BENZYLPIPERAZINE/TRIFLUOROMETHYL PHENYLPIPERAZINE

OFFICIAL NAMES: Benzylpiperazine (BZP), trifluoromethylphenylpiperazine (TFMPP), 1-benzyl-1,4-diazacyclohexane dihydrochloride

STREET NAMES: Legal E, legal X, A2, the substance, piperazine, 2C-T-Z

DRUG CLASSIFICATIONS: Not scheduled, stimulant, hallucinogen

OVERVIEW

Chemicals known as piperazines have industrial applications worldwide, and it is legal to purchase bulk quantities of these chemicals on the Internet for this purpose. By changing chemical groups added to the basic piperazine skeletal structure, different chemicals can be formed that vary considerably in their industrial, medical, and mind-altering properties. Piperazine citrate and related compounds destroy intestinal worms, making these chemicals useful in both medical and veterinary preparations. Other medicinal and mind-altering qualities of piperazines are being exploited as possible treatments of depression, psychosis, Alzheimer's disease, and tumors.

The piperazines influence brain function through their effects on brain chemistry at different receptors, or specialized locations within nerves allowing them to communicate with each other through chemical messengers called neurotransmitters. By stimulating different groups and locations of nerve cells that contain a specific neurotransmitter called serotonin, piperazine derivatives can have varied, profound effects on mood, learning, perceptions, and movement.

Benzylpiperazine (BZP) is one of the more commonly used piperazines on the club scene because it stimulates the brain and central nervous system, to the point of creating hallucinogenic experiences in some users. Although many describe its stimulant effects as noticeably different from those of "speed," or amphetamines, it is not particularly popular because of its many side effects.

Like BZP, 3-trifluoromethylphenylpiperazine monohydrochloride (TFMPP) is a piperazine stimulant. Most users prefer to combine TFMPP with ecstasy (MDMA). Some users report decreased anxiety, increased closeness with others, and feelings of unexplained happiness, but others describe their experiences with these drugs as frightening and extremely unpleasant.

Piperazines are not currently scheduled or classified in the United States, making possession legal. As of August 2001, these chemicals were not controlled under the Controlled Substances Act (CSA). In the United States, some samples of ecstasy pills seized by authorities contain TFMPP. Piperazines sold in bulk over the Internet have made their way to the club and rave scene and are increasingly sold as club drugs to adolescents and young adults, sometimes as ecstasy, but usually as "BZP," "legal E," "legal X," or "A2." A BZP variant known as 2C-T-Z can be snorted or taken by mouth. Toxic reactions to BZP and TFMPP include their stimulant effects such as dangerously rapid heart rhythms and seizures. As of September 2000, there were two reported deaths from BZP/TFMPP.

CHEMICAL/ORGANIC COMPOSITION

Substituting different chemical groups onto the basic piperazine structure creates piperazine derivatives like benzylpiperazine (BZP), also known as N-benzylpiperazine or 1-benzylpiperazine, and trifluoromethylphenylpiperazine (TFMPP). BZP is a benzyl amine, while TFMPP is a phenyl amine.

BZP is an odorless, colorless, or faint yellow oily liquid at room temperature, and freezes at 32°F (0°C). As it is a strong base, meaning that it has a high pH, it can cause burns to the skin, lungs, or intestinal tract if consumed in this form. For human or animal consumption, it must be converted to a monohydrochloride or dihydrochloride salt. Most industrial sources supply a BZP preparation that is 97% pure, but they do not disclose what the impurities consist of, and many impurities in industrial chemicals may be toxic or even fatal if consumed.

INGESTION METHODS

Most piperazines seized at raves have been in tablet form, containing both BZP and TFMPP, ranging in color from pink to yellow or tan, and marked with different symbols including a spider, fly, "A," or a simple straight line. While there is no way of knowing the dose of BZP and/or TFMPP in these tablets, most users prefer doses ranging 35–150 mg. Some users have reported snorting or smoking BZP preparations.

THERAPEUTIC USE

Since the early 1950s, piperazines have been widely used in veterinary medicine as anthelminthic drugs, which rid the lower intestinal tract of parasitic worms. In humans, diethylcarbamazine and piperazine citrate serve a similar function and are used to treat pinworm and roundworm infestations in adults and children. While these drugs have little effect on immature worms, or larvae, which nest in muscles, skin, and other body tissues, they paralyze the muscles of mature worms, dislodging them from the wall of the intestinal tract so that they are eliminated with waves of intestinal movement.

In 1999, pharmaceutical researchers in Japan found that an N-benzylpiperazine derivative stimulates a brain chemical called acetylcholine, which is involved in learning and memory. This eventually led to the discovery of donepezil (Aricept), which helps ward off memory loss in Alzheimer's disease and other age-related dementias, or brain diseases associated with progressive loss of memory, learning, and thinking ability.

Other BZP derivatives are being investigated for possible therapeutic uses in depression, other psychiatric illnesses, epilepsy or seizure disorders, pain, and inflammatory diseases. Phenylpiperazine derivatives were developed to target specific tumors known as neuroblastomas. As of April 2002, no piperazines were being used for these conditions.

USAGE TRENDS

BZP abuse was first reported in the United States and Switzerland in 2000. Because piperazine abuse is relatively recent, there are as of yet no statistics available concerning the scope of the problem. Like ecstasy, BZP and TFMPP have made their way to the club and rave scene, but are also increasingly reported in U.S. high schools and colleges. As piperazine sales target mostly young adults and school children, these groups are believed to account for most illegal use.

The Drug Enforcement Administration (DEA) started seeing small amounts of BZP and TFMPP in 2000; they continued to increase in 2001 and 2002. The DEA has seized several hundred pounds/kilograms of powdered BZP from India. Most of the seizures have taken place in the South, Southwest, Chicago, and Connecticut. The DEA has applied to have BZP and TFMPP emergency scheduled. Emergency scheduling is the authority given by Congress to the administrator of the DEA to temporarily place new drugs that are considered dangerous into Schedule I until they can be properly reviewed and scheduled through normal channels.

MENTAL EFFECTS

Piperazines like BZP and TFMPP stimulate the brain, resulting in sensations and experiences which may be pleasant or unpleasant, frightening, dangerous, or lethal. Animal research has shown that BZP triggers the release of neurotransmitters called dopamine and norepinephrine, while TFMPP acts by stimulating nerve receptors sensitive to serotonin, another neurotransmitter.

At doses of 20–100 mg, both BZP and TFMPP may produce a range of mental experiences lasting six to eight hours. Sought-after effects may include euphoria, alertness, reduced need for sleep, heightened sense of touch and other pleasurable sensations, and a sense of emotional bonding to others that is not necessarily based on shared experiences, common interests, or other reasons for close relationships.

Both drugs can produce significant increases in heart rate and blood pressure. Like speed or amphetamine, the stimulant effects of BZP on the brain are mirrored in the body, and may have equally disastrous results. Animal experiments suggest that piperazines such as TFMPP can actually inhibit learning rather than enhancing it.

PHYSIOLOGICAL EFFECTS

Contact of BZP with the eyes or skin may cause severe irritation and possible burns. If it is inhaled, it may cause severe irritation of the respiratory tract with sore throat, coughing, and shortness of breath, or even chemical burns. Prolonged respiratory exposure may cause delayed lung effects, including fluid in the lungs with breathing difficulty.

When swallowed, piperazines are readily absorbed from the gastrointestinal tract. They are partially broken down or metabolized by the liver and kidney, and the remainder is excreted in the urine. Because there is a wide variability in the rates of piperazine breakdown and excretion by different individuals, there is also a wide range of toxic effects and doses causing toxicity. Physical effects reported by piperazine users include nausea, vomiting, body flushing, stomach pains, frequent urination, bladder infection or irritation, thirst, dry mouth, severe migraine headache, sensations of skin crawling, dilated pupils, and "hangover" feelings lasting up to two days.

Effects on brain centers controlling movement may be experienced as muscle stiffness, tremor or uncontrollable shaking, jaw clenching, and nervous tics. Like amphetamine, piperazines produce increases in heart rate, blood pressure, and body temperature, which can be dangerous or even fatal. At high doses, piperazines may produce hallucinations, seizures or convulsions, and respiratory depression that can cause death.

People who use BZP or TFMPP lose interest in food and may stop eating altogether. After about two weeks on the drug, the effects on food intake and weight loss decrease, and after stopping the drug, there may be a rebound increase in excessive eating and weight gain.

Harmful side effects

Because piperazine abuse is such a recent phenomenon, harmful effects of BZP and TFMPP are not yet well-described, and selective effects in children and women and during pregnancy are still unknown. However, two deaths have already been reported.

Long-term health effects

Government agencies have no well-documented information on the long-term health effects of BZP and TFMPP. According to the Health and Safety Executive of the United Kingdom, piperazines are thought to have significant potential to cause asthma, most likely related to their effects on the immune system, although the mechanism is unclear.

Similar effects of BZP and speed in former addicts, including increased blood pressure and similar short-term mental experiences induced by the drugs, suggest that BZP can be addictive and liable to abuse, especially by former or current addicts of other substances.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

BZP and TFMPP may contaminate ecstasy tablets, and users hoping for an extended or intensified "high" from ecstasy sometimes deliberately combine these drugs. A 2001 report in the medical literature from Zurich, Switzerland, describes a 23-year-old woman who died after consuming both BZP and ecstasy. When she was admitted to the hospital 11 hours after taking the drug combination, she experienced high blood pressure, coma, decreased reflexes, and non-reacting pupils. Excess drinking of water before coming to the hospital had caused extremely low levels of sodium in the blood, brain swelling, and ultimately, death.

Users have reported combining BZP with alcohol, Xanax, dextromethorphan, marijuana, and hydrocodone, and have described most of the experiences as frightening or unpleasant.

Warnings are given against combining piperazines, used to treat parasitic infections, with psychiatric medications known as phenothiazines, as piperazines can dramatically worsen the stiffness, tremor, and other movement abnormalities caused by phenothiazines. The combination may even cause violent seizures or convulsions.

TREATMENT AND REHABILITATION

Emergency treatment depends on the immediate toxic effects of BZP and TFMPP. High blood pressure, abnormal heart rate or rhythm, seizures or convulsions, fever, and abnormal movements all have specific treatments and may require hospitalization for intravenous medications and general supportive care. Coma or decreased level of consciousness, respiratory depression, difficulty breathing, and severe allergic reaction may require treatment in an intensive care unit and assisted respiration. If a user experiences any untoward effects, or if someone inadvertently takes a much larger dose of medicinal piperazines than prescribed, it is prudent to contact a doctor, emergency medical services, or poison control.

As piperazine abuse has been recognized only recently, specific detoxification, addiction, and rehabilitation programs have not yet been developed, nor are success rates known for specific treatments. Presumably, treatment protocols will follow general principles of other substance abuse programs and will include psychological counseling.

PERSONAL AND SOCIAL CONSEQUENCES

As with other mind-altering substances, use of BZP or TFMPP may give rise to hallucinations, anxiety, panic attacks, confusion, impaired judgment, or other psychological symptoms that may jeopardize work or school performance, relationships, or personal safety or that of others. Loss of control or inappropriate behavior may cause others to view the user as untrustworthy, immature, or even crazy. Physical side effects can have temporary or permanent health consequences. Addiction can cause the user to abandon life goals and incur debt, which may lead to loss of employment, theft, or other criminal activity.

LEGAL CONSEQUENCES

BZP and TFMPP are not scheduled, classified, or controlled, nor are they approved drugs. They can legally be purchased from chemical supply houses, but are not intended for human consumption. Using the drugs in race horses may lead to fines, loss of winnings, and suspension of racing privileges. Misrepresenting the drugs as ecstasy can lead to conviction for delivery of a counterfeit substance, which may incur a prison sentence of five years.

A Federal Register document April 29, 1999, was intended to provide guidance on the manufacture and distribution of unapproved piperazine products in food-producing animals. On August 27, 1999, the U.S. Department of Health and Human Services approved a supplemental new animal drug application filed by Fleming Laboratories, Inc., for the use of piperazine in chickens, turkeys, and swine for treatment of certain parasitic infections. The Food and Drug Administration (FDA) provided that firms without approved new drug applications for piperazine for use in food-producing animals could continue to manufacture and distribute piperazine only until August 27, 1999. However, the FDA agreed to distribution of these products until December 31, 1999. After that date, unapproved piperazine products could be subject to regulatory action.

See also Designer drugs; Ecstasy (MDMA)

RESOURCES

Periodicals

Balmelli, C., H. Kupferschmidt, K. Rentsch, and M. Schneemann. "[Fatal Brain Edema after Ingestion of Ecstasy and Benzylpiperazine]." [Article in German]. Dtsch. Med. Wochenschr. 126, no. 28-29 (July 13, 2001): 809-11.

de Boer, D., I. J. Bosman, E. Hidvegi, C. Manzoni, A. A. Benko, L. J. dos Reys, and R. A. Maes. "Piperazine-Like Compounds: A New Group of Designer Drugs-of-Abuse on the European Market." Forensic Science International 121, no. 1-2 (September2001): 47-56.

O'Dell. L. E., M. J. Kreifeldt, F. R. George, and M. C. Ritz. "The Role of Serotonin(2) Receptors in Mediating Cocaine-Induced Convulsions." Pharmacology Biochemistry and Behavior 65, no. 4 (April 2000): 677-81.

Paredes, R. G., J. L. Contreras, and A. Agmo. "Serotonin and Sexual Behavior in the Male Rabbit." Journal of Neural Transmission 170, no. 7 (2000): 767-77.

Tohyama, Y., F. Yamane, M. Fikre-Merid, P. Blier, and M. Diksic. "Effects of Serotine Receptors Agonists, TFMPP and CGS12066B, on Regional Serotonin Synthesis in the Rat Brain: An Autoradiographic Study." Journal of Neurochemistry 80, no. 5 (March 2002): 788-98.

Other

Health & Safety Executive Regulatory Impact Assessments: Proposed Maximum Exposure Limit for Piperazine and Piperazine Dihydrochloride. Jan. 2001. Accessed 4/17/02. <http://www.hse.gov.uk/ria/chemical/piperaz.htm>.

Pendleton, Robert BZP (1 Benzylpiperazine): Frequently Asked Questions. Accessed 4/8/02. <http://www.lycaeum.org/drugs.old/bzp.shtml>.

Piperazine Citrate. Accessed 4/17/02. <http://www.nursespdr.com/members/database/ndrhtml/piperazinecitrate.html>.

U.S. Department Of Justice DEA Diversion Control Program Drugs and Chemicals of Concern. August, 2001. Accessed 4/8/02. <http://www.deadiversion.usdoj.gov/drugs_concern/bzp_tmp/summary.htm>.

Laurie L. Barclay, M.D.