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Psychopharmacology (2009) 207:439–446 DOI 10.1007/s00213-009-1669-2 ORIGINAL INVESTIGATION Determining the subjective and physiological effects of BZP on human females Joanne C. Lin & Nisha Bangs & HeeSeung Lee & Rob R. Kydd & Bruce R. Russell Received: 30 April 2009 / Accepted: 7 September 2009 / Published online: 24 September 2009 # Springer-Verlag 2009 Abstract Background “Party pills” containing benzylpiperazine (BZP) used to be widely and legally available as recreational drugs in New Zealand. There are only two published trials on human subjects (1973), which suggested that 100 mg of BZP produced subjective and physiological effects similar to 10 mg of dexamphetamine. The purpose of this study is to further investigate the subjective and physiological responses to BZP in females. Methods/study design In a randomised, double blind, placebo-controlled study, the subjective and physiological effects of BZP were investigated in 27 healthy, right-handed non-smoking females (mean age 22±3 years). Two groups were tested before and approximately 120 minutes after administration of a single oral dose of either 200 mg BZP (n=14) or placebo (n=13). Participants were required to comment on the subjective effects of BZP using three rating scales—the Addiction Centre for Research Inventory, the Profile of Mood States and the Visual Analogue Scale. Participants’ blood pressure, heart rate and temperature were also measured. Results/findings Statistical analysis using a split-plot analysis of variance and t tests revealed that BZP significantly increases blood pressure and heart rate (p<0.05) Likewise, J. C. Lin (*) : N. Bangs : H. Lee : B. R. Russell School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag, 92019 Auckland, New Zealand e-mail: [email protected] R. R. Kydd Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand the subjective reports revealed that BZP has significant stimulant effects, increases euphoria and dysphoria and increases sociability and drug liking (p<0.05). Discussion/interpretation Physiological and subjective data reflected a clear similarity between the effects of BZP and those of other commonly known stimulants such as amphetamine and 3,4-methylenedioxymethamphetamine. Keywords Benzylpiperazine . Humans . Females . Mood Introduction In recent years, a new group of recreational drugs has emerged. A range of piperazine derivatives was initially found to have psychoactive effects; however, they remained relatively unused until the late 1990s. N-benzylpiperazine (BZP) is perhaps the best known and a common constituent of what have been termed “party pills.” Related piperazines include 1-[3-chlorophenyl]-piperazine (mCPP) and 1-[4methoxyphenyl]-piperazine (pMeOPP), but the vast majority of party pills contains BZP either alone or mixed with trifluoromethylphenylpiperazine (TFMPP; Fig. 1). Party pills started to be used in recreational settings in the late 1990s, and their use quickly escalated, particularly in New Zealand where major users were people in their late teens and early twenties (Wilkins et al. 2006). Generally, party pills are used to enhance confidence and alertness, increase stamina and energy and induce euphoria (Wilkins et al. 2006). Drug websites describe them as being able to produce a “high” similar to the effects produced by 3,4methylenedioxymethamphetamine (MDMA or “Ecstasy”; Erowid Piperazine Vault 2007). The average dose of BZP in party pills was initially about 50 mg but more recently has ranged from 70 to 440 Fig. 1 Structures of a N-benzyl-piperazine and b 1-[3-trifluoromethylphenyl]-piperazine 250 mg with one preparation offering 500 mg per dose. In New Zealand, party pills were marketed under many brand names and were readily available from a variety of sources such as specific party pill shops and liquor stores in addition to being widely sold over the Internet. BZP and related compounds are also actively discussed on drugculture-related websites, where users’ experiences and opinions regarding their effects, dosage and intake can be found (Erowid Piperazine Vault 2007). Many countries, including the USA, have placed strong restrictions on both BZP and TFMPP, and in 2002, both compounds were put into Schedule 1 of the United States Controlled Substances Act based on their potential to cause harm (FDA 2008). Although controversial, TFMPP was later removed from the schedule due to a lack of evidence demonstrating the potential for harm. In contrast, both BZP and TFMPP are still legally available in the UK. However, the World Health Organisation has recently called for submissions regarding the abuse liability and diversion of these drugs with the intention of considering whether to recommend that certain international restrictions be placed on their use. In New Zealand prior to April 2008, the sale of party pills was legal to those over 18 years of age. However, BZP and related piperazines were recently reclassified under the Misuse of Drugs Act (1975), placing them in the same class as cannabis. Initially, party pills were marketed as “herbal highs” due to the structural similarity of BZP to piperidine, a constituent of the piperine alkaloid found in black pepper; indeed, some of the party pills available had black pepper extract added as a constituent and as such could be justifiably sold as “herbal.” Despite the common marketing of BZP and related piperazine-containing party pills as “herbal or natural highs,” BZP and TFMPP are not natural compounds. BZP was originally synthesised by Wellcome Research Laboratories, UK, as a potential anti-parasitic agent for livestock (White and Standen 1953) that was later found to reverse the sedative effects of tetrabenazine, a dopamine (DA)-depleting agent that depresses vesicular monoamine accumulation in rats and mice (Miller et al. 1971). Consequently, it was investigated as a potential antidepressant (Bye et al. 1973; Campbell et al. 1973). BZP is chemically similar in structure to DA and other amphetamines. At present, there are virtually no controlled Psychopharmacology (2009) 207:439–446 studies reporting the effects of BZP on humans. The pharmacokinetic properties and metabolism of BZP in humans has also not been well described, although it has been shown that BZP is excreted primarily by the kidney (Staack et al. 2002; Tsutsumi et al. 2006). Research by Staack et al. (2002) combined with recent studies conducted at the University of Auckland demonstrate that the hepatic enzyme CYP2D6 plays a central role in the degradation of BZP (Murphy et al. 2009; Staack et al. 2002). Early human studies investigating the effects of BZP suggested that the physiological effects are not felt for up to 2 h following oral ingestion (Bye et al. 1973). Research within the University of Auckland has yielded pharmacokinetic data demonstrating that following oral administration of BZP (200 mg) Cmax is reached in approximately 60 min (Antia 2007, personal communication). Research by Baumann et al. (2005) suggested that BZP, when combined with TFMPP, has a relatively narrow therapeutic window as the threshold for inducing seizures was close to the threshold for monoamine release in rats. However, the wide dose range of BZP contained in party pills and the consequential ingestion by approximately 400, 000 users and a very low reported rate of BZP-induced seizures suggests otherwise (Wilkins et al. 2006). Studies investigating the central mechanism of action of BZP have only been reported in rats and monkeys. In rodents, the primary central neurochemical effects of BZP are mediated through interactions with DA and, to a lesser extent, serotonin (5-HT) transporters. Intravenous administration of BZP to male Sprague–Dawley rats produced a dose-dependent elevation in extracellular DA and 5-HT in the nucleus accumbens (3 and 10 mg), whereas 5-HT release was only affected with high doses (Baumann et al. 2005). These pharmacological effects are very similar to amphetamine-induced DA stimulation. In addition to the effects of BZP on DA and 5-HT release, BZP has also been shown to cause peripheral release of noradrenaline (NA) by blocking synaptic reuptake in an in vitro preparation (Magyar et al. 1986). Maygar et al. (1986) suggested that BZP has “yohimbine-like” effects at peripheral α2-adrenoceptors by acting as an antagonist and inhibiting the negative feedback that usually occurs with endogenous NA binding. BZP was also found to be the active metabolite of Nbenzyl-piperazine-picolinyl fumarate (Trelibet or EGYT475), which was developed as an antidepressant in Europe in the early 1980s (Magyar et al. 1986; Tekes et al. 1987). Campbell et al. (1973) and Bye et al. (1973) investigated the subjective and physiological effects of BZP (100 mg oral) in humans. Similar to dexamphetamine (10 mg oral), BZP was found to increase blood pressure and heart rate. Other peripheral effects include sweating, flushing and pupillary dilation (Campbell et al. 1973). The results of Psychopharmacology (2009) 207:439–446 these studies provide a basis for further investigation into the stimulant-like effects of BZP. To date, there is very little data published about the subjective effects of BZP other than that produced by Campbell and Bye and that reported anecdotally by individuals on drug culture-related websites such as Erowid (http://www.erowid.org). Research has shown that the subjective effects of recreational drugs have a major impact on the maintenance and induction of self-administration, and there exists a balance between the benefits and risks of these subjective effects. The balance between positive reinforcing effects, such as euphoria, and negative effects, such as dysphoria and anxiety, is a key determinant of repeated drug use (Foltin and Fischman 1991a). The subjective effects of other common stimulants have been investigated; however, significant sex differences have been described during some phases of the menstrual cycle (Evans 2007). This study aimed to investigate the subjective effects of BZP in females using standardised measures to compare the effects with profiles obtained from other substances of abuse. On the basis of the pharmacological properties of BZP, it was predicted that the profile would be similar to that of other stimulants. In early research by Campbell et al. (1973), equipotent doses of BZP (100 mg oral) and amphetamine (7.5 mg oral) yielded indistinguishable subjective effects, and both drugs were considered desirable by former amphetamine addicts, with many rating BZP higher than amphetamine in terms of subjective drug liking. However, Bye et al. (1973) used an invalidated list of 41 adjectives to assess the subjective effects, and similarly, Campbell et al. (1973) used an assessment of just six closed questions. While these studies showed a potential for BZP to exert amphetamine-like subjective and physiological effects, flaws in their methodology suggest their results are inconclusive. In our research, well-validated methods were used to assess subjective effects in combination with an oral dose of 200 mg of BZP that more closely reflects the doses currently used recreationally without producing adverse effects. Materials and methods Participants Twenty-seven right-handed, non-smoking female participants (18–28 years of age, mean=22±3 years) volunteered to participate in this double-blind placebo-controlled experiment. Participants were recruited by word of mouth and posters. The Northern X Regional Ethics Committee of New Zealand approved this study, and written consent was obtained from all participants before research was undertaken. 441 Participants were excluded on the basis of a history of mental illness, cardiac disease, head trauma, epilepsy and excessive or recent drug use, as well as those not using an oral contraceptive (OC). Excessive drug use was defined as having engaged in binge drinking more than monthly or the use of cannabis or other recreational drugs more than twice a month or in the previous 7 days. Participants were also asked to compare their drug use against their peers and classify themselves as a light, regular or heavy user. Participants who considered themselves heavy users were excluded. All participants were offered a pregnancy test, because the effects of BZP on pregnancy are unknown. A custom-based questionnaire was completed by each participant, detailing their medication history, recreational drug, party pill, alcohol and cigarette use, sleeping patterns and stress levels. Of the participants, 17/27 had previously used recreational drugs, with 12/17 using them in the last year and only 2/17 within the last month. A lower proportion had previously used party pills, with 8/11 in the last year and 1/11 in the last month. Of the 12 participants that had used tobacco, only three had done so in the past month. Many participants used caffeine and alcohol on a regular basis—20/27 and 18/27, respectively. Drugs Placebo and benzylpiperazine hydrochloride tablets (50 mg) were manufactured by School of Pharmacy, University of Auckland NZ, using good manufacturing practice. Placebo tablets contained lactose and other inert ingredients. All tablets were administered with 200 ml of water. Procedure Participants fasted for 12 h before the trial and were asked to abstain from alcohol the evening before. A standard breakfast was given approximately 90 min before drug/ placebo ingestion; this consisted of either water or decaffeinated tea or coffee and one or two pieces of toast with a sugar-free spread, because sugar is known to affect mood. For a review, see Christensen (1993). Following breakfast, participants were required to complete three separate rating scales to determine their mood status and prior medical history. All participants were randomised to either placebo or BZP groups, and administration was double blind; participants were required to wait for 120 min in a low stimulus environment after administration before repeating the mood rating scales. This was to ensure drug absorption, as research from the University of Auckland has demonstrated that the time taken to reach peak concentration is at least 60 min. Ambient temperature was also recorded. 442 Psychopharmacology (2009) 207:439–446 Physiological measures Heart rate, diastolic and systolic blood pressure were measured by a Microlife Automatic Blood Pressure Monitor A100 Plus, which has been validated and determined as suitable for clinical use by the British Hypertension Society (http://www.bhsoc.org/blood_pressure_list.stm). Body temperature of the participants was also measured using a WelchAllyn Suretemp Plus oral thermometer. These measures were recorded prior to and 120 minutes after BZP administration. Subjective and mood effects The effects of BZP and placebo were evaluated using subjective rating scales completed by the participants both before and 120 min after drug or placebo administration— the Addiction Research Centre Inventory (ARCI), Profile of Mood States (POMS) and Visual Analogue Scale (VAS) (Foltin and Fischman 1991a). A shortened version of the ARCI form was used to measure drug-induced effects. The original ARCI form consisted of 550 true or false questions; however, the form used in this study consisted of 49 questions, which were categorised into five empirically derived scales that have proved sensitive for psychoactive drugs (Foltin and Fischman 1991a). These scales measured sedation (Phenobarbital-ChlorpromazineAlcohol Group or PCAG scale), drug-induced euphoria (Morphine–Benzedrine Group or MBG scale), stimulant-like effects (Benzedrine or BG scale), dysphoria (Lysergic Acid Diethylamine or LSD scale) and dexamphetamine-like side effects (Amphetamine or A scale). The POMS standard form, described by McNair et al. (2003) is used to clinically evaluate mood states and is composed of 65 separate items. This grades the tension/ anxiety (T), depression/dejection (D), anger/hostility (A), fatigue/inertia (F), vigour/activity (V) and confusion/bewilderment (C) and total mood disturbance (TMD) felt by the subject at that point in time on a five-point likert scale (ranging from “not at all” to “extremely”) and thus assesses the total mood disturbance of the subject. These were graded according to the POMS standard scoring grid, where each point of Table 1 Mean values (±SD) for blood pressure, heart rate and body temperature *p<0.05 the five-point scales corresponded to one or more of the seven above-mentioned categories. Visual Analogue Scales were used to assess momentary changes in mood within individual subjects. The scales consist of a series of 22 horizontal 100 mm lines, each labelled with an adjective (drug effect, good drug effect, bad drug effect, drug liking, stimulated, high, anxious, sedated, down, hungry, friendly, miserable, on edge, alert, tired, talkative, self-confident, paranoid, social, irritable, confused and sick). Zero millimetre on the line corresponded to “not at all,” and 100 mm corresponded to “extremely.” Participants were required to place a mark on each line indicating how they felt at that moment. Analyses Data was analysed using repeated measures analysis of variance (ANOVA) and one within-subjects factor (time: before, after) and one between-subjects factor (drug group: placebo, BZP). Results were considered significant if p<0.05. Results Physiological measures Data was not collected for three participants due to equipment malfunction. BZP produced significant increases in systolic and diastolic blood pressure and heart rate relative to placebo, with a decrease in body temperature (Table 1). In contrast, placebo administration did not result in any significant changes. Subjective effects Addiction research centre inventory Mean scores from the ARCI for each category are represented in Fig. 2. Of the 27 participants in the study, two were excluded from ARCI form analysis due to incomplete questionnaires—one from each group. Placebo Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats per min) Body temperature (°C) BZP Pre Post Pre Post 118±11 73±8 70±10 36.8±0.2 116±6 74±6 67±10 36.7±0.3 118±12 72±7 71±12 37±0.3 130±11* 80±8* 86±18* 36.6±0.5* Psychopharmacology (2009) 207:439–446 443 Fig. 2 Graph depicting changes in ARCI score before and after administration of BZP. Mean values ± SD, * denotes p<0.05 Of the five ARCI scales, only three demonstrated significant changes—euphoria (MBG), dysphoria (LSD) and dexamphetamine-like side effects (A). Profile of mood states One participant was excluded due to an incomplete questionnaire. Significant effects were demonstrated in five of the seven POMS scales (depression/dejection, fatigue/ inertia, confusion/bewilderment, vigour/activity and total mood disturbance). BZP was associated with a significant decrease in fatigue, contrary to the lack of change in the BG within the ARCI rating scales. However, the lack of a significant change within the BG score is probably due to the wide variation in response by individual participants. Participants in the BZP group also reported feeling more vigorous and/or active by the end of the study, whereas participants in the placebo group felt less so. No significant differences were found for the other subjective effects in either group. Visual analogue scales Statistical analysis of each category in the VAS form showed BZP producing significant time or time × drug effects in 11 of the 22 items in the VAS, specifically: drug effect, good drug effect, bad drug effect, drug liking, stimulated, high, anxious, hungry, talkative, self-confident and social scales. Despite the significant changes in both post-placebo and post-BZP groups in the above-mentioned categories, it is clear that the relative increase in scores is greater with BZP. The wide standard deviations of the data reflect the large variation in response, which was not unexpected due to the subjective nature of these data. The hunger scores of the participants in the post-placebo group increased significantly, in contrast to the post-BZP group where scores only increased by about 23 points, suggesting that participants who received placebo were significantly hungrier at the end of testing than their counterparts who received BZP. Neither BZP nor placebo groups caused a change in any of the remaining categories. Changes in physiological and subjective measures are summarised in Table 2 below. Discussion Administration of BZP was associated with significant increases in both systolic and diastolic blood pressure. This may have been due to peripheral release of NA caused by BZP (Magyar et al. 1986; Tekes et al. 1987). It is well known that increased levels of circulating NA result in increased postsynaptic α1- and α2-receptor activation in the peripheral vascular endothelium with a subsequent contraction of vascular smooth muscle leading to increased peripheral vascular resistance and ultimately blood pressure (Kanagy 2005; Lavian et al. 1991). Amphetamines, for example dexamphetamine, are also known releasers of DA, NA and 5-HT which increase systolic and diastolic blood pressure and heart rate, effects also predominantly attributed to peripheral NA release (Trendelenburg et al. 2001). This increased NA load amplifies activation of β1-receptors on cardiac muscle leading to an increase in heart rate and concomitant increase in blood pressure. Tekes et al. (1987) have previously demonstrated that administering BZP to rats induced hyperthermia at an ambient temperature of 28ºC, an effect thought to be due to the effects of 5-HT release on the thermoregulatory centre 444 Psychopharmacology (2009) 207:439–446 Table 2 Summary of the physiological and subjective effects produced by BZP compared to placebo Dependent measure Physiological measures Systolic blood pressure Diastolic blood pressure Heart rate Body temperature Subjective effects ARCI MBG LSD A POMS D F C V TMD VAS Drug Effect Good Drug Effect Drug liking Stimulated High Anxious Hungry Talkative Self-confident Social a Placebo BZP 200mg – – – – ↑c ↑c ↑c ↓b – – – ↑c ↑c ↑b – – ↓b ↓c – – – ↓b ↑a ↑b ↑ ↑ – – – – ↑ – – – ↑c ↑c ↑c ↑c ↑c ↑b –c ↑c ↑b ↑a Significant time interaction b Significant time × drug interaction c Significant time and time × drug interaction within the hypothalamus. Studies using methamphetamine and MDMA also yield similar results (Farfel and Seiden 1995; Fleckenstein et al. 1997). However, it has also been shown that 5-HT-modulated hyperthermic effects in rats are attenuated at lower ambient temperatures, leading to hypothermia. For example in mice, administration of fenfluramine, another substituted amphetamine, can also impair thermoregulatory function leading to either hyperthermia or hypothermia at high and low ambient temperatures, respectively, in a similar pattern to that induced by both amphetamine and MDMA (Cryan et al. 2000; Malberg and Seiden 1997). The inability of BZP to significantly alter body temperature in humans could have been due to the ambient room temperature—it is possible that 22±1°C was not high enough to induce hyperthermia (Table 1). The absence of a significant change might also be a dose-response effect where a higher dose of BZP might increase body temperature or alternatively an increase in physical activity combined with a higher dose might also induce a significant change. Further research into the role of ambient temperature and the subsequent development of BZPinduced hyper- or hypothermia needs to be carried out in order to make conclusive statements. There is a wellestablished relationship between recreational drug use and dance music events, and the adverse effects of such drugs are strongly related to the environment in which they are used rather than solely from the toxic properties of the substances themselves. Many MDMA-related deaths relate to the temperature of the environment—high ambient temperatures and lack of facilities to balance the effects of dancing, including a lack of water (Bellis et al. 2002). This may have implications on the environments and settings in which BZP is used. Subjective effects Although subjective effects are dependent on previous experience, all of the participants in this trial had regular experience with psychoactive compounds—including caffeine and alcohol—therefore, exaggerated subjective responses to BZP were not expected, irrespective of previous experience. Using the five ARCI scales, only euphoria (MBG), dysphoria (LSD) and dexamphetamine-like side effects (A) displayed significant results. Studies with related stimulants have produced similar results for example, dexamphetamine has been shown to increase scores on the A and MBG scales and decrease the score for sedation (PCAG scale; Zacny and de Wit 1989). The subjective effects experienced by users following administration of MDMA are also similar to those induced by dexamphetamine, particularly an increase in BG and a decrease in PCAG score (Tancer and Johanson 2003). MDMA has also shown a more consistent and reproducible effect on the LSD scale when compared with other stimulants (Camí et al. 2000; Tancer and Johanson 2003). For further comparison, administration of cocaine resulted in an increase in A, MBG, stimulant-like effects (BG) and LSD scores and a decrease in PCAG scores (Fischman and Schuster 1983; Fischman et al. 1985; Foltin and Fischman 1991b). These results allow obvious comparisons to be made between BZP and dexamphetamine, which supports data from pre-clinical research that show a similar mechanism of action. Despite the non-significant change in the stimulantlike effects (BG) and sedation (PCAG) score, the results show clear trends in that direction as does dexamphetamine, i.e. increasing scores for “stimulant-like effects” and decreasing scores for “sedation.” It is likely that the absence Psychopharmacology (2009) 207:439–446 of statistical significance, which was close to threshold, is due to the wide variability in individual response to the subjective effects of BZP. Euphoria is frequently experienced by people taking dexamphetamine, MDMA or cocaine (Foltin and Fischman 1991a; Tancer and Johanson 2003). A property common to these three stimulants is their ability to increase DA concentration in the nucleus accumbens, which is thought to result in the rewarding properties of all recreational drugs (Koob 1992). Consequently, the euphoria experienced following administration of BZP strongly supports the hypothesis that BZP induces DA release within the nucleus accumbens. BZP caused significant dysphoria but in comparison, evidence of dexamphetamine-induced dysphoria is also variable and dose-dependent (Cadet and Brannock 1998; Chait and Johanson 1988; Chait et al. 1985; Martin et al. 1971; Tancer and Johanson 2003). Foltin and Fischmann (1991a, b) postulated that the increase in LSD score was due to a time-dependent rebound effect. It is widely recognised that administration of psychostimulants often produce subjective euphoric effects, so unless the drug is continuously infused, it is expected that the euphoric effects will diminish. This wearing-off effect would consequently result in a less euphoric state, so the dysphoria experienced could be attributed to this (Foltin and Fischman 1991a). This might also explain the increased LSD scores observed with BZP. The subjective euphoric effects demonstrated by administration of BZP combined with “drug-liking” category using VAS provides further insight into the abuse potential of BZP. BZP was associated with a significant decrease in fatigue (F), but there were also non-significant increases in tension (T) and vigour (V), which also decreased in the placebo group. Studies using other stimulants revealed similarities with BZP, for example administration of dexamphetamine (10 mg) resulted in changes within all six categories of the POMS—increases in V and T with decreases in depression (D), anger (A), F and confusion (C; Chait et al. 1985; Foltin and Fischman 1991a). However, exclusive reliance on subjective effects does not take into account external environmental factors, so consideration must be given to variables such as social environment, physical setting, user history and personality traits. The significantly greater increase in hunger scores of participants from the placebo group may be explained by parallels between the mechanisms of action of BZP and other amphetamines, which have historically been used as appetite suppressants (Kuo 2005). BZP has also been sold within New Zealand as an active ingredient of SlimFast™. The appetite suppressing effects exerted by amphetamines are thought to be due to the central release of both DA and 5-HT. For example, the appetite suppressive effects of fenfluramine can be blocked by pre-treatment with 5-HT 445 antagonists (Choi et al. 2002). BZP has been shown to induce both 5-HT and DA release hence the lower “hungry” scores of participants in the BZP group. Studies looking at the effects of stimulants in females have been performed in more recent years, and it has been found that subjective and behavioural responses differ across phases of the menstrual cycle. Responses in several subjective categories have been reported to be greater in the follicular phase compared to the luteal phase. For a review, see Terner and de Wit (2006). Combined OCs containing ethinyl oestradiol and a progestin prevent ovulation by inhibiting follicle-stimulating hormone and luteinising hormone production in the pituitary. This inhibition of ovulation reduces oestradiol secretion and stops progesterone production (Rivera et al. 1999). With combined OC use, endogenous oestradiol and progesterone levels decrease to those typical of the follicular phase of naturally cycling women (Mishell et al. 1972). The use of OC by participants should result in a lack of fluctuation in endogenous oestradiol across the menstrual cycle; therefore, we anticipate little variation in the subjective effects of BZP. However, due to the lack of data in both males and females, further study should be undertaken to determine whether variability across menstrual cycle phases in participants not taking an OC exists with BZP, as with other stimulants. The ARCI is theoretically useful for determining whether the recreational use of an individual drug is likely to induce addiction as are the VAS. BZP clearly shows similarities with MDMA and dexamphetamine in particular, the latter being well known to induce addiction if used on a regular basis. However, despite the reportedly large number of users within NZ and estimates of more than 20 million doses publicly sold during the last 8 years, there have been surprisingly few cases of BZP addiction reported and none published. There have been anecdotal reports, which generally describe a relatively mild withdrawal. It is likely that the absence of reported BZPinduced addiction is due to the relatively slow absorption of BZP into the vasculature when taken orally and the subsequent slow onset of desired subjective effects. However, the long-term effects following regular consumption of BZP remain largely unknown. 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