; experience. The mean 2C-E dose was 11.95 ± 5.30 mg [1 female vertigo; breathing difficulty and face flushing (González et al., ingested 6.5 mg, 1 female 8 mg, 5 males 10 mg, 2 subjects (1 2015; Papaseit et al., 2016, 2018). male and 1 female) 15 mg, and 1 female 25 mg]. In order to The ARCI 49-item short form is a validated instrument that standardize dosing for statistical analysis and to evaluate dose- includes five subscales related to drug sedation (pentobarbital- response relationship, we grouped doses in two intervals: 6.5–10 chlorpromazine-alcohol group, PCAG), euphoria (morphine- and 15–25 mg (taken by 7 and 3 subjects, respectively). All the benzedrine group, MBG), dysphoria and somatic symptoms selected doses were well tolerated. (lysergic acid diethylamide group, LSD), intellectual efficiency Procedures and energy (benzedrine group, BG) and d-amphetamine- Prior to study session, the participants were submitted to like effects (A) (Lamas et al., 1994; Papaseit et al., 2016; a general medical examination and a psychiatric diagnostic Martínez-Riera et al., 2019). Frontiers in Pharmacology | www.frontiersin.org 3 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E The VESSPA-SE is a questionnaire that measures changes (range 16–24). The mean weight-adjusted dose of 2C-E was in subjective effects caused by different drugs including 0.19 ± 0.09 mg/kg (range 0.13–0.43). All subjects had previous stimulants and psychedelics and includes six subscales: sedation recreative experience with 2Cs, psychedelics/hallucinogens, (S), psychosomatic anxiety (ANX), changes in perception cocaine, MDMA, amphetamines, and cannabis. Seven of them (CP), pleasure and sociability (SOC), activity and energy were current tobacco smokers (range 0.5–7 cigarettes/day) and (ACT), and psychotic symptoms (PS) (González et al., 2015; all consumed alcohol daily (mean 1.4 units/day). All drugs of Papaseit et al., 2016). abuse urine tests were negative at baseline. As explained in the statistical analysis for dose-response analysis we grouped doses in Oral Fluid Concentrations of 2C-E two groups (6.5, 8–10, and 15–25 mg), Figures 1–3 are showed as To assess 2C-E concentrations in oral fluid (saliva), it was the two doses groups. Supplementary Figures S1–S3 presented collected with Salivette tubes at baseline, 2, 4, and 6 h after R individual data in order to show the elevated variability of the self-administration. After collection samples were centrifuged acute effects and concentrations. and frozen at -20◦ C until analysis. 2C-E concentrations were analyzed by a modified and validated liquid chromatography– Physiological Effects mass spectrometry method LC-MS/MS) (Papaseit et al., 2018). Effects of 2C-E on physiological signs are summarized in Table 1 and Figure 1, and Supplementary Figure S1 (individual data). Statistical Analysis 2C-E produced a non-significant increase in SBP, DBP, HR and For physiological (SBP, DBP, HR, and T) and subjective effects T. For HR significant differences were detected in the comparison (VAS, ARCI, and VESSPA), differences with respect to baseline of baseline and 4 hand 6 h after administration. Regarding T, only were calculated. Maximum effects (Emax ) were determined and statistically significant differences were detected at 2 and 4 h. No the area under the curve of the effects (AUC0−6 h ) were calculated dose-response relationship was observed. using the trapezoidal rule. For 2C-E oral fluid concentrations, the maximum Subjective Effects concentration (Cmax ), the time needed to reach the maximum The subjective effects induced by 2C-E are presented in Table 2 concentration (Tmax ) and the AUC0−6 h were determined and Figure 2, and Supplementary Figure S2 (individual data). using the Pharmacokinetic Functions for Microsoft Excel In summary, 2C-E significantly increased scores for most of the (Joel Usansky, Atul Desai, and Diane Tang-Liu, Department outcomes measured with VAS. Some effects were related to dose, of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, as higher doses produced more intense effects. The substance CA, United States). produced more intensity of effects in comparison to baseline Although it is remarkably that the participant that selected the for most variables. lowest dose (6.5 mg) presented higher acute effects and oral fluid For VAS scales related to euphoria-stimulation the highest concentrations in comparison to others, this subject was included scores were observed for “intensity,” “stimulated,” “high,” “good in all the analysis. effects,” “liking,” and “content.” When compared to baseline, A one-way analysis of variance (ANOVA) test including all significant differences were detected at 2 and 4 h, except for doses as a factor was used for Emax and AUC0−6 . When the dose “stimulated” (4 h) and “liking” (2, 4, and 6 h). No dose-response factor was statistically significant, a post hoc analysis for the two was observed when comparing both groups of doses. defined groups were done using a Student T-test (lower dose For VAS scales measuring changes in perceptions, statistically group: 6.5–10 mg, n = 7; higher dose group: 10–25 mg, n = 3). significant differences in Emax and AUC0−6 were detected for To evaluate the effects along time and to study the effects all VAS except in “different body feelings.” When compared to of the substance in comparison to baseline, a one-way repeated baseline, significant differences were found in VAS for “changes measures ANOVA, with time as factor (baseline, 2, 4, and 6 h), in colors” (2 h), “changes in lights” (4 h), “different body feeling” was done to evaluate the time-course of effects (for all doses). (h, 4 h), and “different surroundings” at 4 h and 6 h. A dose- When the time condition was statistically significant, a Dunnett response was observed in all VAS except for “changes in hearing,” multiple comparison post hoc test was conducted to compare the “changes in distances,” and “different body feeling.” different time points with baseline (0–2 h, 0–4 h, 0–6 h). With respect to scales measuring hallucinations, the highest All statistical tests were conducted using PAWS Statistics scores were found for “hallucination-seeing of lights/spots” (Emax version 18 (SPSS Inc., Chicago, IL, United States). A p < 0.05 21.00 mm) whilst modest and low scores were observed for value was considered statistically significant. “hallucination-seeing animals, things, insects or people” (Emax 6.20 mm, no significant) and “hallucination-hearing of sounds or voices” (Emax 2.20 mm, significant). Significant effects, baseline RESULTS differences and dose-response were observed for “hallucinations- seeing of light and spots” (6 h) and “hallucination-hearing of Participants sounds or voices.” All ten selected subjects participated in the study (4 females In addition, 2C-E induced “confusion,” “drowsiness,” and and 6 males). Demographics were a mean age of 27 ± 4 years “breathing difficulty.” Differences from baseline were observed (range 24–37), mean weight of 64.60 ± 8.77 kg (range 58– for “drowsiness,” “dizziness,” “bad effects,” and “nausea.” No 78), and mean body mass index (BMI) of 20.26 ± 2.55 kg/m2 dose-response was observed except for “breathing difficulty.” Frontiers in Pharmacology | www.frontiersin.org 4 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E FIGURE 1 | Time course of changes from baseline for physiological effects [◦, 6.5–10 mg of 2C-E (n = 7), , 15–25 mg of 2C-E (n = 3); mean, standard error]. In relation to ARCI questionnaire, significant increases in DISCUSSION the scores of all subscales were detected, however, differences in dose were not statistically significant. Similarly, differences from To the best of our knowledge, this is the first study to assess baseline were observed for all subscales at different times. No the acute behavioral (subjective) and physiological effects and dose-response was observed. oral fluid concentrations of 2C-E after the administration of With respect to the VESSPA, significant changes were known doses (6.5–25 mg) in humans. The main finding is that shown in Sedation, Change in perception and Psychotic 2C-E induced primarily a group of psychedelic-like effects, a symptoms, with significant differences from baseline in all except profile consistent with prior data from surveys and poisonings Psychotic symptoms. Dose-response relationship were detected symptoms (Matthews et al., 2016). Moreover, our study provides for Changes in Perception and Psychotic symptoms. unique results about concentrations of 2C-E in oral fluid. Most of the effects dissipated after 6 h, and all subjects In our non-controlled setting, 2C-E only partially mimicked returned to their usual routine. Two of them presented the prototypical sympathomimetic-like effects of other residual mild visual hallucinations (lights) at 6 h which psychedelic and psychostimulant drugs (Schmid et al., 2015; disappeared 1–2 h later. Dolder et al., 2017) and 2C-B (Papaseit et al., 2018). The physiological actions induced by 2C-E included a mild-moderate Oral Fluid Concentrations increase of HR, without changes in blood pressure. The effects The oral fluid concentration-time curve for 2C-E are shown were lower than those produced by 2C-B (Papaseit et al., in Figure 3, and Supplementary Figure S3 (individual data). 2018) and by MDMA, mephedrone or other amphetamines Concentrations of 2C-E increased rapidly, reaching a peak 2 h administered in dose-controlled conditions (Farré et al., 2015; after ingestion. Concentrations rapidly decrease from 2 to 6 h Papaseit et al., 2016). It is possible that the wide range of doses in after ingestion. Mean maximum concentration (Cmax ) values the present study (from 6.5 to 25 mg) did not permit differences of 5.8 ± 6.4 ng/mL (range 0.93–21.54) were obtained at a to be observed in blood pressure when compared to 2C-B Tmax of 2 h following drug administration. The AUC0−6 was (in a narrow range from 10 to 20 mg) (Papaseit et al., 2018). 18 ± 18 ng·h/mL (range 3.69–57.70). Plasma concentrations For 2C-E the maximal cardiac effect was observed at the 2 h varied considerably among doses and subjects. No significant assessment, maintained over 2–4 h, and returned to baseline at differences between the two grouped doses were found for 6 h post-administration. Cmax or AUC0−6 (Table 2). All ten subjects presented positive In this study, 2C-E produced mixed euphoria, pleasure concentrations of 2C-E at 4 h; only 5, however, had 2C-E and well-being feelings, and alterations in mental functions concentrations in saliva at 6 h. like psychedelics such as 2C-B (González et al., 2015; Frontiers in Pharmacology | www.frontiersin.org 5 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E FIGURE 2 | Time course of changes from baseline for subjective effects [◦, 6.5–10 mg of 2C-E (n = 7); , 15–25 mg of 2C-E (n = 3); mean, standard error]. Papaseit et al., 2018), psilocybin (Griffiths et al., 2006), salvinorin experience after 2C-B or 2C-E use, as previously postulated for A (Johnson et al., 2011) and ayahuasca (Riba et al., 2001, 2004) other psychedelics (Bouso et al., 2016). It is noteworthy that and psychostimulants such as MDMA (Papaseit et al., 2016), 2C-E increased some somatic VAS scales (drowsiness, dizziness, amphetamine (Cami et al., 2000), and mephedrone (Papaseit and confusion) in a similar manner to 2C-B. et al., 2016). Under 2C-E influence participants reported Moreover, alteration in perception varied from changes euphoria, stimulation, and altered state of consciousness due in perceptions to hallucinations, that were experienced by to the psychedelic experience. Changes in mood were more 5 volunteers (3 only visual and 2 visual and auditory pronounced than perceptual ones. As an example, the mean VAS hallucinations). Of these, 5 subjects reported visual (seeing of ratings of “high,” “good effects,” and “liking” reached up to 50% of lights or spots, 14–72 mm), 1 subject visual (seeing things/people, the maximum possible VAS scores, but they were still lower than 50 mm) and 2 participants auditory (hearing sounds/voices, those observed in experimental dose-controlled conditions for 8–14 mm score), effects. Results differ in intensity from 2C-B, MDMA, and other stimulants as mephedrone (Mas et al., other psychedelics probably because in this study subjects 1999; Farré et al., 2015; Papaseit et al., 2016, 2018). It is possible self-administered low to moderate doses of the substance. that euphoria could be an important issue of the psychedelic Additionally, 2C-E produced higher increases in sociability Frontiers in Pharmacology | www.frontiersin.org 6 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E In a similar manner to 2C-B, the sole 2C-compound with previous observational data in humans after dose-controlled administration, 2C-E induced modest sympathomimetic effects, similar feelings of well-being, euphoria, and changes in perception although with more profound hallucinations (Caudevilla-Gálligo et al., 2012; González et al., 2015; Papaseit et al., 2018). As expected, in our study 2C-E produced the prototypical effects of psychedelic substances that include visual hallucinations, perceptual changes, somatic symptoms, and activation of euphoria. Although it also induced headache, confusion, and breathing difficulty, no severe adverse reactions were observed. Our results show that in a recreational setting, self- FIGURE 3 | Time course of 2C-E concentrations in oral fluid [1, 6.5 mg of administration of low-moderate doses of 2C-E by healthy 2C-E (n = 1); ◦, 8–10 mg of 2C-E (n = 6), , 15–25 mg of 2C-E (n = 3); mean, experienced users is well tolerated and relatively safe. standard error]. The results are consistent with a relatively low number of severe acute toxicity cases associated to 2C-E use (Iwersen-Bergmann et al., 2019). (VESPA SOC subscale) and augmented ratings on change The pharmacokinetics of 2C-E in humans has not yet perceptions, effects widely related to MDMA and LSD (Papaseit been fully known. Our results on oral fluid concentrations et al., 2016; Dolder et al., 2017; Puxty et al., 2017). Overall, the of 2C-E are the first data in humans to be reported. 2C-E subjective effects induced by 2C-E appear to be closely related to concentrations ranged from 0.93 to 21.54 ng/mL, with an average psychedelic drugs indicating that it produces mind-altering and peak concentration of 5.8 ± 6.4 ng/mL observed at 2 h after hallucinogenic effects which could be primarily mediated by the administration. Oral fluid 2C-E showed a similar time course 5HT2A receptor. with effect outcomes. Nevertheless, because the study included TABLE 1 | Summary of result on the physiological effects observed after self-administration of 2C-E. Effects Parameter ANOVA Comparison T-Student to baseline Doses (6.5–25 mg) (n = 10) Doses 6.5–10 mg 15–25 mg T-value p-value (6.5–25 mg) (n = 7) (n = 3) (n = 10) Mean ± SD F p-value Dunnett’s test Mean ± SD Mean ± SD Physiological effects Systolic blood Emax 15 ± 23 0.047 0.995 15 ± 28 15 ± 5.8 ND ND pressure AUC0−6 41 ± 74 0.050 0.994 43 ± 89 35 ± 22 ND ND T-C NS Diastolic blood Emax 1.6 ± 20 0.840 0.554 2 ± 22 0.7 ± 20 ND ND pressure AUC0−6 −2.1 ± 63 0.873 0.539 −5.9 ± 74 6.7 ± 39 ND ND T-C NS Heart rate Emax 18 ± 19 2.883 0.138 12 ± 17 33 ± 19 ND ND AUC0−6 58 ± 56 4.799 0.058 41 ± 57 98 ± 34 ND ND T-C b, c Temperature Emax 0.5 ± 0.2 2.366 0.185 0.1 ± 0.2 0.3 ± 0.2 ND ND AUC0−6 0.3 ± 0.5 1.122 0.440 0.2 ± 0.5 0.6 ± 0.6 ND ND T-C b Emax = peak effects 0–6 h (differences from baseline). AUC0−6 = area under the curve from 0 to 6 h. Units: mmHg (systolic blood pressure and diastolic blood pressure), beats per minute (heart rate), ◦ C (temperature). For Emax and AUC0−6 a one-way ANOVA was used to examine the effect of all doses. A p < 0.05 was considered statistically significant. Only if a statistical difference were detected an unpaired T-Student was used to examine differences between the grouped doses (6.5–10 mg vs. 15–25 mg). A p < 0.05 was considered statistically significant. ND, not done. For T-C a one-way ANOVA and a post hoc Dunnett’s test for multiple comparisons was used. Statistical differences between are presented as “a” p < 0.05, “a” p < 0.01 (times 0–2 h), “b” p < 0.05, “b” p < 0.01 (times 0–4 h), “c” p < 0.05, “c” p < 0.01 (times 0– 6 h). Frontiers in Pharmacology | www.frontiersin.org 7 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E TABLE 2 | Summary of result on the subjective effects and saliva concentrations observed after self-administration of 2C-E. Effects Parameter ANOVA Comparison to T-Student baseline Doses (6.5–25 mg) (n = 10) Doses 6.5–10 mg 15–25 mg T-value p-value (6.5–25 mg) (n = 7) (n = 3) (n = 10) Mean ± SD F p-value Dunnett’s test Mean ± SD Mean ± SD Visual analog scale (VAS) Intensity Emax 46 ± 17 1.045 0.468 43 ± 11 55 ± 27 ND ND AUC0−6 147 ± 68 5.464 0.045 134 ± 52 177 ± 104 −0.916 0.387 T-C a, b Stimulated Emax 37 ± 28 1.423 0.349 29 ± 25 55 ± 31 ND ND AUC0−6 114 ± 104 3.666 0.093 86 ± 87 179 ± 130 ND ND T-C b High Emax 48 ± 23 1.924 0.245 48 ± 21 54 ± 44 ND ND AUC0−6 145 ± 99 6.003 0.038 134 ± 74 185 ± 189 ND ND T-C a, b Good effects Emax 50 ± 27 0.839 0.555 72 ± 86 62 ± 30 ND ND AUC0−6 150 ± 110 3.875 0.085 116 ± 74 212 ± 133 ND ND T-C a, b Liking Emax 51 ± 30 0.751 0.598 49 ± 24 55 ± 48 ND ND AUC0−6 181 ± 134 1.691 0.287 170 ± 113 205 ± 203 ND ND T-C a, b, c Content Emax 47 ± 30 1.048 0.467 44 ± 25 53 ± 47 ND ND AUC0−6 145 ± 110 1.784 0.269 130 ± 92 180 ± 161 ND ND T-C a, b Changes in colors Emax 32 ± 21 6.786 0.030 23 ± 7.9 52 ± 32 −2.426 0.041 AUC0−6 102 ± 111 51.871 < 0.001 55 ± 16 209 ± 173 −2.545 0.034 T-C a, b Changes in shapes Emax 27 ± 27 3.717 0.091 15 ± 16 53 ± 32 ND ND AUC0−6 73 ± 91 14.974 0.005 34 ± 35 165 ± 128 −2.665 0.029 T-C NS Changes in lights Emax 35 ± 28 9.468 0.015 23 ± 18 64 ± 32 −2.665 0.029 AUC0−6 99 ± 90 34.980 0.001 59 ± 39 193 ± 114 −2.930 0.019 T-C c Hallucinations- Emax 21 ± 26 8.564 0.018 6.6 ± 12 55 ± 16 −5.388 0.001 seeing of lights or spots AUC0−6 61 ± 88 13.026 0.007 16 ± 28 166 ± 92 −4.220 0.003 T-C c Hallucinations- Emax 6.2 ± 16 1.002 0.485 1.4 ± 3.8 17 ± 28 ND ND seeing animals, things, insects, or people AUC0−6 11 ± 26 0.987 0.491 2.9 ± 7.6 29 ± 46 ND ND T-C NS Changes in hearing Emax 4.1 ± 7.4 15.425 0.005 4.0 ± 8.5 4.3 ± 5.1 −0.062 0.952 AUC0−6 12 ± 23 19.891 0.003 12 ± 27 11 ± 14 0.080 0.938 T-C NS Hallucinations- Emax 2.2 ± 4.9 13.444 0.007 0.0 ± 0.0 7.3 ± 7.0 −3.026 0.016 hearings of sounds or voices AUC0−6 4.9 ± 11 29.642 0.001 0.0 ± 0.0 16 ± 15 −3.189 0.013 T-C NS (Continued) Frontiers in Pharmacology | www.frontiersin.org 8 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E TABLE 2 | Continued Effects Parameter ANOVA Comparison to T-Student baseline Doses (6.5–25 mg) (n = 10) Doses 6.5–10 mg 15–25 mg T-value p-value (6.5–25 mg) (n = 7) (n = 3) (n = 10) Mean ± SD F p-value Dunnett’s test Mean ± SD Mean ± SD Different body Emax 46 ± 23 1.559 0.315 46 ± 20 46 ± 33 ND ND feeling AUC0−6 135 ± 78 3.792 0.088 120 ± 46 169 ± 133 ND ND T-C a, b Unreal body feeling Emax 20 ± 26 6.413 0.033 9.4 ± 13 43 ± 38 −2.231 0.056 AUC0−6 58 ± 101 26.999 0.001 19 ± 26 150 ± 161 −2.273 0.053 T-C NS Changes in Emax 22 ± 30 1.286 0.387 13 ± 25 44 ± 34 ND ND distances AUC0−6 60 ± 98 5.499 0.045 26 ± 50 139 ± 149 −1.899 0.094 T-C NS Different Emax 29 ± 29 2.311 0.191 17 ± 18 56 ± 32 ND ND surroundings AUC0−6 82 ± 100 8.625 0.018 37 ± 38 187 ± 129 −3.001 0.017 T-C b, c Unreal Emax 13 ± 27 14.432 0.006 0.0 ± 0.0 43 ± 36 −3.428 0.009 surroundings AUC0−6 45 ± 102 29.938 0.001 0.0 ± 0.0 150 ± 153 −2.843 0.022 T-C NS Confusion Emax 15 ± 22 1.891 0.250 0.0 ± 0.0 2.3 ± 2.08 ND ND AUC0−6 35 ± 49 6.297 0.034 9 ± 12 30 ± 37 −1.461 0.182 T-C NS Fear Emax 3.1 ± 5.2 0.802 0.573 1.1 ± 3.0 7.7 ± 7.1 ND ND AUC0−6 6.7 ± 12 0.785 0.581 2.3 ± 6.1 17 ± 16 ND ND T-C NS Depression or Emax 3.0 ± 5.3 3.774 0.089 1.3 ± 3.0 7.0 ± 8.2 ND ND sadness AUC0−6 7.0 ± 12 2.437 0.178 2.6 ± 6.0 17 ± 16 ND ND T-C NS Drowsiness Emax 22 ± 28 10.050 0.013 15 ± 18 38 ± 44 −1.221 0.257 AUC0−6 66 ± 89 17.533 0.004 48 ± 64 106 ± 140 −0.933 0.378 T-C a Dizziness Emax 15 ± 21 1.916 0.246 9.9 ± 16 27 ± 30 ND ND AUC0−6 44 ± 71 4.783 0.058 22 ± 36 97 ± 114 ND ND T-C a Bad effects Emax 8.4 ± 10 2.761 0.147 9.3 ± 12 8.7 ± 4.5 ND ND AUC0−6 23 ± 29 1.938 0.243 22 ± 33 26 ± 20 ND ND T-C a Headache Emax 14 ± 17 1.509 0.327 8.3 ± 12 26 ± 22 ND ND AUC0−6 28 ± 33 3.647 0.094 25 ± 39 32 ± 22 ND ND T-C NS Nausea Emax 11 ± 10 0.262 0.891 11 ± 11 12 ± 7.3 ND ND AUC0−6 32 ± 30 0.761 0.593 28 ± 31 40 ± 30 ND ND T-C a Vertigo Emax 12 ± 20 0.316 0.857 8.7 ± 18 19 ± 26 ND ND AUC0−6 20 ± 32 0.143 0.959 17 ± 37 25 ± 23 ND ND T-C NS (Continued) Frontiers in Pharmacology | www.frontiersin.org 9 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E TABLE 2 | Continued Effects Parameter ANOVA Comparison to T-Student baseline Doses (6.5–25 mg) (n = 10) Doses 6.5–10 mg 15–25 mg T-value p-value (6.5–25 mg) (n = 7) (n = 3) (n = 10) Mean ± SD F p-value Dunnett’s test Mean ± SD Mean ± SD Breathing difficulty Emax 2.7 ± 6.5 90.601 < 0.001 0.3 ± 0.8 8.3 ± 11 −2.103 0.069 AUC0−6 10 ± 27 319.150 < 0.001 0.6 ± 1.6 32 ± 47 −1.910 0.093 T-C NS Face flushing Emax 13 ± 20 0.374 0.819 16 ± 17 27 ± 29 ND ND AUC0−6 20 ± 20 0.883 0.535 53 ± 59 72 ± 90 ND ND T-C NS Addiction research center inventory (ARCI) PCAG (sedation) Emax 3.1 ± 4.6 0.443 0.775 3.1 ± 4.3 3.0 ± 6.1 ND ND AUC0−6 14 ± 13 1.101 0.447 12 ± 13 18 ± 14 ND ND T-C a MBG (euphoria) Emax 4.4 ± 4.4 0.904 0.526 3.1 ± 3.5 7.3 ± 5.7 ND ND AUC0−6 16 ± 19 1.549 0.318 11 ± 14 28 ± 28 ND ND T-C b, c LSD (dysphoria and Emax 4.5 ± 2.7 1.469 0.337 3.6 ± 1.0 6.7 ± 2.5 ND ND somatic symptoms) AUC0−6 12 ± 9.8 3.802 0.088 7.4 ± 6.3 23 ± 7.55 ND ND T-C a, b BG (intellectual Emax 1.5 ± 2.2 0.330 0.847 1.1 ± 2.0 2.3 ± 3.1 ND ND efficieny and energy) AUC0−6 4.1 ± 6.6 0.419 0.790 4.0 ± 5.6 4.3 ± 10 ND ND T-C b A Emax 4.2 ± 1.9 0.755 0.596 3.7 ± 1.2 5.3 ± 2.9 ND ND (amphetamine-like effects) AUC0−6 14 ± 8.1 0.658 0.647 13 ± 5.9 19 ± 12 ND ND T-C a, b, c Evaluation of subjective effects of substances with abuse potential (VESSPA-SEE) S (sedation) Emax 6.7 ± 3.3 9.231 0.016 5.8 ± 3.5 8.7 ± 2.08 −1.275 0.238 AUC0−6 19 ± 11 3.051 0.126 16 ± 11 24 ± 12 ND ND T-C a ANX Emax 4.0 ± 2.9 1.996 0.234 3.3 ± 3.1 5.7 ± 1.5 ND ND (psychosomatic anxiety) AUC0−6 13 ± 10 3.178 0.118 11 ± 10 19 ± 8.7 ND ND T-C a, b CP (changes in Emax 4.2 ± 4.7 8.452 0.019 1.7 ± 1.2 10 ± 4.6 −4.736 0.001 perception) AUC0−6 13 ± 17 17.663 0.004 4.3 ± 3.9 33 ± 18 −4.311 0.003 T-C b SOC (pleasure and Emax 8.2 ± 7.7 2.389 0.183 5.9 ± 5.2 13 ± 11 ND ND sociability) AUC0−6 26 ± 29 3.212 0.116 18 ± 20 47 ± 40 ND ND T-C b ACT (activity and Emax 6.0 ± 6.3 1.205 0.412 3.9 ± 4.4 11 ± 7.9 ND ND energy) AUC0−6 18 ± 20 1.362 0.365 11 ± 12 35 ± 27 ND ND T-C b (Continued) Frontiers in Pharmacology | www.frontiersin.org 10 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E TABLE 2 | Continued Effects Parameter ANOVA Comparison to T-Student baseline Doses (6.5–25 mg) (n = 10) Doses 6.5–10 mg 15–25 mg T-value p-value (6.5–25 mg) (n = 7) (n = 3) (n = 10) Mean ± SD F p-value Dunnett’s test Mean ± SD Mean ± SD PS (psychotic Emax 3.1 ± 4.1 3.753 0.090 1.2 ± 1.1 7.3 ± 5.7 −2.919 0.019 symptoms) AUC0−6 11 ± 18 15.680 0.005 3.1 ± 3.0 28 ± 17 −2.418 0.042 T-C NS Oral fluid concentrations 2C-E Cmax 5.8 ± 6.4 0.491 0.745 7.3 ± 7.2 2.4 ± 1.7 ND ND AUC0−6 18 ± 18 0.532 0.720 22 ± 21 7.3 ± 4.7 ND ND T-C a Emax = peak effects 0–6 h. Emax = peak effects 0–6 h (differences from baseline). AUC0−6 = area under the curve from 0 to 6 h. Units: mm [visual analog scale (VAS)], and score [Addiction Research Center Inventory (ARCI), Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SEE)] and expressed as mean. Cmax = maximal concentrations 0–6 h (differences from baseline) measured by ng/mL. For Emax and AUC0−6 a one-way ANOVA was used to examine the effect of all doses. A p < 0.05 was considered statistically significant. Only if a statistical difference were detected an unpaired T-Student was used to examine differences between the grouped doses (6.5–10 mg vs. 15–25 mg). A p < 0.05 was considered statistically significant. ND, not done. For T-C a one-way ANOVA and a post hoc Dunnett’s test for multiple comparisons was used. Statistical differences between are presented as “a” p < 0.05, “a” p < 0.01 (times 0–2 h), “b” p < 0.05, “b” p < 0.01 (times 0–4 h), “c” p < 0.05, “c” p < 0.01 (times 0–6 h). five different 2C-E doses in a limited number of subjects, a dose- picture. Future studies should be carried out in controlled concentration relationship was not observed. We do not have conditions and with a larger sample. In addition, it should an explanation for the high variability observed, with higher be noted that 2C-E profiles may vary considerably due to concentrations after lower doses. Problems in the collection of the dose administered and the interindividual differences in the samples or an erratic distribution of 2C-E in saliva could pharmacodynamic-pharmacokinetics. be possible causes. Concentrations in oral fluid were present in all subjects until 4 h, and5 of them were positive at 6 h post- administration. Oral fluid, in contrast to plasma, is a suitable, CONCLUSION non-invasive, and easy biological matrix to collect in a non- controlled setting. Nevertheless, the interpretation of oral fluid The results of this non-controlled, observational study in a real- 2C-E concentrations without data from plasma is extremely life setting of recreational use provide useful preliminary data difficult (not obtained in this study or any other). of the acute pharmacodynamic effects and pharmacokinetics Our study has several limitations mainly associated with in oral fluid of 2C-E. Taken together, the current findings its design as naturalistic-observational. An expectancy bias suggest that self-administered oral 2C-E induced a constellation could appear due to the non-placebo-controlled design. Because of alterations in perceptions, hallucinations, and euphoric- participants selected the dose according to their preferences, it mood which displayed marked similarities to psychedelic resulted in low-moderate doses (ranging from 6.5 to 25 mg), experience. Even at low-moderate doses, notable perceptual and some doses were only used by one participant. A limited changes and hallucinations were the most prominent 2C- number of subjects could be responsible for a lack of power E effects. High interindividual variability among doses was in some measures. Our findings may not refer to other 2C- observed. Participants with self-administered higher doses were E routes of administration. Moreover, the recreational setting more susceptible to experiencing the most intense subjective could have influenced the effects reported by participants. The effects. Based on these preliminary data, oral fluid can limited number of time-point measures did not permit to be an appropriate, non-invasive, biologic matrix to detect know the real peak effect/concentration times that will need acute 2C-E use. more intensive evaluations. However, it should be noted that It can be concluded that further research in humans is needed there are a number of strengths: the participation of female to compare the effects of 2C-E with other classical and new subjects, the dose selection by the subjects according to their psychedelic substances. preferences (6.5–25 mg representing real-life quantities), effects previously experienced with the same or similar psychedelic substances, the recreational scenario, and the use of validated DATA AVAILABILITY STATEMENT rating scales, questionnaires, and analytic techniques. We cannot discard that a more controlled dose-response study using defined The datasets generated for this study are available on request to drug doses equal for all subjects would produce a different the senior author (MF, magi.farre@uab.cat). Frontiers in Pharmacology | www.frontiersin.org 11 March 2020 | Volume 11 | Article 233 Papaseit et al. Acute Effects of 2C-E ETHICS STATEMENT [HOME/2014/JDRU/AG/DRUG/7082, Predicting Risk of Emerging Drugs with In silico and Clinical Toxicology The protocol was approved by the local Research Ethics (PREDICT)]. Esther Papaseit has a Juan Rodes fellowships (ISC- Committee (CEIC-Parc de Salut Mar, Barcelona, Spain). The III, JR16/00020) and MG has a Rio Hortega fellowships (ISC-III, study was conducted in accordance with the Declaration of CM18/00168). Helsinki and Spanish laws concerning clinical research. The participants provided their written informed consent previous to participate in this study. ACKNOWLEDGMENTS We are grateful to Pol Quintana (MD) for their valuable AUTHOR CONTRIBUTIONS assistance throughout the clinical study. MF, RT, MV, MG, MT, ES, JR, and EO conceptualized the study design. MF, EO, MG, ES, and MV collected the data. EO and OP SUPPLEMENTARY MATERIAL analyzed the oral fluid. MV analyzed the 2C-E contents. EP and CP-M analyzed the data. EP, EO, CP-M, MT, MG, MV, OP, ES, JR, The Supplementary Material for this article can be found RT, and MF wrote, revised, and approved the manuscript. online at: https://www.frontiersin.org/articles/10.3389/fphar. 2020.00233/full#supplementary-material FIGURE S1 | Time course of individual changes from baseline for selected FUNDING physiological effects (n = 10; mean, standard error). This work was supported in part by grants from Instituto FIGURE S2 | Time course of individual changes from baseline for selected de Salud Carlos III (ISCIII, FIS-FEDER and FIS-PI17/01962), subjective effects (n = 10; mean, standard error). ISCIII-Red de Trastornos Adictivos (RTA RD16/0017/003 FIGURE S3 | Time course of individual 2C-E concentrations in oral fluid (n = 10; and RD16/0017/0010) and The European Commission mean, standard error). REFERENCES (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart. Eur. 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Sacks, J., Ray, M. J., Williams, S., and Opatowsky, M. J. (2012). Fatal toxic leukoencephalopathysecondary to overdose of a new psychoactive designer Copyright © 2020 Papaseit, Olesti, Pérez-Mañá, Torrens, Grifell, Ventura, Pozo, de drug 2C-E ("Europa"). Proc 25, 374–376. Sousa Fernandes Perna, Ramaekers, de la Torre and Farré. This is an open-access Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K. H., Vollenweider, F. X., article distributed under the terms of the Creative Commons Attribution License et al. (2015). Acute effects of lysergic acid diethylamide in healthy subjects. Biol. (CC BY). The use, distribution or reproduction in other forums is permitted, provided Psychiatry 78, 544–553. doi: 10.1016/j.biopsych.2014.11.015 the original author(s) and the copyright owner(s) are credited and that the original Sexton, J. D., Crawford, M. S., Sweat, N. W., Varley, A., Green, E. E., and Hendricks, publication in this journal is cited, in accordance with accepted academic practice. No P. S. (2019). Prevalence and epidemiological associates of novel psychedelic use use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 13 March 2020 | Volume 11 | Article 233