Simultaneous Polysubstance Use Among Danish 3,4Methylenedioxymethamphetamine and Hallucinogen Users: Combination Patterns and Pr

human psychopharmacology Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. Published online 14 June 2012 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2234

Simultaneous polysubstance use among Danish 3,4- methylenedioxymethamphetamine and hallucinogen users: combination patterns and proposed biological bases

Cecilie L. Licht1*, Maria Christoffersen1, Mads Okholm1,LærkeDamgaard1, Anders Fink-Jensen2, Gitte M. Knudsen1 and David Erritzoe1

1Neurobiology Research Unit (NRU) and Center for Integrated Molecular Brain Imaging (Cimbi), University of Copenhagen and Rigshospitalet, Copenhagen, Denmark 2Psychiatric Centre Copenhagen and Laboratory of Neuropsychiatry, Department O, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

Objective To describe patterns of simultaneous polysubstance use (SPU) among Danish 3,4-methylenedioxymethamphetamine (MDMA) (“Ecstasy”) and hallucinogen users. Methods A cross-sectional survey of 98 active MDMA and/or hallucinogen users recruited through homepage advertisements, flyers, and word of mouth in Denmark. Lifetime and recent substance use and SPU at last recalled use was described by structured interviews. Hair samples from a subset of participants were analyzed for MDMA. Results The participants had used an average of 12.6 (95% confidence interval: 11.7–13.4) psychoactive substances during their lifetime. SPU was prevalent among MDMA, D-lysergic acid diethylamide (LSD), and psilocybin users, in particular with alcohol and cannabis. Among MDMA users, 69% had combined MDMA with amphetamines, 56% with hallucinogens, and 47% with cocaine. At last recalled use, MDMA was taken with 2.1 Æ 1.2 substances in 32 different combinations. The participants preferred specific drug combinations and named several, which in their experience enhanced or counteracted each other. Alcohol and cannabis were typically used before, during, and after MDMA, LSD, and psilocybin, whereas amphetamines were predominantly taken before these substances. When LSD was combined with MDMA, the majority took MDMA after LSD. Conclusions Simultaneous polysubstance use was common among Danish MDMA and hallucinogen users, and patterns of preferred substance combinations were evident. Copyright © 2012 John Wiley & Sons, Ltd. key words—substance-related disorders; 3,4-methylenedioxymethamphetamine; ecstasy; hallucinogens; designer drugs; street drugs

INTRODUCTION particular, the simultaneous use of several drugs (simul- Substance-related disorders may have severe detrimental taneous polysubstance use, SPU) during the course of a effects on the health, social relationships, and employ- single drug use session is common among street drug ment of substance users, leading to substantial human users (Barrett et al., 2006; EMCDDA, 2009; Tossmann and ﬁnancial loss to society. Many street drug users take et al., 2001) and may increase drug consumption (Barrett several different substances during their lifetime, a et al., 2006), morbidity and mortality from substance use (EMCDDA, 2009; Schifano et al., 2003), as well as phenomenon known as polysubstance use (EMCDDA, ﬂ 2009; Tossmann et al., 2001; Wu et al., 2006). In in uence the development of drug tolerance in complex ways (Parrott, 2005). Often, particular substances are combined to enhance psychoactive effects or to relieve *Correspondence to: Dr. C. L. Licht, Neurobiology Research Unit (NRU) and unwanted after effects (Boys et al., 2001; Winstock Center for Integrated Molecular Brain Imaging (Cimbi), University of Copenha- et al., 2001). Whereas distinct characteristics of SPU gen and Rigshospitalet, Section 9201, Blegdamsvej 9, 2100 Copenhagen O, Denmark. Tel: +45 35456712; Fax: +45 35456713. E-mail: [email protected] have been described for different groups of street drug users and for users of particular substances including Dr. D. Erritzoe, Neuropsychopharmacology Unit, Imperial College London, 3,4-methylenedioxymethamphetamine (MDMA) (Barrett Burlington-Danes Building, Hammersmith Campus, 160 Du Cane Road, London W12 0NN, UK. Tel: +44 02075947047; Fax: +44 02075946548. et al., 2005; Tossmann et al., 2001), few studies have E-mail: [email protected] examined the order of substance administration and

Received 15 February 2012 Copyright © 2012 John Wiley & Sons, Ltd. Accepted 3 May 2012 simultaneous polysubstance use among mdma users 353 the doses used during SPU. Given that substances can for LSD among 16–44-year olds (Ekholm et al., 2006). interact at many functional levels (pharmacokinetic However, in the dance club environment of European and pharmacodynamic) and that such interactions are metropolises, past month and lifetime prevalence rates affected by relative timing and dosage, this type of of hallucinogens of 8.1–21.6% and 21.1–66.8%, respec- information is important in understanding the biologi- tively, have been found (Tossmann et al., 2001). cal bases and effects of specific SPU patterns. Aims of the study MDMA is a widely used substance of abuse among teenagers and young adults with a past year and life- The aim of the present study was to examine patterns time prevalence of 1.7% and 5.8%, respectively, of lifetime and recent SPU, including drug order, among 15–34-year olds in the EU (EMCDDA, dosing, and adverse effects of MDMA use, among 2010). In Denmark (a member of the EU), the past year Danish MDMA and hallucinogen users. A detailed prevalence in 2010 was 0.8% among 16—34-year and qualitative description of SPU patterns may in olds (Sundhedsstyrelsen, 2010). MDMA exerts its the light of known psychopharmacological effects of main effects on serotonin (5-hydroxytryptamine, 5-HT), combining specific drugs further understanding of dopamine, and norepinephrine transporters, releasing SPU involving MDMA and hallucinogens. monoamines into the extracellular space, and has psychostimulant, empathogenic, and mild hallucinogenic METHODS properties (Capela et al., 2009; Gudelsky and Yamamoto, 2008). When used repeatedly and in high Participants doses, MDMA may have neurotoxic effects on seroto- Young Danish adults between the age of 18 and nergic neurons, although this contention is a subject of 35 years, who reported a lifetime history of at least 15 ongoing debate (Baumann et al., 2007; Capela et al., illicit drug experiences (excluding cannabis) and use 2009; Kish et al., 2010; Thomasius et al., 2003). The of MDMA or hallucinogens (at least once) within the use of MDMA may cause acute hyperthermia, which past 12 months, were included in the study. Participants exacerbates longer term adverse effects on memory were recruited between November 2005 and April 2008 and mood (Parrott, 2006). Polysubstance use is reported through advertisements posted on homepages used by by nearly all MDMA users and includes alcohol, nicotine, Danish hallucinogen and MDMA users and on flyers cannabis, amphetamines, cocaine, and hallucinogens distributed at music events, as well as by word of (Carlson et al., 2005; Parrott et al., 2001; Topp et al., mouth. A total of 284 subjects expressed interest in 1999). In particular, psychostimulant and hallucinogen the study, and 166 met the inclusion criteria. Interviews use has been significantly related to extent of MDMA were completed with 98 (87% male, 13% female) parti- use (Hammersley et al., 1999). Simultaneous use of cipants. It was not possible to schedule the remaining MDMA and other psychoactive substances was prevalent 68 for interview because of practical limitations. Each among participants in the European and Canadian techno subject provided informed consent and received a finan- dance scene and included several kinds of compounds cial compensation of DKK 110/h (EUR 15/h) for the 2- (Barrett et al., 2005; Tossmann et al., 2001). Importantly, hour duration of the interviews. A subset of participants simultaneous use of alcohol and MDMA prolonged was also included in a positron emission tomography feelings of euphoria in a controlled clinical experiment (PET) study (Erritzoe et al., 2011). The Research Ethics (Hernandez-Lopez et al., 2002) and may increase abuse Committee for the Capital Region of Denmark (H-KF-01- liability of MDMA (Jones et al., 2010). 124/04) approved the study. Hallucinogens are a group of perception-altering substances including psilocybin (“magic”) mushrooms, Structured interviews mescaline (peyote cacti), and ayahuasca, as well as A modified Danish version of the Customary Drinking semi-synthetic compounds such as D-lysergic acid and Drug Use Record (CDDR) domain “use frequency diethylamide (LSD), which exert their main effects as and quantity” was used to describe the participants’ agonists at the 5-HT2A receptor (Halpern, 2003; alcohol and substance use in details (Brown et al., Nichols, 2004). The use of hallucinogenic compounds 1998). The CDDR substance use domain collects in the general population is less prevalent than MDMA information on recent (past 3 months) and lifetime with past year and lifetime prevalence of 0.2–5.9% and alcohol and substance use (quantity and frequency of 0.3–14.1% for psilocybin mushrooms, and “very low” 13 specified substance types and any additional drugs and 0–6.1% for LSD among 15–34-year olds in the EU named by the participant), age of initiation, and doses (EMCDDA, 2010). In Denmark, the past year prevalence typically administered. The CDDR substance use in 2005 was 0.4% for psilocybin mushrooms and 0.1% domain had 1-week test–retest reliability coefficients

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup 354 c. l. licht ET AL. of 0.83 (alcohol) and 0.92 (drugs), and good convergent in milligrams of powder or number of tablets; the latter validity as evidenced by correlations of recent alcohol was converted to milligrams on the basis of an average and substance use assessed by the CDDR with a time- MDMA content of 60 mg in Danish ecstasy tablets line follow-back assessment of alcohol and other drug between 2003 and 2007 (Johannsen, 2008). Numbers use (r = 0.68 (alcohol) and r = 0.74 (drugs)) (Brown of co-administered drugs were analyzed by Kruskal– et al., 1998). The CDDR assessment of recent (past Wallis test followed by Dunn’s Multiple Comparison 3 months) and lifetime alcohol and substance use was Test, comparing each drug with MDMA. Order of supplemented with questions regarding the last recalled substance administration during SPU at last recalled event of substance administration for each substance use was categorized as the use of a substance (e.g., alco- used (dose used, substances combined, and substance hol) “before”, “after”,or“before, during, and after” the administration sequence), and an estimate of the lifetime target substance (MDMA, LSD, or psilocybin). The frequency of combining specific pairs of substances category “before, during, and after” encompassed both (“rarely” (<10%), “often” (approximately 50%), or mixed and indiscriminant administration patterns and “always” (>90%)). A supplementary form detailing was therefore designated “interspersed”. Uneven distri- times of use (single number) of each substance used butions of use patterns between the three categories were during each year of use was applied to increase precision tested by Chi-square test (degrees of freedom =2). of the reported lifetime use history (Skinner and Sheu, Mann–Whitney test and Fisher’s exact test (proportions) 1982). As part of the structured interview, data on were used for group comparisons. For proportions, 95% adverse effects (physical, psychological, and cognitive) confidence intervals were calculated by the modified during MDMA use, in the days following use, and in Wald method. the long term were collected from a subset of participants (n = 69; data were not collected from 24 participants RESULTS because of practical limitations), and the participants were asked if they could ascribe the adverse effects Sample characteristics during MDMA use or in the days following use to a par- Structured interviews were performed with 98 (13% ticular MDMA tablet or substance combination. A subset female) young Danish active MDMA and/or halluci- of participants (n = 59; collection of these data began after nogen users with a history of moderate illicit substance the first 39 participants had been interviewed) were also use. The majority (95%) of participants were Caucasian, asked about any preferred or avoided substance combi- and the mean age was 25.7 years (SD = 4.5). The nations and of any drug combinations, which in their subjects were all polysubstance users having used an experience either enhanced (intensified or augmented) average of 12.6 (SD = 4.3, range = 5–23) different sub- or attenuated each other, using open-ended questions. stances including tobacco, and all participants reported Among the participants for whom data on adverse effects using alcohol and cannabis. Among the participants, of MDMA use were not collected, 18 participants also did 73% had graduated from high school, and at the time not provide data about preferred/avoided substance of interview, 85% were engaged in full-time education combinations. Demographic data including participants’ or employment. General substance use characteristics education and current occupation was collected using of substances used by a minimum of 10% of the partici- amodified Danish version of the Structured Clinical pants are presented in Table 1. Substances ever used by Interview for adolescents (Brown et al., 1998). less than 10% were the tryptamine hallucinogens ayahuasca (9%) and alpha-methyltryptamine (6%); the Hair analysis phenethylamine hallucinogens DOB/DOI/DON/DOM Hair samples (3.5 cm scalp hair segments) were col- (9%), TMA-2 (7%), 2C-T-7 (4%), and 2C-T-4 (3%); lected from a subset of participants (n = 21), who also barbiturates (5%), and phencyclidine (1%). The most participated in a PET-study (Erritzoe et al., 2011), at frequently ever used compounds, apart from alcohol the time of interview to confirm self-reported MDMA and cannabis, were amphetamines (95%, predominantly use during the past 4 months by gas chromatography– amphetamine), MDMA (95%), cocaine (93%), and mass spectrometry (Johansen and Jornil, 2009). psilocybin mushrooms (88%). LSD had been used at some point by 68% of the sample, and additional Data analysis hallucinogens were reported by 11–48% of the partici- Percentages of participants having ever used each pants. In the subgroup of participants for which hair substance, and the average debut age, lifetime usage analysis was performed, self-reported MDMA use was (number of exposures), and substance use in the past confirmed for 14 out of 15 subjects and non-use for 6 3 months, were determined. MDMA use was reported out of 6 subjects (p = 0.0001, Fisher’s exact test).

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup simultaneous polysubstance use among mdma users 355 Table 1. Substance use characteristics of sample

Ever used Debut agea Lifetime usagea Active usea,b Days of use/monthc

% (95% CI) Mean (95% CI) Mean (95% CI) % (95% CI) (95% CI)

Alcohol 100 (95–100) 13 (13–14) 878 (723–1033) 95 (88–98) 13.7 (10.7–16.7)d Cannabis 100 (95–100) 15 (15–16) 986 (714–1257) 73 (64–81) 9.4 (7.0–11.8) Amphetaminese 95 (88–98) 18 (17–19) 166 (96–235) 49 (40–59) 2.0 (1.0–3.0) MDMA 95 (88–98) 19 (19–20) 97 (64–130) 47 (37–57) 1.2 (0.8–1.6) Cocaine 93 (86–97) 19 (19–20) 84 (48–119) 53 (43–63) 1.3 (0.7–1.9) Psilocybinf 88 (80–93) 19 (18–19) 23 (16–31) 29 (20–39) 0.9 (0.6–1.2) Inhalantsg 79 (69–86) 18 (17–19) 34 (17–52) 12 (6–21) 1.3 (0.0–2.6) Tobacco 78 (68–85) 13 (13–14) na 86h (76–92) Daily LSDf 68 (59–77) 20 (19–21) 26 (15–37) 33 (23–45) 0.8 (0.4–1.2) Opioidsi 61 (51–70) 20 (19–21) 110 (À60-280) 33 (23–46) 2.9 (À0.3–6.1) Benzodiazepinesj 58 (48–67) 20 (19–21) 45 (19–72) 30 (19–43) 3.4 (1.4–5.3) Ketamine 50 (40–60) 22 (21–24) 18 (9–27) 35 (23–49) 1.4 (0.4–2.5) GHB (including GBL) 50 (40–60) 21 (20–22) 91 (7–174) 24 (14–38) 3.5 (À1.1–8.1) 2C-Bf 48 (38–58) 21 (20–23) 10 (5–14) 19 (10–33) 0.6 (0.3–1.0) 2C-If 32 (23–41) 22 (20–23) 5 (2–7) 3 (0–18) 0.3 (na) DMTf 28 (20–37) 21 (20–23) 6 (2–9) 11 (3–29) 0.6 (0.1–1.0) Salvia divinorumf 23 (16–33) 21 (20–23) 10 (4–17) 22 (9–42) 0.4 (0.2–0.6) LSAf 22 (15–32) 20 (18–22) 4 (3–5) 23 (10–44) 0.5 (0.1–0.8) Mescalinef 16 (10–25) 21 (19–23) 2 (1–4) 0 (0–23) na 2C-Ef 15 (9–24) 21 (19–23) 3 (1–4) 7 (0–32) 1.0 (na) DIPTf 11 (6–19) 20 (17–23) 4 (1–7) 0 (0–30) na

MDMA, 3,4-methylenedioxymethamphetamine; LSD, D-lysergic acid diethylamide; GHB, gamma-hydroxybutyric acid; GBL, gamma-butyrolactone; DMT, N,N-dimethyltryptamine; 2C-B, 4-bromo-2,5-dimethoxyphenethylamine; 2C-I, 2,5-dimethoxy-4-iodophenethylamine; LSA, D-lysergic acid amide; 2C-E, 2,5-dimethoxy-4-ethylphenethylamine; DIPT, diisopropyltryptamine; na, not applicable; 95% CI, 95% conﬁdence interval. n = 98. aAmong subjects reporting use of index drug. bPast 3 months. cAmong subjects who had used index drug in the past 3 months. dUnits per week in last 3 months. eAmphetamine, methamphetamine, Ritalin, ephedrine pills. fHallucinogen. g Glue, lighter gas, “poppers”, paint, N2O. hCurrent daily tobacco users. iCodeine, ketogan, morphine, heroin. jRohypnol, stesolid, valium (non-prescription).

Lifetime simultaneous polysubstance use Participants named 57 preferred and 36 avoided To delineate patterns of SPU, the participants were combinations. The most prevalent preferred combina- asked if they had ever combined speciﬁc substances tions were alcohol and cannabis (n = 9), alcohol and or groups of substances in a single session of substance cocaine (n = 7), alcohol and amphetamines (n = 6), use. The lifetime history of combinations of MDMA and MDMA and cannabis (n = 5). Most prevalent and the most widely used hallucinogens psilocybin avoided combinations were alcohol and cannabis and LSD with each of 13 substances used by at least (n = 11, in particular alcohol before cannabis), MDMA 50% of the sample is presented in Table 2. The most and amphetamines (n = 9), alcohol and gamma- prevalent co-administered substances among MDMA hydroxybutyric acid (GHB, n = 7), hallucinogens and users were alcohol (96%), cannabis (82%), and amphe- amphetamines (n = 6), and MDMA and cocaine (n =5). tamines (69%). In addition, 56% (95% CI: 46–66%) of The participants also named 53 (100 reports) substance MDMA users reported combining MDMA with any combinations, which enhanced each other, and 42 combi- hallucinogen in a single session. Among psilocybin nations (82 reports), which counteracted each other. The and LSD users, the most frequently co-administered most prevalent observations were cannabis enhancing substances were cannabis (81% and 78%), alcohol the effects of hallucinogens (n =17) and MDMA (64% and 79%), and MDMA (31% and 52%). (n = 7), MDMA and hallucinogens enhancing each other Whereas alcohol and cannabis was most frequently (n = 11), hallucinogens enhancing each other (n =6), co-used “often” or “always” with MDMA, psilocybin, amphetamines (n = 8) and cocaine (n = 6) counteracting and LSD, combinations of the latter three drugs with hallucinogens, and cocaine counteracting the effects of other substances were most often infrequent. MDMA (n =7).

MDMA (%) Psilocybin (%) LSD (%)

Combined with Rarely Often Always Rarely Often Always Rarely Often Always

Alcohol 16 28 52 10 33 21 12 33 34 Cannabis 20 32 30 17 34 30 16 28 34 Amphetamines 31 26 12 15 6 7 18 6 7 MDMA —— — 21 9 1 31 15 6 Cocaine 34 12 1 14 5 0 13 4 1 Psilocybin 18 10 0 —— — 18 6 1 Inhalants 11 5 0 9 1 1 16 3 0 LSD 32 9 1 15 6 0 —— — Opioids 3 5 2 1 1 0 7 3 0 Benzodiazepines 9 6 0 3 5 0 7 0 0 Phenethylaminesa 24 1 1 10 1 0 21 1 0 Ketamine 18 3 0 7 1 1 13 3 0 GHB 18 5 0 8 2 0 13 4 0

MDMA, 3,4-methylenedioxymethamphetamine; LSD, D-lysergic acid diethylamide; GHB, gamma-hydroxybutyric acid. aPhenethylamines: 2C-B, 2C-E, 2C-I, 2C-T-4, 2C-T-7. Values shown are percentages of MDMA (n = 93), psilocybin (n = 86), or LSD (n = 67) users combining at different frequencies with each of the compounds listed on the left. Frequency categories: “rarely” (<10%), “often” (~50%), and “always” (>90%). Each user may be counted in more than one substance category.

Simultaneous polysubstance use at last recalled (95% CI: 11–26%)) than of adding amphetamines or administration cocaine to psilocybin (10% (95% CI: 5–19%) and 2% – – Table 3 shows SPU at the last recalled administration (95% CI: 0 9%)) or LSD (10% (95% CI: 5 20%) and – of each of the 13 substances used by at least 50% of 6% (95% CI: 2 15%)). MDMA was combined with Æ the sample. SPU with any substance was reported for 2.1 1.2 additional substances (excluding tobacco) in 60–97% of the last recalled sessions of each substance; the last recalled MDMA session. This was similar for most often with cocaine (97%), MDMA (92%), amphetamines, cocaine, LSD, and ketamine (1.7 Æ 1.0 amphetamines (90%), and LSD (90%), and least to 1.8 Æ 1.5), whereas cannabis, psilocybin, inhalants, frequent with opioids (60%), cannabis (62%), and opioids, benzodiazepines, and GHB were combined GHB (65%) use. Among MDMA users, 19% (95% with signiﬁcantly less compounds than MDMA CI: 13–29%) had combined MDMA with any halluci- (0.9 Æ 1.0 to 1.5 Æ 1.2) (data not shown). MDMA users nogen (LSD, psilocybin, phenethylamines, or salvia reported taking MDMA in the context of 32 different divinorum) at the last recalled MDMA session. There substance combinations involving up to six additional was a higher prevalence of adding amphetamines or substances at their last recalled MDMA use (data not cocaine to MDMA (23% (95% CI: 15–32%) and 17% shown).

Table 3. Substance co-administration at last recalled administration of each substance

Any Alcohol Cannabis Amphetamines MDMA Cocaine Other

Cannabis (98) 62 (52–71) 52 (42–62) — 5(2–12) 7 (3–14) 3 (1–9) 22 (15–32) Amphetamines (93) 90 (82–95) 84 (75–91) 35 (27–46) — 13 (7–21) 10 (5–18) 25 (17–34) MDMA (93) 92 (85–97) 77 (68–85) 49 (40–59) 23 (15–32) — 17 (11–26) 39 (29–49) Cocaine (91) 97 (90–99) 87 (78–92) 40 (30–50) 13 (8–22) 14 (8–23) — 21 (14–30) Psilocybin (86) 69 (58–77) 44 (34–55) 44 (34–55) 10 (5–19) 9 (5–18) 2 (0–9) 24 (17–35) Inhalants (77) 75 (65–84) 53 (42–64) 23 (15–34) 6 (2–15) 13 (7–22) 4 (1–11) 30 (21–41) LSD (67) 90 (80–95) 63 (51–73) 46 (35–58) 10 (5–20) 16 (9–27) 6 (2–15) 40 (29–52) Opioids (60) 60 (47–71) 38 (27–51) 33 (23–46) 5 (1–14) 7 (2–16) 3 (0–12) 8 (3–18) Benzodiazepines (57) 81 (68–89) 47 (35–60) 35 (24–48) 23 (14–35) 14 (7–26) 9 (3–19) 18 (10–30) GHB (49) 65 (51–77) 35 (23–49) 33 (21–47) 12 (5–25) 6 (1–17) 8 (3–20) 14 (7–27) Ketamine (49) 82 (68–90) 59 (45–72) 43 (30–57) 12 (5–25) 12 (5–25) 10 (4–22) 39 (26–53)

MDMA, 3,4-methylenedioxymethamphetamine; LSD, D-lysergic acid diethylamide; GHB, gamma-hydroxybutyric acid. Percentages of users of each substance in the left column reporting co-administration with any substance (excluding tobacco), alcohol, cannabis, amphetamines, MDMA, cocaine, or other substances at the last recalled use. 95% conﬁdence intervals are given in parentheses. The number of user reports for each substance is given in parentheses in the left column. Each substance user may be counted in more than one substance category.

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup simultaneous polysubstance use among mdma users 357 Dosage and order of administration during alcohol was most often used in an interspersed pattern simultaneous polysubstance use when combined with LSD (p < 0.001) or psilocybin < The average MDMA dose used at the last recalled ad- (p 0.001). Cannabis was also most frequently used – in an interspersed manner when combined with MDMA ministration event was 185 mg (95% CI: 153 216 mg) < < < or around three Ecstasy tablets. At the last recalled (p 0.001), LSD (p 0.05), or psilocybin (p 0.001). MDMA administration, the simultaneous use of MDMA In addition, 41% administered cannabis primarily after and either one of the following substances: alcohol, taking MDMA, whereas only 7% used cannabis before cannabis, amphetamines, cocaine, psilocybin, LSD, or MDMA. Among users combining MDMA and amphe- GHB, had no significant effect on MDMA dose (data tamines, 71% reported taking amphetamines before MDMA, whereas only 14% took amphetamines after not shown). Only 8% of the MDMA users did not com- < bine MDMA with another substance (except tobacco) at MDMA (p 0.001). A similar pattern of initial use of amphetamines was seen for psilocybin (p < 0.05) and the last MDMA use. This group used an average dose of fi 178 mg (95% CI: 86–270 mg) MDMA at the last for LSD (not signi cant). When LSD was combined fi with MDMA, 82% of users administered MDMA after recalled event, which was not signi cantly different < from MDMA doses administered when combining with LSD (p 0.01). any of the seven substances mentioned previously (data not shown). The effect of SPU on psilocybin or LSD Adverse effects of MDMA use and simultaneous dose could not be analyzed because of high variability polysubstance use in substance units reported and unknown concentration As shown in Table 5, the majority of MDMA users fi of active substance per substance unit, leading to dif - reported having at some point experienced acute and/ culties in standardizing the doses used. or subchronic adverse effects related to MDMA use: The order of substance administration during a single 67% (95% CI: 55–77%) during MDMA use and 93% drug taking session (last recalled event) was analyzed (95% CI: 84–97%) in the days after use, whereas for MDMA, psilocybin, and LSD. As shown in Table 4, 19% (95% CI: 11–30%) reported long-term adverse alcohol was most often used interspersed with (i.e., before, effects of their MDMA use. During MDMA use, during, and after) rather than primarily before or after physical adverse effects (62%) were more frequently < MDMA administration (p 0.001), and similarly, experienced than psychological adverse effects (35%), whereas in the days after MDMA use, psychological Table 4. Substance administration order for simultaneous polysubstance use involving MDMA, LSD, or psilocybin Table 5. Adverse effects of MDMA use: role of MDMA dose and Before After Interspersed Chi-square simultaneous polysubstance use (%) (%) (%) (df =2) During use, % Days after use, % Long term, % MDMA (95% CI) (95% CI) (95% CI) Alcohol (72) 19 6 75 58.33*** Cannabis (46) 7 41 52 15.70*** Adverse effects 67 (55–77) 93 (84–97) 19 (11–30) Amphetamines (21) 71 14 14 13.71*** Physical effects 62 (51–73) 58 (46–69) 9 (4–18) Cocaine (16) 50 25 25 2.00 Psychological 35 (25–47) 72 (61–82) 10 (5–20) GHB (7) 29 43 29 0.29 effects LSD Cognitive effects nd nd 16 (9–27) Alcohol (42) 24 14 62 16.00*** Cannabis (31) 13 32 55 8.19* Specific cause 59 (44–72) 38 (27–50) na Amphetamines (7) 71 14 14 4.57 Large 30 (19–45) 11 (5–21) na MDMA (11) 18 82 0 12.18** MDMA dose Psilocybin Impure MDMA 13 (6–26) 5 (1–13) na Alcohol (38) 16 5 79 36.21*** Particular 11 (4–23) 3 (0–11) na Cannabis (38) 11 26 63 16.63*** MDMA pills Amphetamines (9) 78 11 11 8.00* Co-use of 20 (10–33) 19 (11–30) na MDMA (8) 38 50 13 1.75 substances (any) Co-use of alcohol 13 (6–26) 8 (3–17) na MDMA, 3,4-methylenedioxymethamphetamine; LSD, D-lysergic acid Co-use of 2(0–12) 8 (3–17) na diethylamide; GHB, gamma-hydroxybutyric acid. amphetamines Various substances administered before, after, or interspersed with (i.e., before, during, and after) MDMA (n =93), LSD (n = 67), or psilocybin (n =86). MDMA, 3,4-methylenedioxymethamphetamine; 95% CI, 95% confidence Number of co-administration events with each substance is indicated in interval; nd, no data; na, not applicable. parentheses. Self-reported adverse effects of MDMA use among a subset of MDMA *p < 0.05, users (n = 69). Upper section: percentages of MDMA users. Lower section: **p < 0.01, percentages of total reports of adverse effects during or in the days after ***p < 0.001. MDMA use, respectively.

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup 358 c. l. licht ET AL. adverse effects were slightly more prevalent than Over-representation of men were also evident in a physical ones (72% vs. 58%). study of the techno scene in seven European metropo- The most prevalent acute physical adverse effects lises (Tossmann et al., 2001) and in some but not all were vomiting (n = 11), nausea (n = 10), and jaw ten- previous studies of MDMA users, for example (Wu sion (n = 10), whereas in the days after MDMA use, et al., 2009). Participants in our study reported using tiredness/weakness (n = 19) and jaw soreness/tension on average 12.6 different substances during their life- (n = 8) were predominant. Acutely, the most frequently time, which is similar to previous MDMA studies from reported psychological effects were paranoia (n =8) Australia (Breen et al., 2006; Topp et al., 1999). and anxiety/fear (n = 7), whereas depressed/low mood (n = 33) and an empty/blank state of mind (n = 5) were Simultaneous polysubstance use with MDMA most prevalent subchronically. Subjective increases in During SPU, MDMA was typically combined with body temperature (hyperthermia) during MDMA use two additional compounds, which is in line with the were noted by 78% (95% CI: 67–86%) of MDMA most probable consumption pattern found within the users, whereas perception disturbances during MDMA European techno scene (Tossmann et al., 2001) and use was reported by 67% (95% CI: 55–77%). The among ecstasy users in Glasgow (Hammersley et al., perception disturbances consisted primarily of changes 1999). The general pattern of SPU with MDMA was in visual perceptions with only a couple of participants similar to a large European study, with the exception having experienced true hallucinations. of a lower MDMA and cannabis co-use in our sample Among those with experiences of acute adverse (Tossmann et al., 2001). In our sample, the simulta- effects, 59% (95% CI: 44–72%) ascribed them to neous use of any particular substance with MDMA specific causes; most prevalent were large MDMA had no effect on MDMA dose, which is somewhat doses (30%, 95% CI: 19–45%) and co-use of other surprising as co-use with specific substances has been substances (20%, 95% CI: 10–33%), particularly co-use shown to affect alcohol (cocaine and methylphenidate) of alcohol (13%, 95% CI: 6–26%) (Table 5). Adverse and nicotine (8 out of 10 substances tested) consump- effects in the days after MDMA use were also ascribed tion (Barrett et al., 2006). Given that several com- to specific causes by a subset of participants; 19% (95% pounds are usually combined with MDMA at the CI: 11–30%) mentioned SPU of MDMA with other sub- same time, and that co-administration patterns as well stances, most frequently alcohol (8%, 95% CI: 3–17%) as typical MDMA dosage vary considerably among and amphetamines (8%, 95% CI: 3–17%), and 11% MDMA users, such individual drug effects may be dif- (95% CI: 5–21%) named large doses of MDMA. ficult to discern with our sample size and study design. Adverse effects of MDMA use were primarily ascribed to large MDMA doses, which is in agreement with DISCUSSION previous reports (Parrott, 2006), and to co-use of other This report describes lifetime and simultaneous poly- substances, particularly alcohol and amphetamines. substance use among Danish MDMA and hallucinogen The high prevalence of MDMA and alcohol co-use users. The study sample reported extensive lifetime in our sample is in line with an Australian study, where polysubstance use, and in the majority of last recalled 65% of regular MDMA users reported drinking alco- drug sessions, SPU of alcohol and/or illicit substances hol when taking MDMA (Breen et al., 2006). The were reported. Significant orders of drug use during enhancement and prolongation of MDMA-induced SPU were evident for MDMA, psilocybin, and LSD euphoria by alcohol co-consumption (Hernandez- with other substances. Adverse effects during or in Lopez et al., 2002) may be mediated by both pharma- the days after MDMA use were primarily ascribed to codynamic and pharmacokinetic mechanisms; ethanol large MDMA doses and to co-use of other substances. potentiates the 5-HT and dopamine releasing properties of MDMA in rat striatum in vitro (Riegert et al., The study sample 2008), and co-administration of ethanol and MDMA The participants of our study were recruited by increases the concentration of MDMA in plasma and purposive sampling of individuals with recent MDMA brain in rat (Hamida et al., 2009) and in plasma in and/or hallucinogen use and a lifetime history of humans (Hernandez-Lopez et al., 2002). This may moderate illicit drug use. The resulting sample was explain why in our sample, adverse effects during or predominantly male, which most likely reflects the in the days after MDMA use were ascribed to the higher past year prevalence of MDMA use among combined use of alcohol and MDMA by several users. 16–34-year-old men (1.9%) relative to women Co-use of alcohol and MDMA increases central effects (0.6%) in Denmark (Sundhedsstyrelsen, 2009). and the plasma concentration of MDMA, thereby

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup simultaneous polysubstance use among mdma users 359 having effects similar to large MDMA doses. In rat co- cannabistoassistthe“come-down” of MDMA, a administration of alcohol potentiates MDMA-induced strong psychostimulant, may be due to the relaxing hyperlocomotion (Mohamed et al., 2011), as well as effects of cannabis (Topp et al., 1999). Also, given that the rewarding properties of MDMA as shown by the CB1 cannabinoid receptor mediates some of the conditioned place preference (Jones et al., 2010). rewarding properties of MDMA (Mohamed et al., The majority of participants in our study reported 2011), cannabis consumption when the central concen- combining MDMA and alcohol in an interspersed tration of MDMA tapers may counteract feelings of manner (i.e., alcohol before, during, and after MDMA), depression and anhedonia. In rat, co-administration of whereas previous studies have found alcohol to be THC counteracts MDMA-induced hyperthermia and ingested predominantly before MDMA and less partially prevents MDMA-induced reductions in 5-HT frequentlyinaninterspersedmanner(Barrettet al., levels in some brain regions (Morley et al., 2004). 2006; Barrett et al., 2005). However, alcohol intake However, THC co-administration did not prevent post-MDMA use has also been described; polysubstance MDMA-induced hyperthermia in humans but rather users from the UK reported using alcohol to “improve delayed the onset and prolonged the duration (Dumont the effects” and “help ease after effects” of MDMA (Boys et al., 2009). As cannabis can reduce MDMA-induced et al., 2001), which is in agreement with a large UK study oxidative stress and neurotoxicity in experimental where 60% of MDMA users used alcohol to assist animals, it has been proposed that co-consumption “come-down” after MDMA (Winstock et al., 2001). may prevent some of the long-term adverse effects of In our sample, the second-most prevalent co- MDMA (Parrott et al., 2007). Although the long-term administered substance with MDMA was cannabis, effects of simultaneous use of MDMA and cannabis which is in agreement with previous reports of wide- in humans have not been determined yet, it has been spread MDMA and cannabis co-use (Hammersley shown that their concurrent use (i.e., simultaneous and et al., 1999; Parrott et al., 2007; Topp et al., 1999; separate) has additive detrimental effects on cognition Tossmann et al., 2001; Winstock et al., 2001). The and psychopathology (Parrott, 2006). high prevalence of cannabis and MDMA co-use may Co-use of MDMA with psychostimulants such as reflect psychosocial factors, such as the association of amphetamines and cocaine was common in our sample, use of each substance with common genetic and envi- which is in agreement with findings among MDMA ronmental risk factors, as well as functional causes users from the European techno scene (Tossmann (Parrott et al., 2007). Focusing on functional causes, et al., 2001). A number of participants reported avoid- in the present study, seven participants stated that can- ing co-use of MDMA and amphetamines or MDMA nabis enhanced (intensified or augmented) the effects and cocaine, and seven participants stated that cocaine of MDMA, which is in line with a previous study counteracted the effects of MDMA. However, the where 36% of cannabis users used cannabis to common occurrence of combining MDMA with either “improve the effects” of ecstasy (Boys et al., 2001). psychostimulant suggests that the combinations have This effect has also been shown in preclinical studies, desirable subjective effects. In line with this, in a previ- where in rat, co-administration of a cannabinoid ous study, 65% of individuals reporting MDMA and agonist enhanced the reinforcing properties of MDMA amphetamine co-use and 43% of individuals reporting as shown by reduced MDMA self-administration (Sala MDMA and cocaine co-use stated that the respective and Braida, 2005), and in mice, co-administration of psychostimulant was used to enhance the effects of delta-9-tetrahydrocannabinol (THC, the main active MDMA (Boys et al., 2001). This is also supported by component of cannabis) increased the rewarding prop- preclinical experiments, where MDMA treatment facili- erties of a low dose of MDMA but antagonized a high tated cocaine self-administration and cocaine-associated dose (Robledo et al., 2007). Previous studies have also conditioned place preference (Mohamed et al., 2011). found that 51–82% of recreational MDMA users took Although pretreatment with MDMA increased sensitiv- cannabis to help the “come-down” after MDMA (Boys ity to the locomotor effects of amphetamine in rat, it et al., 2001; Topp et al., 1999; Winstock et al., 2001), reduced self-administration of methamphetamine which most frequently includes irritability, trouble (Mohamed et al., 2011). Central to their rewarding sleeping, and lowered mood (Topp et al., 1999). In properties, amphetamine and cocaine increased dopamine agreement with both of these observations, in our study, levels in the striatum in humans (Martinez et al., 2007; 52% had used cannabis in an interspersed manner with Schlaepfer et al., 1997) and in the nucleus accumbens in MDMA (e.g., to enhance), and 41% had used it only rats (cocaine) (Panos and Baker, 2010), and MDMA had after MDMA (e.g., to assist “come-down”), whereas a similar effects in the striatum in pigs (Rosa-Neto et al., mere 7% had used it only before MDMA. The use of 2004) and in the nucleus accumbens in rats (Panos and

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup 360 c. l. licht ET AL. Baker, 2010). Importantly, the simultaneous administra- a hallucinogen at the last recalled MDMA use, which tion of MDMA and cocaine increased dopaminergic is a slightly larger proportion than the 12.4% of MDMA levels in the nucleus accumbens in rat more than the users in the European techno scene (Tossmann et al., administration of each drug alone, providing neuro- 2001). From the perspective of both LSD and psilocybin chemical support for the enhanced rewarding properties users in our sample, the third most frequently co-used of the drug combination (Panos and Baker, 2010). substance was MDMA, which is in agreement with data Interestingly, co-administration of MDMA and cocaine from club-going drug users in New York City (Grov either enhanced (at 10 mg/kg MDMA) or counteracted et al., 2009). In our sample, 11 participants stated that (at 5 mg/kg MDMA) each other’srewardingproperties MDMA and hallucinogens enhanced each other. Such in the place preference test in rat (Diller et al., 2007). enhancing effects were also reported by polydrug users This dependence on relative doses could explain why in the UK, where 65% of LSD users had taken LSD to in our sample, co-use is relatively common, although “improve the effects” of MDMA and 21% of MDMA some participants have experienced cocaine counteract- users had taken MDMA to “improve the effects” of ing the effects of MDMA. LSD (Boys et al., 2001). Preclinical research supports In our sample, amphetamines were administered the subjective experiences; in rat, LSD and MDMA before MDMA by 71% of participants, whereas no co-administration potentiated each other in a drug sequence order was significant for MDMA and discrimination test (Schechter, 1998). Among LSD cocaine co-use. These results are in agreement with users who at last recalled use combined LSD with data from Canadian rave attendees (Barrett et al., MDMA, 82% took MDMA after LSD. Although this 2005). One reason for the high prevalence of taking is in partial agreement with LSD not being used to help amphetamines before MDMA could be that ampheta- the “come-down” from MDMA (Winstock et al., 2001), mines are used to increase energy levels before a night among participants of the Scottish dance scene LSD was of dancing, whereas MDMA is mainly used during mainly taken at the same time as MDMA (Forsyth, dancing (Boys et al., 1997). In rat, co-administration 1996). The use of MDMA after LSD in our sample of methamphetamine and MDMA have more adverse may in part be due to the natural time course of the long-term effects on the 5-HT, dopamine, and nor- evening, as a study of Australian ravers found a prefer- adrenaline system, and on behavior than either com- ence for using LSD before and during raves and MDMA pound by itself (Clemens et al., 2005;Clemens et al., primarily during raves (Boys et al., 1997). However, 2007), suggesting that co-use of amphetamines and many subjective reports do not mention any preferred MDMA would exacerbate the long-term detrimental sequence of administration (Schechter, 1998). effects of MDMA in humans (Clemens et al., 2007). In agreement with the preclinical data, co-use of amphetamines and MDMA was prevalent among the Simultaneous polysubstance use with hallucinogens specific causes ascribed to adverse effects in the days Among hallucinogens, SPU was more common with after MDMA use. This is also in line with predictions LSD than with psilocybin, and LSD was combined with of the bioenergetic stress model of MDMA, which pro- more substances in a single session than psilocybin. The poses that factors increasing metabolic activation and majority of both LSD and psilocybin users had co-used stress during MDMA use will augment the longer term alcohol and cannabis at least once and had typically detrimental effects associated with MDMA use done so “often” or “always”. The high prevalence of (Parrott, 2009). The widespread co-use of MDMA co-administration of alcohol is somewhat puzzling, as and psychostimulants may also be due to interactions LSD blocked and psilocybin attenuated the subjective at the level of substance craving, as MDMA adminis- response to alcohol in humans (Barrett et al., 2000). tration reinstated methamphetamine (Clemens et al., However, among our participants, only four stated that 2007) and cocaine (Schenk et al., 2008) seeking alcohol and hallucinogens counteracted each other. In in rats, which were abstinent for the respective a study of polydrug users in the UK, only 4.7% had psychostimulant. used alcohol to “improve the effects” of LSD and About half of MDMA users in our sample had 11.6% to “help ease the after effects” of LSD, and only combined MDMA with a hallucinogen at some point 0.8% had used alcohol to “improve the effects” of during their life, most commonly with LSD (called psilocybin mushrooms (Boys et al., 2001). Co-use of “candy-flipping”) or psilocybin, which is in line with a alcohol may be widespread simply because alcohol is lifetime prevalence of LSD and MDMA co-administration a ubiquitous compound, which is used indiscriminately of 30% among British MDMA users (Winstock et al., during a typical night out. This is in agreement with 2001). In our sample, 19% had combined MDMA with alcohol predominantly being combined with LSD or

Copyright © 2012 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2012; 27: 352–363. DOI: 10.1002/hup simultaneous polysubstance use among mdma users 361 psilocybin in an interspersed manner (i.e., mixed or content of other psychoactive substances. However, indiscriminant manner). In contrast to the counteracting the most prevalent mixed Ecstasy tablet on the Danish effects of hallucinogens and alcohol, cannabis was market, containing MDMA and amphetamines, reported by 17 participants to enhance the effects of accounted for 31% in 2006 but for only a few percent hallucinogens. This is partially supported by a UK in 2007 and 2008 (Johannsen, 2008). Thus, although a polydrug study, where 15.7% had used cannabis to small proportion of our sample may have been exposed “improve the effects” of LSD, whereas only 1.3% had to both MDMA and amphetamines in a single Ecstasy used it to “enhance effects” of hallucinogenic mush- tablet, this is unlikely to affect general patterns of rooms (Boys et al., 2001). In our sample, cannabis was SPU. Finally, although this study is focused on pairwise primarily used interspersed with (i.e., before, during, drug combinations, it is clear from the present and and after) or only after LSD, which is in partial agree- previous reports that MDMA is usually used in multi- ment with cannabis being used to “ease the after effects” combinations with two to five additional drugs of LSD among UK polydrug users (Boys et al., 2001). (Tossmann et al., 2001). Amphetamines were the fourth most frequently co- administered compounds with both LSD and psilocybin with lifetime co-use prevalences of 31% and CONCLUSIONS 28%, respectively. The extent of co-use of LSD and Simultaneous polysubstance use was extensive among amphetamines at the last LSD session is in agreement experienced Danish MDMA and hallucinogen users with data from Australian ravers (Boys et al., 1997). and involved a range of psychoactive substances. Partic- However, lifetime co-use of methamphetamine with ular substance combinations and orders of administration either LSD or psilocybin was negligible among club- were preferred and others avoided possibly because of going drug users in New York City (Grov et al., the psychopharmacological effects of combining specific 2009). The differences in co-use prevalences may be drugs. due to the fact that amphetamine enhances whereas methamphetamine counteracts effects of LSD (Passie et al., 2008). Several participants stated that cocaine CONFLICT OF INTEREST counteracted the effects of hallucinogens, and although No conflict of interest declared. a fifth of LSD or psilocybin users had co-administered cocaine at least once, this was typically infrequent, and only a few percent had done so at the last recalled hal- ACKNOWLEDGEMENTS lucinogen use. Compared with the present study, even lower lifetime prevalences of cocaine and hallucinogen We are thankful to the individuals who participated in this co-use were reported by club-going drug users in New study. We would like to thank Professor S. Tapert for the advice on collection of socioeconomic and substance use York City (Grov et al., 2009) most likely because data through structured interviews, Dr. K. Holst for the our sample included more predominant hallucinogen statistical advice, and R. Sichlau for the assistance with data users. entry. The study was financially supported by the Lundbeck Study limitations Foundation. 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