BZP safety review
· “There is no information available anywhere in the world on exactly what BZP does.”
This statement is only partially correct. Certainly BZP has not been subjected to full clinical trials as would be
required for a new medicinal product, and the information that is available is not as complete as we would like. However
there is some limited information available on both the pharmacology and toxicology of BZP.
· Pharmacologically it has been demonstrated that BZP has two primary mechanisms of action, firstly through
stimulation independent non-selective monoamine release (which has not been proved directly but can be inferred from the
observed pharmacological effects of the drug), and secondly through non-selective agonist action at a variety of
serotonin receptors (which is well established as a mechanism of action for several piperazine derivatives, including
BZP).
· Firstly, BZP induces non-selective monoamine release of dopamine, serotonin and noradrenalin. The exact
mechanism by which this takes place has not been established, but based on the observed pharmacology of the drug it
would appear likely that BZP triggers vesicular release of monoamines in a similar manner to amphetamines, although its
10x lower potency (relative to dexamphetamine) would suggest considerably lower affinity for the target site.
· Amphetamine mediated non-selective vesicular monoamine release occurs following binding of the amphetamine
molecule to the VMAT-2 vesicular monoamine transporter as a false substrate. The amphetamine molecule is transported to
the interior of the monoamine storage vesicle and causes the storage vesicle to migrate to the cell membrane, fuse with
it and release the stored monoamines into the synapse.
· Alternatively the monoamine release produced by BZP could be taking place through interaction with monoamine
transporters, either by inhibiting reuptake (similar to cocaine or SSRIs) or by reversing the direction of monoamine
transport (similar to MDMA). This putative mechanism of action is thought to be less important, as the affinity of BZP
for the 5HTT and DAT transporters is relatively low, and also the subjective pharmacological effects of BZP are more
similar to those of dexamphetamine, suggesting a primarily amphetamine-like mechanism for the observed monoamine
release.
· BZP also produces a range of other effects distinct from those of dexamphetamine. These effects result from a
second mechanism of action which is well established and has been demonstrated both in vitro and in vivo several times
over the last 20 years, in peer-reviewed scientific publications. This second mechanism of action is as a non-selective
serotonin agonist. Several different piperazine derivatives are known to act as serotonin agonists at a variety of
target receptors, principally the 5HT1A, 5HT1B, 5HT2A and 5HT2C receptors.
· BZP has been shown to possess some 5HT1A agonist activity, which could cause hyperthermia in high doses. 5HT1B
receptors regulate serotonin release, so when these become activated, further serotonin release is inhibited.
Consequently BZP-induced serotonin release is likely to be partially self-limiting due to its activation of the
auto-inhibitory 5HT1B target. BZP has relatively low affinity for the 5HT2A and 5HT2C receptors (which are the targets
for hallucinogens such as LSD). However activation of these receptors is likely to become important at very high doses
and could produce some hallucinogenic effects.
· The toxicology of BZP is less well studied. However there is a certain amount of research that has been done in
this field, principally relating to the after-market experience derived from the legal sale of BZP on the New Zealand
market for the past seven years.
· Based on sales figures, approximately 10 million doses of BZP products are believed to have been consumed during
this time period. Around 200 hospital presentations resulting from adverse drug reactions to BZP have been reported over
the 7 year time period, none of which have resulted in death. However, according to Dr Paul Gee from Christchurch
Hospital, “Two patients suffered life-threatening toxicity with status epilepticus and severe respiratory and metabolic
acidosis.”
·
· Statistically this would suggest that around 1 in every 50,000 episodes of BZP use are likely to result in
hospital admission, and around 1 in every 5,000,000 episodes of use are likely to result in serious adverse reaction
that could be potentially life-threatening.
·
· Typically, around 750 hospital presentations resulting directly from consumption of alcohol are reported every
year in Auckland alone, including several fatalities. This does not include traffic accidents, or alcohol-related
violence (approximately 80% of all violent crimes are committed by offenders under the influence of alcohol). Around
10,000 hospital presentations are reported each year in New Zealand following adverse reactions to prescription drugs,
again typically including several deaths. The NZ taxpayer spent 70 million dollars on alcohol related hospital bills
last year, while Chirstchurch hospital reported a cost of $3,500 for BZP related cases over 6 months.
·
· It would be relevant to note that the rate of emergency department presentations in Christchurch following
consumption of BZP products is around 70x higher than that observed in Auckland per capita. The main difference between
the Auckland and Christchurch BZP markets is in the dosage forms sold. In Auckland, most manufacturers of BZP products
are members of the Social Tonics Association of New Zealand (STANZ), which has a voluntary code of practice designed to
minimise the risks involved in sales of these products. As part of the STANZ code of practice, a maximum dosage limit of
200mg BZP per pill has been imposed, thereby limiting the dose that can be sold. In Christchurch however, some BZP
product manufacturers have refused to join STANZ or abide by the code of practice, and have persisted in selling BZP
pills containing up to 1000mg in a single pill.
·
· STANZ has lobbied the government to make the dose limit from our voluntary code of practice into a compulsory
limit imposed by law. Under the Misuse of Drugs Act Amendment No.3 (2005), BZP was scheduled as a Class D legal
recreational drug, subject to age and advertising restrictions. This amendment also made provision for the imposition of
compulsory dosage restrictions, but STANZ was told that such compulsory limits would not be imposed until there was
evidence to support such a change. Following the publication of Dr Gee’s study, we would argue that there is now solid
evidence supporting the introduction of compulsory dosage restrictions and have urged government to place an arbitrary
maximum dosage limit of 200mg BZP under urgency.
· Another important factor which emerged from Dr Gee’s study was the age of patients presenting to hospital with
BZP-related adverse events. 47 out of 60 (78.3%) of cases involved patients aged 21 years or younger; 19 of these (31.7%
of total) were under the age of 18 and should not legally have had access to BZP products at all.