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 Rationale Trifluoromethylphenyl piperazine (TFMPP) is an active constituent of a relatively new group of recreational drugs known as ‘party pills’. TFMPP has been anecdotally reported to induce mild psychedelic effects similar to lysergic acid diethylamide and psilocybin. There has been no research about the subjective effects of TFMPP in humans. Objectives This study aimed to investigate the subjective effects of TFMPP in human males. Methods A randomised, double-blind, placebo-controlled trial design was used to investigate the subjective effects of TFMPP in 30 healthy, non-smoking male volunteers (mean age 24±4 years). Participants were randomised into two groups and given either TFMPP 60 mg (n=15) or placebo (n=15). Each participant completed three rating scales, the Addiction Research Centre Inventory (ARCI), the Profile of Mood States (POMS) and the Visual Analogue Scales (VAS), both before and 120 min after drug administration.
Results Results from the ARCI indicated that TFMPP produced increases in ‘dysphoria’ and ‘dexamphetaminelike effects’. TFMPP also increased ratings of ‘tension/ anxiety’ and ‘confusion/bewilderment’ as rated on the POMS. Results from the VAS indicated increases in ‘drug liking’, ‘high’ and ‘stimulated’ ratings relevant to placebo. Conclusions Increased ratings of ‘dexamphetamine-like effects’, ‘tension/anxiety’, ‘stimulated’ and ‘high’ following TFMPP administration resemble the subjective effects of common amphetamine-type stimulants. However, increases in ‘dysphoria’ and ‘confusion/bewilderment’ ratings following TFMPP are more commonly associated with drugs that have greater effects on serotonin release, binding and reuptake such as 1-[3-chlorophenyl]-piperazine, fenfluramine and lysergic acid diethylamide. Keywords Trifluoromethylphenyl piperazine (TFMPP) . Piperazine . Party pills . Human . Mood
Introduction R. K. Jan (*) : J. C. Lin : H. Lee : J. L. Sheridan : B. R. Russell School of Pharmacy, University of Auckland, Private Bag 92019, Auckland, New Zealand e-mail:
[email protected] R. R. Kydd Department for Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand I. J. Kirk Department of Psychology, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, New Zealand
Trifluoromethylphenyl piperazine (TFMPP; Fig. 1a) is a common constituent of a relatively new group of recreational drugs commonly known in New Zealand as ‘party pills’. These recreational substances contain other piperazine derivatives such as benzylpiperazine (BZP), 1-[3-chlorophenyl]-piperazine (mCPP; Fig. 1b) and 1-[4methoxyphenyl]-piperazine. However, the major active components of most party pills in New Zealand are TFMPP and BZP, usually in combination, as TFMPP is seldom used alone (Sheridan et al. 2007). Party pills became widely used recreationally in New Zealand in the late 1990s. They were marketed as legal and safe alternatives to illicit stimulants such as methamphet-
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Fig. 1 Chemical structures of a 1-[3-trifluoromethylphenyl]-piperazine, b 1-[3-chlorophenyl]-piperazine, c 3,4-methylenedioxymethamphetamine and d fenfluramine
amine and 3,4-methylenedioxymethamphetamine (MDMA) commonly known as ‘ecstasy’ (Fig. 1c). The inclusion of vitamins, electrolytes and herbal extracts such as cayenne pepper in piperazine-containing party pills was used to justify their advertising as ‘natural’ and ‘safe’ (Sheridan et al. 2007), when they are purely synthetic. Young people in New Zealand generally use party pills as stimulants to increase energy, endurance and self-confidence or bring about a general sense of “exhilaration” (Sheridan and Butler 2007; Wilkins et al. 2006). In New Zealand, a legal market for party pills emerged after 2000 (Wilkins et al. 2006) and for a number of years party pills containing BZP and TFMPP could be legally purchased in New Zealand by individuals aged 18 years or older. However, since April 2008, BZP, TFMPP and related piperazines were placed under the control of the New Zealand Misuse of Drugs Act 1975 (Misuse of Drugs Amendment Act 2008). In other parts of the world, piperazine-based party pills were legally available in many countries during the early 2000s. In light of the increased use of these pills in the late 1990s and concerns about safety, many countries placed restrictions on the sale of both BZP and TFMPP. The USA temporarily placed both BZP and TFMPP into the USA Schedule 1 of the Controlled Substance Act (US Drug Enforcement Administration, Department of Justice 2002). TFMPP was later controversially removed from the Schedule and is currently not a controlled substance in the USA due to a lack of evidence of potential harm (FDA 2009). Other countries have also banned these substances. For example, in December 2009, the UK government classified piperazines as Class C, under the Misuse of Drugs Act 1971 (the same class as gamma hydroxybutyrate and ketamine; The UK Home Office 2009), and they are also illegal in all states in Australia. The central mechanisms of action of TFMPP and BZP have been studied in rodents (Baumann et al. 2005; Conn and Sanders-Bush 1987) and rhesus monkeys (Fantegrossi et al. 2005). BZP was found to have similar pharmacological effects to amphetamine in both rats and monkeys. In contrast, TFMPP has little resemblance to dopaminergic stimulants (Fantegrossi et al. 2005; Herndon et al. 1992) and lacks adrenergic effects (Herndon et al. 1992). In rhesus monkeys, TFMPP did not induce reinforcement of cocaine and its discriminative stimulus properties did not generalise to amphetamine (Fantegrossi et al. 2005).
TFMPP was not self-administered by rhesus monkeys trained to self-administer cocaine (Fantegrossi et al. 2005); whether this lack of self-administration behaviour is comparable to that of other psychedelic substances including phenethylamines such as 2,5-dimethoxy-4methylamphetamine (Fantegrossi et al. 2008) and 3,4,5trimethoxyphenethylamine (mescaline; Deneau et al. 1969; Fantegrossi et al. 2008) is unknown. The effects of TFMPP are almost exclusive to the serotonergic system; for that reason, it has been widely used as a biomarker of serotonin (5-HT) activity (Miranda et al. 2002) and to study the pharmacology of the serotonergic pathway (Auerbach et al. 1990). TFMPP is relatively selective for 5-HT1 and 5-HT2 receptors, with minimal affinity for 5-HT3 receptors (Robertson et al. 1992). TFMPP is a partial agonist at 5-HT2A (Grotewiel et al. 1994) and an agonist at 5-HT2C receptor subtypes (Conn and Sanders-Bush 1987). Of the 5-HT1 receptor subtypes, TFMPP was found to be a partial agonist at both 5-HT1B (Herndon et al. 1992; Kennett and Curzon 1988; McKenney and Glennon 1986; Schechter 1988) and 5-HT1A (Schoeffter and Hoyer 1989) receptors. TFMPP has also been shown to increase 5-HT release in hippocampal slices, the diencephalon (Auerbach et al. 1990, 1991) and the nucleus accumbens (Baumann et al. 2005). Cloëz-Tayarani et al. (1992) reported that TFMPP has an inhibitory effect on potassium-evoked gammaaminobutyric acid (GABA) release from guinea pig hippocampal synaptosomes. It was hypothesised that TFMPP's inhibitory effect on GABA release is modulated through 5-HT3 receptors (Cloëz-Tayarani et al. 1992). The putative 5-HT receptor agonist properties of TFMPP resemble those of lysergic acid diethylamide (LSD; Cunningham et al. 1986; Fantegrossi et al. 2008), mCPP (Fig. 1b) and fenfluramine (Fig. 1d), an amphetamine analogue which was prescribed as an appetite suppressant in the 1990s then withdrawn in 1997 due to an increase in the incidence of cardiac adverse events (FDA 1997). Both mCPP and fenfluramine are more selective for 5-HT receptors and transporters than dopamine (DA) and noradrenaline (NA) transporters (Baumann et al. 1995; Rothman et al. 1999). Fenfluramine is a pure, indirect 5-HT receptor agonist (Garattini et al. 1978) whilst mCPP is a 5HT agonist with 5-HT releasing effects and widely used as a 5-HT receptor probe in clinical research (Hamik and Peroutka 1989; Kahn and Wetzler 1991).
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The pharmacokinetic properties of TFMPP and BZP have not been widely investigated. However, our laboratory has shown that an oral dose of TFMPP (60 mg) takes approximately 90 min to reach peak plasma concentration in humans (Antia et al. 2010). Studies using human liver microsomes revealed that TFMPP is metabolised by hepatic cytochrome P450 (CYP) enzymes, predominately by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4 isoenzymes (Antia et al. 2009). The subjective effects of recreational drugs play a significant role in the induction and maintenance of selfadministration or addiction, and repeated drug use is strongly determined by weighing positive reinforcing effects against negative effects (Foltin and Fischman 1991). When used alone, TFMPP has been anecdotally reported to induce mild psychedelic effects similar to LSD and psilocybin (Erowid Piperazine Vault 2009). To date, there has been no trial reporting the effects of TFMPP in humans. This study used validated rating scales to assess the subjective effects of an oral dose of TFMPP (60 mg) in humans. The 60-mg dose of TFMPP was deemed appropriate for this research because it is at the upper end of the dose range marketed in party pill preparations. This study investigates the effects of TFMPP in males only, as significant sex differences have been previously reported during some phases of the menstrual cycle when investigating the subjective effects of other stimulants in females (Evans 2007).
Materials and methods Participants Thirty healthy, non-smoking male participants (18– 39 years of age, mean = 24 ± 4 years) volunteered to participate in this randomised, double-blind, placebocontrolled trial. The study was approved by the Northern X Regional Ethics Committee of New Zealand, and written consent was obtained from all participants before research was undertaken. Participants were recruited on the basis of self-reported good general health and non-smoking status. Participants were excluded if they had a history of cardiac disease, endocrine disorders, uncontrolled asthma, mental illness, head trauma or neurological disorders such as epilepsy. Participants were asked to complete a questionnaire detailing their lifetime medication history and recreational drug, party pill, alcohol and tobacco cigarette use. They were also asked to classify themselves as light, regular or heavy users of the above-mentioned substances compared with their peers. Participants who took part in excessive drug use or classified themselves as heavy users were excluded.
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Excessive drug use was defined by binge drinking more often than monthly and/or the use of recreational drugs including cannabis more often than twice monthly. Recent use of recreational drugs, with the exception of alcohol, in the previous seven days resulted in exclusion. Recruitment of subjects naive to recreational drugs was avoided so as to prevent exaggerated responses to the subjective questionnaires. Drugs TFMPP was sourced from Stargate International New Zealand and checked for purity using mass spectroscopy. Capsules, identical in appearance, containing TFMPP (60 mg) or placebo (methylcellulose) were manufactured by the School of Pharmacy, University of Auckland, New Zealand, using good manufacturing practice. All capsules were administered with 200 ml of water. Procedure Participants fasted for 12 h before the experiment and abstained from alcohol the evening before. Approximately 90 min prior to TFMPP/placebo administration, each participant was given a standard breakfast consisting of one to two pieces of toast with a sugar-free spread and either water or decaffeinated tea or coffee. Following breakfast and before drug administration, participants completed three different mood rating scales and were then randomised to either TFMPP (n=15) or placebo (n=15) groups in a double-blind manner. TFMPP takes 90 min to reach peak plasma concentration (Antia et al. 2010); therefore, participants were required to wait in a low-stimulus environment for 120 min after drug ingestion to ensure complete absorption whilst allowing for subjectto-subject variation. The questionnaires were then completed again 120 min after TFMPP or placebo administration Subjective and mood effects The Addiction Research Centre Inventory (ARCI) questionnaire is a validated tool used to differentiate illicit drugs (Foltin and Fischman 1991; Lin et al. 2009). The shortened version of the ARCI questionnaire is widely used and is thought to be sufficiently sensitive to differentiate the experiences associated with a variety of stimulants (Foltin and Fischman 1991; Martin et al. 1971). It consists of 49 ‘true/false’ questions describing feelings and perceptions, and answers are used to obtain total scores on five scales representing different psychoactive drug types. The five scales measure ‘sedation’ (phenobarbital–chlorpromazine– alcohol group or PCAG scale), ‘stimulant-like effects’ (Benzedrine or BG scale), ‘dysphoria’ (lysergic acid
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diethylamide or LSD scale), ‘dexamphetamine-like effects’ (amphetamine or A scale) and ‘drug-induced euphoria’ (morphine–Benzedrine group or MBG scale). The Profile of Mood States (POMS) is used clinically for assessing mood states including drug-induced mood changes (McNair et al. 2003). The POMS consists of 65 adjectives that are rated on a five-point Likert scale which ranges from ‘not at all’ to ‘extremely’. Scores from individual adjectives were used to generate a ‘Total Mood Disturbance’ (TMD) score, as well as total scores on six other POMS scales including: ‘tension/anxiety’ (T), ‘depression/dejection’ (D), ‘anger/hostility’ (A), ‘fatigue/inertia’ (F), ‘vigour/activity’ (V) and ‘confusion/bewilderment’ (C). The Visual Analogue Scales (VAS) are validated and widely used to evaluate momentary emotional and mood changes (Folstein and Luria 1973). The VAS used in this study consisted of 22 scales, each being a 100-mm horizontal line describing an adjective and labelled ‘not at all’ at 0 mm and ‘extremely’ at 100 mm. Participants were required to place a vertical line on the scale to indicate how they felt at the time. The VAS used in this study included ratings of ‘stimulated’, ‘high’, ‘anxious’, ‘sedated’ and ‘drug liking’, as recommended by Foltin and Fischman (1991) for the assessment of subjective effects of stimulant drugs. Other scales included in the VAS used in this study were ‘drug effect’, ‘good drug effect’, ‘bad drug effect’, ‘down’, ‘hungry’, ‘friendly’, ‘miserable’, ‘on edge’, ‘alert’, ‘tired’, ‘talkative’, ‘self-confident’, ‘paranoid’, ‘social’, ‘irritable’, ‘confused’ and ‘sick’.
0.51, respectively, both p
