Benzylpiperazine

Benzylpiperazine (BZP) is a recreational drug with euphoric, stimulant properties. Its mechanism of action is believed to be similar to MDMA and the effects produced by BZP are comparable to those produced by amphetamine. Adverse effects have been reported following its use including psychosis, renal toxicity, and seizures. It does not appear to be very addictive and no deaths have been reported following a sole ingestion of BZP. It is banned in a few countries, including the United States, Australia and in parts of Europe. However, its legal status is less restrictive in some other countries such as Ireland, the United Kingdom, New Zealand and Canada.

History
The first mention of benzylpiperazine was a paper received for publication in August 1943 studying the removal of benzyl groups from piperazines from work done as early as 1941. It is often claimed that BZP was originally synthesized as a potential anthelmintic (anti-parasitic) agent for use in farm animals. However, there are some references to BZP in the literature that predate interest in piperazines as anthelmintics. The majority of the early work with the piperazines were investigations into their potential use as anthelmintics with the earliest clinical trials in the literature relating to piperazine being articles in the British Medical Journal in the 1950s. It was discovered that BZP had side effects and was largely abandoned as a worm treatment. It next crops up in the literature in the 1970s when it was investigated as a potential antidepressant medication, but rejected when research reported that BZP had amphetamine-like effects and was liable to abuse. The study suggested that BZP “should be placed under statutory control similar to those regulating the use of amphetamine.”

In the early 1990s, the United States Drug Enforcement Administration noted the drug was being used recreationally in California. It also reported that BZP was being used as an adulterant in illicit drugs. Not long after, there was an explosion in the drug's use worldwide &mdash; a situation which was soon followed by legislative control in many countries. Since 1999 benzylpiperazine has become increasingly popular in New Zealand where they initially had a complete lack of regulation; quickly becoming widely used (subsequently the New Zealand Government created a new schedule limiting the sale of party pills to those 18 years and older; restricted advertising, packaging, and labelling; and required package health warnings). Their popularity now means that an estimated 5 million pills will be sold in New Zealand in 2007. Piperazine based stimulants began to appear in Europe in 2000 but had remained virtually unavailable in the rest of the world until recently. In early 2006 pills containing the active ingredients BZP and TFMPP first began to appear in the city of Vancouver, Canada, where they quickly gained popularity with late-night partygoers as a safer alternative to the illicit street drugs currently available there. BZP based "Legal Highs" are marketed to Canadians under the name "Lovely" and the pills are often referred to as "Lovelies" by the locals.

Production
BZP is a piperazine derivative which comes as either the hydrochloride salt or a free base. The hydrochloride salt is a white solid while the base form is a slightly yellowish-green liquid. BZP base is corrosive and causes burns.

Where legal, BZP is often produced in small specialist laboratories. The raw materials can be purchased from various chemical supply agencies and formed into tablets or capsules using relatively cheap production techniques. The resulting product can be marketed at extremely high markup (end-user prices can be as high as 300 times the bulk cost of raw ingredients).

BZP is often marketed ostensibly as a "dietary supplement"* to avoid meeting stricter laws that apply to medicines and drugs, despite the fact that BZP has no dietary value. As of late 2005 the Misuse of Drugs Act ensured it can no longer be classified or marketed as a dietary supplement in New Zealand. Some retailers claim that BZP is a "natural" product, describing it as a "pepper extract" or "herbal high." In fact, the drug is entirely synthetic, and has not been found to occur naturally.


 * There is much evidence that BZP can be used as a thermogenic aid to weight loss, this adds some legitimacy to market claims as a dietary supplement.

Mechanism of action
BZP has been shown to have a mixed mechanism of action, acting on the serotonergic and dopaminergic receptor systems in a similar fashion to MDMA. BZP has amphetamine-like actions on the serotonin reuptake transporter, which increase serotonin concentrations in the extracellular fluids surrounding the cell and thereby increasing activation of the surrounding serotonin receptors. BZP has a lower potency effect on the noradrenaline reuptake transporter and the dopamine reuptake transporter. BZP has a high affinity action at the alpha2-adrenoreceptor, it is an antagonist at the receptor, like yohimbine, which inhibits negative feedback, causing an increase in released noradrenaline.

BZP also acts as a non-selective serotonin receptor agonist on a wide variety of serotonin receptors; binding to 5HT2A receptors may explain its mild hallucinogenic effects at high doses, while partial agonist or antagonist effects at the 5HT2B receptors may explain some of BZPs peripheral side effects, as this receptor is expressed very densely in the gut, and binding to 5HT3 receptors may explain the common side effect of headaches, as this receptor is known to be involved in the development of migraine headaches.

There is much that is still not known about the pharmacokinetics of benzylpiperazine. It's metabolism is mainly through the enzymes CYP2D6 and COMT.

Effects


The effects of BZP are largely similar to amphetamines, with one study finding that former amphetamine addicts were unable to distinguish between dextroamphetamine and BZP administered intravenously. Users report alertness, euphoria and a general feeling of well being. The perception of certain sensations such as taste, colour or music may be subjectively enhanced. The average duration is longer than that of dextroamphetamine, typically lasting 4-6 hours with reports as long as 8 hours depending on the dose. A recent study has shown that mixtures of BZP with other piperazine drugs such as TFMPP share certain pharmacodynamic traits with MDMA.

Subjective Effects
Upon ingestion of between 50 mg and 200 mg of BZP, the user may experience any or all of the following:

Coming up:
 * Changes in body temperature
 * Slight nausea
 * Flushing
 * Rapid mood elevation
 * Increased heart rate
 * Enhanced sociability
 * Repetitive thought patterns
 * Dilation of pupils (see photo)
 * Decreased appetite
 * "Rushing" sensation
 * Mild to moderate synesthesia
 * Skin tingling
 * Feelings of euphoria, wonder, amazement, elation
 * Increased desire to move
 * Closed-eye hallucinations with music
 * Temporary impotence
 * Time Dysmorphia

Coming down:
 * Mild headache
 * Nausea
 * Hangover-like symptoms (common with high doses)
 * Fatigue
 * Insomnia
 * Confusion
 * Loss of appetite

Tolerance
Research into BZP's tolerance is sparse. Anecdotal evidence from online sources claim tolerance to the central action of BZP will develop quickly. Due to tiredness associated with the body's recovery from stimulants, such as BZP, it is uncommon for users to be able to sustain a week long intake.

Toxic effects of BZP
As with most sympathomimetic stimulants there appear to be significant side effects associated with BZP use. BZP reportedly produces insomnia and a mild to severe hangover after the drug effect wears off, however, some manufacturers in New Zealand have started including recovery pills which contain 5-HTP and vitamins which allegedly ease these hangovers.

The major side effects include dilated pupils, dryness of the mouth, extreme alertness, pruritus, confusion, agitation, tremor, dystonia, headache, dizziness, anxiety, insomnia, vomiting, chest pain, tachycardia, hypertension, palpitations, collapse, hyperventilation, hyperthermia, and problems with urine retention. The more severe toxic effects include psychosis, renal toxicity, and seizure.

The majority of the toxic effects information came from a study conducted between 1 April 2005 to 1 September 2005. The study recorded all presentations associated with party pill use at the Emergency Department of Christchurch Hospital, New Zealand by recording them on a prospective data collection form. The aim was to study the patterns of human toxicity related to the use of benzylpiperazine-based 'party pills'. 61 patients presented on 80 occasions. Patients with mild to moderate toxicity experienced symptoms such as insomnia, anxiety, nausea, vomiting, palpitations, dystonia, and urinary retention. Significantly fourteen toxic seizures were recorded with two patients suffering life-threatening toxicity with status epilepticus and severe respiratory and metabolic acidosis. They concluded that BZP appears to induce toxic seizures in neurologically normal subjects. The results of this study and others like it showed that BZP can cause unpredictable and serious toxicity in some individuals, but the data and dosage collection were reliant on self reporting by drug users, which may result in under-reporting, and there were complicating factors of the frequent presence of alcohol and other drugs.

However, well over 20 million pills containing BZP have been consumed in New Zealand with no available record attributing deaths or lasting injuries to a single ingestion of BZP. Additionally a retrospective study carried out at an Auckland emergency department found that BZP presentations only made a minor contribution to their overdose database with most cases not producing any significant toxicity. Several cases where BZP individually or combined with alcohol or other medicines or illicit drugs resulting in complications exist. One such example is the well publicised case of a combination of BZP and MDMA by a 23 year old from Greymouth, New Zealand. Ben Rodham, a DJ, ingested BZP and MDMA in February 2007, which nearly resulted in his death. Ben was put into an induced coma in an effort to prevent him from dying. He later recovered. Two deaths have been officially recorded in connection with the use of BZP. In both cases, the individual had consumed a quantity of BZP as well as MDMA. In the first case in Zurich in 2001 a 23-year-old took two BZP tablets as well as ecstasy and drank more than 10 litres of water in a 15-hour period, subsequently dying of cerebral edema due to hyponatremia resulting from water intoxication. In the second case a 25 year old male ingested a large quantity of alcohol alongside BZP and MDMA. The cause of death of this individual has not been released. It is uncertain what role the BZP may have had in these deaths; death from hyponatremia is a well known consequence of drinking too much fluid after consuming MDMA, it is likely that the additional hyponatremic effects from the BZP may have increased the hyponatremic effects from the MDMA, to the point that death resulted.

Addictive Effects
1 in every 45 (2.2%) last year users of BZP in New Zealand is classed as dependent upon it, although 97.9% of users said that "it would not be difficult to stop using legal party pills", and 45.2% of people who reported using both BZP and illegal drugs such as methamphetamine reported that they used BZP so that they did not have to use methamphetamine, which was perceived as more harmful. Studies undertaken on animals have indicated that BZP can substitute for methamphetamine in addicted rats, although it is ten times less potent and produces correspondingly weaker addictive effects.

Legal issues
The drug was classified as a Schedule I controlled substance in the United States in 2002, following a report by the DEA which incorrectly stated that BZP was 10 to 20 times more potent than amphetamine, when in fact BZP is ten times less potent than dexamphetamine. The DEA subsequently admitted this mistake, but nevertheless retained the Schedule 1 classification. BZP is banned in all Australian states. Victoria, the last state in which it was legal, changed its classification on September 1 2006. This is the date BZP and piperazine analogs become illegal in the federal schedules which are now enacted by all Australian states and territories. BZP is also a banned substance in Japan, along with TFMPP. Both Australia and Japan admit that their scheduling decisions were made primarily in response to the Schedule 1 classification given to BZP in the USA, although some instances of BZP use had been reported by law enforcement authorities in both countries. BZP is also banned in Denmark and Sweden.

Piperazine and salts of piperazine are classified as Prescription Only Medicines in the UK. Any products containing salts of piperazine would be licensable under the Medicines Act and consequently anyone manufacturing and supplying it legally must hold the relevant licenses to do so. BZP is not a salt of piperazine, but mislabelling of BZP products as containing "piperazine blend" (perhaps in a poorly judged attempt by marketers to conceal the identity of the active ingredient from competitors) has resulted in some prosecutions of suppliers in the UK by the Medicines and Healthcare Products Regulatory Agency.

In some other places (such as New Zealand), BZP is legal. It is classed in New Zealand as a "Restricted Substance" by the Misuse of Drugs Act and restricted to those over 18 years, but will likely be banned by the end of 2007. Products containing BZP are marketed by manufacturers and sellers as a harm-reduction measure, however the legislation is currently under review pending the findings of a number of research projects into the effects of the drug. Research into the long term effects of BZP use are scarce. To date, the drug has been considered to be of low risk of harm to users, but more information is required, and the New Zealand government is considering introducing tighter restrictions in 2007. BZP and TFMPP are legal and uncontrolled recreational drugs in many countries such as Canada, Ireland, New Zealand and the United Kingdom, and are not controlled under any UN convention, so the compounds themselves are legal throughout most of the world, although in most countries their use is restricted to pharmaceutical manufacturing and recreational use is unknown. Benzylpiperazine is, however, to be the subject of a European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) risk assessment, the results of which will determine what, if any, control is placed on BZP throughout the European Union. The risk assessment comes about as the result of a joint Europol – EMCDDA report which concluded that BZP needs to be looked at in more detail. The results will be published in June 2007.