Download Determining the subjective and physiological effects

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.
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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
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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
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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
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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.
Acknowledgements This study was sponsored by the Health
Research Council of New Zealand. The authors thank Hsi-tung Hsiao
and Jovan Krstik for assistance with data collection.
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