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Home , Benzylpiperazine, Chlorphentermine, Dexfenfluramine, Fenfluramine, Party pills, Piperazine

Psychopharmacology (2010) 211:347–353 DOI 10.1007/s00213-010-1911-y

ORIGINAL INVESTIGATION

Determining the subjective effects of TFMPP in human males

Reem K. Jan & Joanne C. Lin & HeeSeung Lee & Janie L. Sheridan & Rob R. Kydd & Ian J. Kirk & Bruce R. Russell

Received: 25 March 2010 /Accepted: 2 June 2010 /Published online: 16 June 2010 # Springer-Verlag 2010

Abstract Results Results from the ARCI indicated that TFMPP Rationale Trifluoromethylphenyl (TFMPP) is an produced increases in ‘’ and ‘dexamphetamine- active constituent of a relatively new group of recreational like effects’. TFMPP also increased ratings of ‘tension/ drugs known as ‘’. TFMPP has been anecdotally ’ and ‘/bewilderment’ as rated on the reported to induce mild psychedelic effects similar to POMS. Results from the VAS indicated increases in ‘drug lysergic acid diethylamide and . There has been liking’, ‘high’ and ‘stimulated’ ratings relevant to placebo. no research about the subjective effects of TFMPP in Conclusions Increased ratings of ‘dexamphetamine-like humans. effects’, ‘tension/anxiety’, ‘stimulated’ and ‘high’ following Objectives This study aimed to investigate the subjective TFMPP administration resemble the subjective effects of effects of TFMPP in human males. common -type . However, increases Methods A randomised, double-blind, placebo-controlled in ‘dysphoria’ and ‘confusion/bewilderment’ ratings fol- trial design was used to investigate the subjective effects of lowing TFMPP are more commonly associated with drugs TFMPP in 30 healthy, non-smoking male volunteers (mean that have greater effects on release, binding and age 24±4 years). Participants were randomised into two reuptake such as 1-[3-chlorophenyl]-piperazine, fenflur- groups and given either TFMPP 60 mg (n=15) or placebo amine and lysergic acid diethylamide. (n=15). Each participant completed three rating scales, the Research Centre Inventory (ARCI), the Profile of Keywords Trifluoromethylphenyl piperazine (TFMPP) . Mood States (POMS) and the Visual Analogue Scales Piperazine . Party pills . Human . Mood (VAS), both before and 120 min after drug administration.

Introduction R. K. Jan (*) : J. C. Lin : H. Lee : J. L. Sheridan : B. R. Russell School of Pharmacy, University of Auckland, Trifluoromethylphenyl piperazine (TFMPP; Fig. 1a)isa Private Bag 92019, common constituent of a relatively new group of recrea- Auckland, New Zealand tional drugs commonly known in New Zealand as ‘party e-mail: [email protected] pills’. These recreational substances contain other R. R. Kydd piperazine derivatives such as (BZP), Department for Psychological Medicine, 1-[3-chlorophenyl]-piperazine (mCPP; Fig. 1b)and1-[4- Faculty of Medical and Health Sciences, University of Auckland, methoxyphenyl]-piperazine. However, the major active Private Bag 92019, Auckland, New Zealand components of most party pills in New Zealand are TFMPP and BZP, usually in combination, as TFMPP is I. J. Kirk seldom used alone (Sheridan et al. 2007). Department of Psychology, Faculty of Science, Party pills became widely used recreationally in New University of Auckland, Private Bag 92019, Zealand in the late 1990s. They were marketed as legal and Auckland, New Zealand safe alternatives to illicit stimulants such as methamphet- 348 Psychopharmacology (2010) 211:347–353

Fig. 1 Chemical structures of a 1-[3-trifluoromethylphenyl]-piperazine, b 1-[3-chlorophenyl]-piperazine, c 3,4-methylenedioxymethamphetamine and d amine and 3,4-methylenedioxymethamphetamine (MDMA) TFMPP was not self-administered by rhesus monkeys commonly known as ‘ecstasy’ (Fig. 1c). The inclusion of trained to self-administer (Fantegrossi et al. vitamins, electrolytes and herbal extracts such as cayenne 2005); whether this lack of self-administration behaviour pepper in piperazine-containing party pills was used to is comparable to that of other psychedelic substances justify their advertising as ‘natural’ and ‘safe’ (Sheridan et including such as 2,5-dimethoxy-4- al. 2007), when they are purely synthetic. Young people in methylamphetamine (Fantegrossi et al. 2008) and 3,4,5- New Zealand generally use party pills as stimulants to trimethoxyphenethylamine (; Deneau et al. 1969; increase energy, endurance and self-confidence or bring Fantegrossi et al. 2008) is unknown. about a general sense of “exhilaration” (Sheridan and The effects of TFMPP are almost exclusive to the Butler 2007; Wilkins et al. 2006). system; for that reason, it has been widely used In New Zealand, a legal market for party pills emerged as a biomarker of serotonin (5-HT) activity (Miranda et al. after 2000 (Wilkins et al. 2006) and for a number of years 2002) and to study the pharmacology of the serotonergic party pills containing BZP and TFMPP could be legally pathway (Auerbach et al. 1990). TFMPP is relatively purchased in New Zealand by individuals aged 18 years or selective for 5-HT1 and 5-HT2 receptors, with minimal older. However, since April 2008, BZP, TFMPP and related affinity for 5-HT3 receptors (Robertson et al. 1992). TFMPP were placed under the control of the New is a partial at 5-HT2A (Grotewiel et al. 1994)andan Zealand (Misuse of Drugs agonistat5-HT2C receptor subtypes (Conn and Sanders-Bush Amendment Act 2008). 1987). Of the 5-HT1 receptor subtypes, TFMPP was found to In other parts of the world, piperazine-based party pills were be a partial agonist at both 5-HT1B (Herndon et al. 1992; legally available in many countries during the early 2000s. In Kennett and Curzon 1988; McKenney and Glennon 1986; light of the increased use of these pills in the late 1990s and Schechter 1988) and 5-HT1A (Schoeffter and Hoyer 1989) concerns about safety, many countries placed restrictions on receptors. TFMPP has also been shown to increase 5-HT the sale of both BZP and TFMPP.The USA temporarily placed release in hippocampal slices, the diencephalon (Auerbach et both BZP and TFMPP into the USA Schedule 1 of the al. 1990, 1991) and the nucleus accumbens (Baumann et al. Act (US Drug Enforcement Adminis- 2005). Cloëz-Tayarani et al. (1992) reported that TFMPP has tration, Department of Justice 2002). TFMPP was later an inhibitory effect on potassium-evoked gamma- controversially removed from the Schedule and is currently aminobutyric acid (GABA) release from guinea pig hippo- not a controlled substance in the USA due to a lack of campal synaptosomes. It was hypothesised that TFMPP's evidence of potential harm (FDA 2009). Other countries have inhibitory effect on GABA release is modulated through also banned these substances. For example, in December 5-HT3 receptors (Cloëz-Tayarani et al. 1992). 2009, the UK government classified piperazines as Class C, The putative 5-HT receptor agonist properties of TFMPP under the (the same class as resemble those of lysergic acid diethylamide (LSD; gamma hydroxybutyrate and ; The UK Home Office Cunningham et al. 1986; Fantegrossi et al. 2008), mCPP 2009), and they are also illegal in all states in Australia. (Fig. 1b) and fenfluramine (Fig. 1d), an amphetamine The central mechanisms of action of TFMPP and BZP analogue which was prescribed as an suppressant have been studied in rodents (Baumann et al. 2005; Conn in the 1990s then withdrawn in 1997 due to an increase in and Sanders-Bush 1987) and rhesus monkeys (Fantegrossi the incidence of cardiac adverse events (FDA 1997). Both et al. 2005). BZP was found to have similar pharmacolog- mCPP and fenfluramine are more selective for 5-HT ical effects to amphetamine in both rats and monkeys. In receptors and transporters than (DA) and contrast, TFMPP has little resemblance to noradrenaline (NA) transporters (Baumann et al. 1995; stimulants (Fantegrossi et al. 2005; Herndon et al. 1992) Rothman et al. 1999). Fenfluramine is a pure, indirect 5-HT and lacks adrenergic effects (Herndon et al. 1992). In receptor agonist (Garattini et al. 1978) whilst mCPP is a 5- rhesus monkeys, TFMPP did not induce reinforcement of HT agonist with 5-HT releasing effects and widely used as cocaine and its discriminative stimulus properties did not a 5-HT receptor probe in clinical research (Hamik and generalise to amphetamine (Fantegrossi et al. 2005). Peroutka 1989; Kahn and Wetzler 1991). Psychopharmacology (2010) 211:347–353 349

The pharmacokinetic properties of TFMPP and BZP Excessive drug use was defined by binge drinking more have not been widely investigated. However, our laboratory often than monthly and/or the use of recreational drugs has shown that an oral dose of TFMPP (60 mg) takes including cannabis more often than twice monthly. approximately 90 min to reach peak plasma concentration Recent use of recreational drugs, with the exception of in humans (Antia et al. 2010). Studies using human , in the previous seven days resulted in exclusion. microsomes revealed that TFMPP is metabolised by hepatic Recruitment of subjects naive to recreational drugs was cytochrome P450 (CYP) enzymes, predominately by avoided so as to prevent exaggerated responses to the CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4 subjective questionnaires. isoenzymes (Antia et al. 2009). The subjective effects of recreational drugs play a Drugs significant role in the induction and maintenance of self- administration or addiction, and repeated drug use is TFMPP was sourced from Stargate International New stronglydeterminedbyweighing positive reinforcing Zealand and checked for purity using mass spectroscopy. effects against negative effects (Foltin and Fischman Capsules, identical in appearance, containing TFMPP 1991). When used alone, TFMPP has been anecdotally (60 mg) or placebo (methylcellulose) were manufactured reported to induce mild psychedelic effects similar to LSD by the School of Pharmacy, University of Auckland, New and psilocybin (Erowid Piperazine Vault 2009). To date, Zealand, using good manufacturing practice. All capsules there has been no trial reporting the effects of TFMPP in were administered with 200 ml of . humans. This study used validated rating scales to assess the subjective effects of an oral dose of TFMPP (60 mg) in Procedure humans. The 60-mg dose of TFMPP was deemed appro- priate for this research because it is at the upper end of the Participants fasted for 12 h before the experiment and dose range marketed in party pill preparations. This study abstained from alcohol the evening before. Approximately investigates the effects of TFMPP in males only, as 90 min prior to TFMPP/placebo administration, each significant sex differences have been previously reported participant was given a standard breakfast consisting of during some phases of the menstrual cycle when investi- one to two pieces of toast with a sugar-free spread and gating the subjective effects of other stimulants in females either water or decaffeinated tea or coffee. (Evans 2007). Following breakfast and before drug administration, participants completed three different mood rating scales and were then randomised to either TFMPP (n=15) or Materials and methods placebo (n=15) groups in a double-blind manner. TFMPP takes 90 min to reach peak plasma concentration (Antia et Participants al. 2010); therefore, participants were required to wait in a low-stimulus environment for 120 min after drug ingestion Thirty healthy, non-smoking male participants (18– to ensure complete absorption whilst allowing for subject- 39 years of age, mean=24±4 years) volunteered to to-subject variation. The questionnaires were then complet- participate in this randomised, double-blind, placebo- ed again 120 min after TFMPP or placebo administration controlled trial. The study was approved by the Northern X Regional Ethics Committee of New Zealand, and Subjective and mood effects written consent was obtained from all participants before research was undertaken. The Addiction Research Centre Inventory (ARCI) ques- Participants were recruited on the basis of self-reported tionnaire is a validated tool used to differentiate illicit drugs good general health and non-smoking status. Participants (Foltin and Fischman 1991; Lin et al. 2009). The shortened were excluded if they had a history of cardiac disease, version of the ARCI questionnaire is widely used and is endocrine disorders, uncontrolled asthma, mental illness, thought to be sufficiently sensitive to differentiate the head trauma or neurological disorders such as . experiences associated with a variety of stimulants (Foltin Participants were asked to complete a questionnaire detail- and Fischman 1991; Martin et al. 1971). It consists of 49 ing their lifetime medication history and recreational drug, ‘true/false’ questions describing feelings and perceptions, party pill, alcohol and tobacco cigarette use. They were also and answers are used to obtain total scores on five scales asked to classify themselves as light, regular or heavy users representing different types. The five of the above-mentioned substances compared with their scales measure ‘sedation’ (phenobarbital–– peers. Participants who took part in excessive drug use or alcohol group or PCAG scale), ‘-like effects’ classified themselves as heavy users were excluded. (Benzedrine or BG scale), ‘dysphoria’ (lysergic acid 350 Psychopharmacology (2010) 211:347–353 diethylamide or LSD scale), ‘dexamphetamine-like effects’ 0.51, respectively, both p<0.001). Both subscales were (amphetamine or A scale) and ‘drug-induced ’ associated with significant time × drug effects (Table 1). (–Benzedrine group or MBG scale). Further analysis of the significant time × drug effects using The Profile of Mood States (POMS) is used clinically for simple effects tests revealed significant increases in the post- assessing mood states including drug-induced mood TFMPP LSD scores (Fig. 2). There was also a significant changes (McNair et al. 2003). The POMS consists of 65 difference between the TFMPP- and placebo-treated groups adjectives that are rated on a five-point Likert scale which post-dosing (Fig. 2). Simple effects tests yielded similar ranges from ‘not at all’ to ‘extremely’.Scoresfrom results for the A subscale of the ARCI (Fig. 3). individual adjectives were used to generate a ‘Total Mood Disturbance’ (TMD) score, as well as total scores on six Profile of Mood States other POMS scales including: ‘tension/anxiety’ (T), ‘depres- sion/dejection’ (D), ‘anger/hostility’ (A), ‘/inertia’ (F), TFMPP administration was associated with significant ‘vigour/activity’ (V) and ‘confusion/bewilderment’ (C). increases in drug (F(1, 28)=5.1, partial η2=0.16, p< The Visual Analogue Scales (VAS) are validated and 0.031) and time × drug (Table 1) effects in the ‘tension/ widely used to evaluate momentary emotional and mood anxiety’ (T) scale of the POMS. Further analysis of the time changes (Folstein and Luria 1973). The VAS used in this × drug effect using simple effects tests amongst the study consisted of 22 scales, each being a 100-mm TFMPP-treated group showed a significant increase in horizontal line describing an adjective and labelled ‘not at ‘tension/anxiety’ post-dosing. There was also a difference all’ at 0 mm and ‘extremely’ at 100 mm. Participants were between TFMPP and placebo-treated groups, whereby the required to place a vertical line on the scale to indicate how TFMPP-treated group exhibited significantly higher scores they felt at the time. The VAS used in this study included post-dosing (Table 1). TFMPP administration caused a ratings of ‘stimulated’, ‘high’, ‘anxious’, ‘sedated’ and significant increase in drug effect (F(1, 28)=5.3, partial ‘drug liking’, as recommended by Foltin and Fischman η2=0.16, p<0.028) in the ‘confusion/bewilderment’ (C) (1991) for the assessment of subjective effects of stimulant scale, as well as significant decreases in time (F(1, 28)=5.6, drugs. Other scales included in the VAS used in this study partial η2=0.17, p<0.026) and drug (F(1, 28)=4.3, partial were ‘drug effect’, ‘good drug effect’, ‘bad drug effect’, η2=0.13, p<0.047) effects in the ‘fatigue/inertia’ (F) scale. ‘down’, ‘hungry’, ‘friendly’, ‘miserable’, ‘on edge’, ‘alert’, However, no significant interaction effects were found. ‘tired’, ‘talkative’, ‘self-confident’, ‘paranoid’, ‘social’, ‘irritable’, ‘confused’ and ‘sick’. Visual Analogue Scales

Analyses TFMPP administration caused significant time effects in the ‘drug liking’ and ‘high’ adjectives of the VAS (F(1, 28)= Data were analysed using Statistical Package for Social 22.2 and 20.5, partial η2=0.44 and 0.42, respectively, both Sciences Version 16 and a 2×2 repeated-measures analysis p<0.001). TFMPP also caused a significant drug effect in of variance with time (pre-dosing and 120 min post-dosing) the ‘high’ adjective (F(1, 28)=8.7, partial η2=0.24, p< as the within-subjects factor and treatment (TFMPP and 0.006). Both ‘drug liking’ and ‘high’ were associated with placebo) as the between-subjects factor. When there was a significant time × drug effects (Table 1). TFMPP produced significant time × drug interaction (p<0.05), simple effects significant increases in the main effects of time (F(1, 28)= tests were conducted to test differences between pre- and 8.4, partial η2=0.23, p<0.007) and drug (F(1, 28)=14.0, post-drug dosing scores within each group, as well as partial η2=0.33, p<0.001) in the ‘stimulated’ adjective of differences between the two groups both pre- and post-drug the VAS; however, there was no significant time × drug dosing. Statistical significance was determined by p<0.05. effect. Further analysis of the significant interaction effects in ‘drug liking’ and ‘high’ using simple effects tests revealed that scores from both scales were significantly higher within Results the TFMPP-treated group post-dosing (Table 1). Moreover, the TFMPP-treated group scored significantly higher post- Addiction Research Centre Inventory dosing than the placebo-treated group (Table 1).

TFMPP administration caused significant increases in two of the five ARCI scale scores—‘dysphoria’ (LSD) and Discussion ‘dexamphetamine-like effects’ (A) relative to placebo. There was a significant time effect for both the LSD and This study investigated the acute subjective effects of A subscales (F(1, 28)=15.1 and 29.1, partial η2=0.35 and TFMPP versus placebo in human males using validated Psychopharmacology (2010) 211:347–353 351

Table 1 Summary of subjective effects scales showing significant time × drug interactions and significant simple effects tests

Subjective effect Time × drug interaction [F, p value, partial η2 (df 1, 28)] Simple effects tests [F, p value (df 1, 28)]

Post-TFMPP vs pre-TFMPP Post-TFMPP vs post-placebo

ARCI LSD 5.2, 0.030, 0.16 19.0, 0.0002 5.5, 0.026 A 11.1, 0.002, 0.29 38.1, 0.0001 4.1, 0.052 POMS T 5.1, 0.032, 0.15 8.4, 0.007 8.1, 0.008 VAS Drug liking 7.6, 0.010, 0.21 27.9, 0.0001 5.2, 0.031 High 6.0, 0.021, 0.18 24.3, 0.0001 7.8, 0.009

rating scales. The results from this study showed that an al. 1975). The effects of TFMPP (Auerbach et al. 1990; oral dose of TFMPP (60 mg) produced significantly Baumann et al. 2005), mCPP (Baumann et al. 1995; Kahn different subjective effects in comparison to placebo. and Wetzler 1991) and fenfluramine (Garattini et al. 1978; Researchers ensured that all participants in this trial had Rothman et al. 1999) are thought to be mediated through previous experience with recreational substances including serotonergic mechanisms. The pharmacological similarities and alcohol; thus, exaggerated subjective responses between these drugs may explain the resemblances in their to TFMPP were not expected. subjective effects. The subjective effects of TFMPP in this study appear to Similarities between the effects of TFMPP and common be closely related to those of mCPP and fenfluramine. amphetamine-type stimulants were also found. TFMPP TFMPP administration resulted in increases in the ARCI increased scores on the ‘dexamphetamine-like effects’ (A) ‘dysphoria’ (LSD) subscale which corresponded with an subscale of the ARCI. Comparable effects on the ‘A’ increase in ‘tension/anxiety’ (T) and ‘confusion/bewilder- subscale have been observed following dexamphetamine ment’ (C) subscales of the POMS questionnaire. mCPP administration (Zacny and de Wit 1989). However, dex- (Tancer and Johanson 2003) and fenfluramine (Foltin and amphetamine has been shown to have additional effects on Fischman 1991) have been shown to increase ratings in the other ARCI scales that were not observed following ‘A’ and ‘LSD’ scales of the ARCI. mCPP has also been TFMPP administration, e.g. an increase in ‘drug-induced shown to increase ratings of ‘anxiety’ and ‘confusion’ on euphoria’ (MBG) and ‘stimulant-like effects’ (BG) and a the POMS (Tancer and Johanson 2003), and dysphoria has decrease in ‘sedation’ (PCAG) scores (Foltin and Fischman been reported with high doses of fenfluramine (Griffith et 1991; Zacny and de Wit 1989). Our results show a decrease in the ‘fatigue/inertia’ (F) scale of the POMS following TFMPP administration; however, no significant time × drug

Fig. 2 Graph illustrating changes in mean±SE ARCI scores for the Fig. 3 Graph illustrating changes in mean±SE ARCI scores for the ‘LSD’ subscale before and after placebo and TFMPP administration ‘A’ subscale before and after placebo and TFMPP administration 352 Psychopharmacology (2010) 211:347–353 interaction was found. This effect was also observed in the Acknowledgements This study was sponsored by the Health placebo group, possibly suggesting a placebo effect. Research Council of New Zealand. The authors would like to acknowledge Dr. John Sollers and Associate Professor Nathan Moreover, our results showed that TFMPP lacked the Consedine for their statistical advice. The authors have no conflict euphoric effects produced by common stimulants such as of interest to declare. dexamphetamine, cocaine and MDMA (Foltin and Fischman 1991; Tancer and Johanson 2003). These stimulants share the ability to increase synaptic concen- trations of both DA (Koob 1992) and NA (Rothman et al. 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