GBL

OFFICIAL NAMES: Gamma butyrolactone (GBL), dihydro-2(3H)-furanone, 4-butanolide, 2(3H)-furanone dihydro, tetrahydro-2-furanone, butyrolactone gamma, gamma hydroxybutyric acid (GHB), 1,4 butanediol (BD; tetramethylene glycol; SucolB), sodium oxybate (Xyrem)

STREET NAMES: Renewtrient, revivarant, revivarant G, blue nitro, blue nitro vitality, blue moon, BLO, blow, gamma G, rem-force, longevity, GH revitalizer, insom-X, firewater, invigorate, G3, GH-gold (GHG), genx (genex), jolt, verve (verv), liquid gold, N-force, pure raine, reactive, rejoov, rejuv+nite, regenerize, remedy GH, thunder, X-12

DRUG CLASSIFICATIONS: Schedule I, depressant

OVERVIEW

GBL and related chemicals, GHB and BD, are used to make floor stripper, paint thinner, and other industrial products. All three substances are central nervous system depressants with sedative-hypnotic and hallucinogenic properties. Health food stores sold GHB as a dietary supplement after it was synthesized in 1960, before its dangerous, addictive, and even lethal effects came to light. In the 1980s, GHB was popular among body builders, who believed it could release a growth hormone that would stimulate muscle growth. In 1990, after more than 30 reports of GHB-linked illness, the Food and Drug Administration (FDA) declared that GHB was unsafe and illegal except in the carefully controlled environment of agency-approved drug studies. Despite these warnings, GHB continues to be illegally promoted for muscle building, for releasing inhibitions and feeling high, and for combating depression, sleep problems, and weight gain.

After the FDA banned the use of GHB in 1990, some supplement manufacturers switched ingredients to either GBL or BD, similar chemicals that the body converts to GHB, and which have the same potentially deadly effects. GBL-related products are illegally marketed and promoted with false claims to build muscles, improve physical and athletic performance, enhance sex, reduce stress, induce sleep, release growth hormone, relieve depression, and prolong life. They have been sold in health food stores as dietary supplements, advertised in muscle-building magazines, and listed as "party drugs" on Internet sites. Their most notorious use is as "date rape" drugs, as they are odorless and colorless, induce loss of consciousness, and cause memory loss in the victim, preventing identification of the attacker.

The FDA has determined that dietary supplements containing these chemicals are actually unapproved drugs because of their harmful and life-threatening effects, including breathing problems, unconsciousness or coma, vomiting, epileptic fits or seizures, and death. It is now illegal to sell anything for human consumption that contains GBL, GHB, or BD. In an attempt to avoid legal consequences, manufacturers of many of the products formerly sold as dietary supplements have changed the name or the intended use of the product, such as calling it a cleaning solution. However, information provided about the products continues to promote many of the former claims that these substances are performance boosters or sexual enhancers.

Because the public ignored these warnings and laws, causing a serious health hazard, the FDA had to reissue warnings on GHB in 1997 and 1998, and extended its warnings to include GBL and BD. On January 21, 1999, the FDA asked manufacturers to recall their GBL containing products and issued press releases warning consumers not to take them. The Trimfast Group, Inc. agreed to recall its products, Revivarant and Revivarant G, and most other companies followed suit. The Drug Enforcement Administration (DEA) listed GBL as a scheduled substance in January 1999. On February 18, 2000, GBL became a List I chemical, subject to the criminal, civil, and administrative sanctions of the Controlled Substances Act (CSA).

To protect the public health, the FDA threatened to use all potential regulatory actions against manufacturers that did not voluntarily recall products containing GBL and related drugs, GHB and BD. In 1999, the FDA declared BD a Class I health hazard, a potentially life-threatening substance, and the DEA made BD a scheduled substance in April 2000. The DEA is continuing to crack down on sales of BD, which should decrease the legally available supply, but which could increase the number of addicts going through withdrawal.

Only public education can help stop illegal use of GBL and its deadly chemical cousins. The National Institute on Drug Abuse (NIDA) is donating $54 million to warn teens, young adults, parents, educators, and public officials about the dangers of GBL and other club drugs, in partnership with Join Together, National Families in Action, the American Academy of Child and Adolescent Psychiatry, and the Community Anti-Drug Coalitions of America.

Part of the reason use of GBL and similar products have gone unchecked is that the FDA has less authority to control dietary supplements, which are not subject to the same strict review procedures as are drugs. Consumers should be aware that products available in health food stores or even on supermarket shelves can be just as dangerous as prescription drugs. Just because a product is labeled "natural" does not mean it is safe, and "natural" poisons like wild mushrooms cause many emergency room visits, cases of brain damage, and even deaths each year.

CHEMICAL/ORGANIC COMPOSITION

Gamma butyrolactone (GBL) is also known by other chemical names, including dihydro-2(3H)-furanone, 4-butanolide, 2(3H)-furanone dihydro, tetrahydro-2-furanone, and butyrolactone gamma. When GBL enters the body, it is broken down to gamma hydroxy-butyric acid (GHB), an equally dangerous chemical that is also sold illegally. Because the body absorbs GBL better than it does GHB, any given amount of GBL is more potent than the same amount of GHB. Dietary supplements, which are now illegal because they contain GBL, GHB, or the related chemical 1,4 butanediol (BD), could list these ingredients on the label, or they might list tetramethylene glycol or 2(3H)-furanone dihydro. However, some of these products have no label at all. Now that GBL is illegal, it is sometimes made in secret laboratories. As a result, the purity, potency, and contaminants of the drug are completely unpredictable, adding to the dangers involved in using it.

INGESTION METHODS

As GBL is an industrial and household solvent, there have been unintentional poisonings. The clear liquid or light-colored powder can be mixed with water, alcohol, or soda, allowing the unwary to drink it accidentally or be tricked into drinking it when someone secretly laces the drink. At night clubs and "raves," partygoers often carry the drug around in eye-drop bottles, water bottles, or disguised as mouthwash with added food coloring and flavorings.

The typical dose is 1–2 tsp to 5 g of powder mixed in a beverage, depending on the purity, which can vary considerably. Renewtrient and other products containing GBL or related chemicals are sometimes sold in capsules.

THERAPEUTIC USE

GBL and related drugs, GHB and BD, are illegal substances and currently have no approved medical indications in the United States.

USAGE TRENDS

According to NIDA, young people are freely experimenting with GBL despite the grave legal and health consequences, and GBL abuse has increased substantially in recent years. GBL and related drugs are popular on the club scene, especially with the college crowd, as an alternative to drinking alcohol, because they are relatively inexpensive compared with other drugs and because they have no calories.

Scope and severity

Since 1990, the DEA has documented more than 15,600 overdoses and law enforcement encounters related to GHB, as well as 72 deaths. As of 2000, the FDA has investigated 124 cases involving large-scale interstate manufacture and distribution of GHB. Law enforcement agencies have investigated 850 incidents involving GHB, including 150 home laboratories and 500 seized and analyzed drug supplies. As of December 1999, the FDA's Office of Criminal Investigations had recorded 116 arrests, 55 convictions, and 38 indictments related to GBL.

The DEA has documented at least 15 sexual assault cases involving 30 victims under the influence of GHB. In a study of urine samples from victims of alleged sexual assault, 711 urine samples were positive for drugs, including 48 that tested positive for GHB. In response to a 1999 Glamour magazine survey, 19% of female college students questioned said they knew someone who was the victim of date-rape related to GHB.

More than half of GHB-related emergency room visits are for unexpected reaction and overdose following recreational use. The U.S. government's Drug Abuse Warning Network (DAWN) reported an alarming rise in GHB-related emergency room visits, from 20 in 1992, 55 in 1994, 764 in 1997, 2,973 in 1999, to 4,969 in 2000.

However, this is probably a gross underestimate of the actual scope of the problem. Laboratories often fail to detect or identify GHB because it leaves the body in about 12 hours, and many doctors who are unfamiliar with this relatively new drug of abuse fail to recognize the signs and symptoms of GBL-related poisoning. A Los Angeles Police Department agent cited his personal knowledge of more than 200 deaths, 300 addicts, hundreds of rape victims, and thousands of overdoses, all related to GHB and related products.

In 1999, GHB accounted for 32 percent of calls to Boston poison centers involving illegal drugs. In Chicago and San Francisco, GHB use is lower than that of the club drug MDMA (ecstasy), but GHB accounts for a disproportionately large share of club drug overdoses.

From October 1998 through January 1999, poison control centers identified 34 emergency room visits in New Mexico and Texas following the use of products containing GBL, including Firewater, Blue Nitro Vitality, RenewTrient, Revivarant, and Revivarant-G. Symptoms requiring urgent care included cardiac arrest, respiratory depression, coma or decreased level of consciousness, dangerously slow or rapid heart rhythm, fainting, seizures, confusion, combative behavior, memory loss, anxiety and nervousness, nausea and vomiting, tremors and twitching, and inappropriately elevated mood. In 13 patients, symptoms were severe enough to warrant hospitalization.

From January 1999 to August 2000, the FDA received 48 reports of acute BD intoxication, including loss of consciousness, dangerously low respiratory rates, vomiting, and slowed heartbeat. In a series of nine toxic reactions to BD reported in the New England Journal of Medicine in early 2001, the effects of BD were similar to those of GBL and GHB, and included addiction, withdrawal, and death.

Age, ethnic, and gender trends

GHB and related products are popular with high school and college students. More than 60% of GHB abusers are between the ages of 18 and 25 years. Of the 72 individuals known to have died from GHB since 1995, 40% were between the ages of 15 and 24 years, and 27% were between the ages of 25 and 29 years. According to DAWN statistics, 60% of GHB-related emergency room visits are in patients age 25 and under.

In a 2001 study of 295 gay and bisexual men, 29% reported using GBL or GHB during their most recent circuit party weekend.

MENTAL EFFECTS

Like alcohol and barbiturates, GBL and related drugs, GHB and BD, powerfully and rapidly depress brain function. These drugs easily enter the brain, where they have a devastating effect on brain chemistry. Mild effects could include enhanced sensations of pleasure, sleepiness, depression, feelings of intoxication, loosened inhibitions, aggressive or combative behavior, or poor judgment. More serious and frightening effects include out-of-body experiences, uncontrolled body movements, and vertigo, a sensation of dizziness.

Psychiatric symptoms include hallucinations (seeing or hearing things that are not there) or delusions (false beliefs). Very few users remember their experience because of the associated memory loss. Individual variability in how the body handles these drugs, and an even greater variability in the composition of illegally produced drugs, makes it virtually impossible to control or anticipate how much brain function will shut down, and increases the risk of deadly overdose.

PHYSIOLOGICAL EFFECTS

When swallowed, GBL is converted in the body to GHB, causing psychological symptoms and brain depression as indicated above, as well as other symptoms that include low blood pressure or heart rate, low body temperature, and nausea and vomiting. As GBL and related drugs shut down vital brain functions, breathing slows down and may even stop. If emergency treatment is not available, respiratory depression or dangerous slowing of heart rate can cause death.

Physical effects begin within 15–30 minutes of taking the drug and last three to six hours. The sometimes deadly effects of GBL and related drugs appear to be dose-related, so that the larger the dose, the more frequent and severe the ill effects. At GHB doses of 0.5–1.5 grams, the user may feel relaxed or drunk; doses of1.0–2.5 grams increase muscle relaxation and impair coordination; and doses over 2.5 grams can cause nausea, vomiting, drowsiness, breathing difficulty, slow heart rate, coma, and death.

Harmful side effects

Overall, the DEA has reported more than 72 deaths and 5,500 emergency room overdoses associated with GHB, and serious ill effects related to GBL and related drugs, GHB and BD, in at least five children under 18 years of age. All five children had vomiting and became unconscious, and most had respiratory depression and dangerous slowing of heart rate. As GBL crosses the placenta, a pregnant woman exposes her unborn baby to its dangerous effects.

Slow, shallow breathing, and irregular or slow heart rhythms related to use of these drugs can deprive the brain of oxygen and blood flow, causing unconsciousness, coma, epileptic fits or seizures, loss of muscle tone, and permanent brain damage. Lack of oxygen and blood flow to other vital organs can cause other serious complications such as kidney failure, requiring dialysis; or pulmonary edema associated with fluid collection in the lungs; shortness of breath; coughing up blood; and heart failure. The combination of unconsciousness, difficulty breathing, and vomiting can cause aspiration, or choking to death on vomit.

From October 1998 through January 1999, poison control centers in New Mexico identified 14 patients seen in emergency rooms for symptoms related to use of products containing GBL. Five of these patients had also consumed alcohol and/or other drugs. The most common symptoms and signs were nausea and vomiting in 10 (71%), decreased level of consciousness in nine (64%), slow heart rate in seven (50%), prolonged unconsciousness in six (43%), fainting in six (43%), seizures in four (29%), confusion in four (29%), combative behavior in four (29%), respiratory depression in three (21%), memory loss in two (14%), and inappropriately elevated mood in two (14%). Three were hospitalized, one with cardiac arrest, one with respiratory arrest, and one after a car crash associated with the effects resulting from use of GBL.

During the same timeframe, there were 20 emergency room visits for complications of GBL use reported in Texas. These patients ranged in age from 11 to 41 years, and 10 had also consumed alcohol and/or other drugs. Ten had to be hospitalized, including one with respiratory arrest. The most common symptoms and signs were decreased level of consciousness in 13 (65%), prolonged unconsciousness in nine (45%), respiratory depression in nine (45%), anxiety and nervousness in seven (35%), nausea and vomiting in six (30%), confusion in six (30%), tremors and twitching in four (20%), rapid heart rate in three (15%), and combative behavior in three (15%).

In a series of nine toxic reactions to BD reported in the New England Journal of Medicine in early 2001, the effects of BD were similar to those of GBL and GHB, and included addiction, withdrawal, and death. The eight patients seen at Hennepin County Medical Center, Minneapolis, Minnesota, had used BD recreationally, to enhance bodybuilding, or to treat depression or sleep problems. One patient was seen twice with toxic effects and had withdrawal symptoms after her second episode, including hallucinations, sleeplessness, fear, agitation, and uncontrollable body movements. Reactions in most patients included vomiting, loss of bowel and bladder control, agitation, striking out at others, fading in and out of consciousness, respiratory depression, and death. Six patients, including two who died, had not used alcohol or any other drugs with BD. Those who died had taken5.4–20 g of BD, and the others took doses ranging from 1 to 14 g.

Long-term health effects

GBL and related drugs can cause physical and psychological dependence and addiction with sustained use. Withdrawal symptoms in users of high doses, especially when used for longer than four months, can include sleeplessness, muscle cramps, tremor, anxiety, hallucinations, and delusions lasting from 48 hours to 12 days after last use.

In a series reported in 2001 of five patients seen for abrupt withdrawal from GBL, symptoms included rapid heart rate, high blood pressure, delusions of being persecuted or harmed, hallucinations, and fluctuating states of consciousness. Most of the patients were body builders, and ranged in age from 23 to 33 years. Patients had been taking GBL for two to nine months, and developed withdrawal symptoms one to six hours after their last dose, with symptoms lasting up to 14 days.

In testimony before the FDA, drug researcher Deborah Zvorsec reported that GHB users need increasing amounts of the substance to feel good. By the time they realize they have become tolerant or even addicted, they develop severe anxiety, sleeplessness, panic attacks, and hallucinations when they try to stop. Detoxification, even with medical supervision, resembles the terrifying state of hallucinations and extreme anxiety called "DTs," or delirium tremens, that accompany alcohol withdrawal. After detoxification most patients suffer from severe depression and anxiety lasting weeks to months, and some also have muscle twitching and tremors, or uncontrolled shaking. Very few are able to refrain from using GHB again. "GHB is perhaps the most addictive drug ever abused," Zvorsec testified.

While some users may recover completely and rapidly from intoxication with GBL or related drugs, previous exposure does not predict future response. These users may be lulled into a false sense of security, thinking they are immune to any toxic reactions, only to suffer serious reaction or even death the next time.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

As GBL and related drugs are powerful sedatives that depress brain function and respiration, they are especially dangerous when mixed with alcohol or other drugs with similar effects. They can cause seizures and are more deadly when mixed with ecstasy or other club drugs that excite the nervous system. On the club scene or at raves, combining these drugs is unfortunately a common practice.

TREATMENT AND REHABILITATION

After a single episode of intoxication with GBL or related drugs, symptoms usually resolve with supportive care within 2–96 hours, provided users get emergency treatment before permanent complications develop. There is no antidote for these poisons. Treatment consists of careful medical observation and supportive therapy until symptoms of toxicity subside.

Repeated users of GBL or related drugs should have intensive monitoring and medical intervention for withdrawal symptoms when discontinuing use. Withdrawal can take 10–14 days even with medical assistance, and should be followed by counseling for anxiety, depression, and substance abuse for as long as is needed. Attempting withdrawal without medical assistance is dangerous, and can result in suicide from intense depression or accidental overdose if the user tries to taper off the drug. Even with medical help, very few who go through withdrawal are cured of their addiction and, instead, continue to use the drug.

Patients undergoing abrupt withdrawal from GBL are monitored in the intensive care unit and are typically hospitalized for about five days for supportive care and treatment with pentobarbital, a strong sedative sometimes used for anesthesia. Withdrawal symptoms are so severe that benzodiazepines, which are milder tranquilizers than pentobarbital and which are typically the first line of treatment for drug withdrawal, were not effective. After discharge, patients received gradually decreasing doses of pentobarbital or benzodiazepines to control their symptoms of anxiety, delusions, and hallucinations.

PERSONAL AND SOCIAL CONSEQUENCES

Users of GBL or related drugs may experience memory loss, lapses in judgment, aggressive outbursts, embarrassing or strange behavior, confusion, anxiety, or depression. Any or all of these symptoms affect the individual both directly and by influencing how others perceive the user, causing loss of friendship, trust, and respect. Users who suffer from delusions or hallucinations may even be perceived as being mentally ill.

Erratic behavior associated with psychiatric symptoms like these can cause violence, accidents, suicide, or harm to self or others with permanent physical and legal consequences and irreversible damage to relationships, school work, and employment prospects. Hallucinations and delusions can be terrifying, leave permanent psychological damage, and even endanger life.

Addicted users who need increasing amounts of the drug to prevent withdrawal symptoms may end up spending up to $200 per day, or $70,000 per year, according to Dr. Zvorsec, causing significant problems with debt or even turning to crime to support the habit.

Those who trick others into using GBL or related drugs by slipping it into their drink are viewed as rapists. Offering the drug to others with or without their knowledge or consent may result in criminal charges of sexual assault, rape, manslaughter, or poisoning, punishable by fines and imprisonment.

LEGAL CONSEQUENCES

In California, a chiropractor who distributed liquids containing GHB at a party, causing other partygoers to get sick, was punished with a $2,000 fine and imprisonment. In Michigan, four men were accused of manslaughter and poisoning when they slipped GHB or GBL into a ninth-grader's drink, causing her to vomit, go into a coma, and die. Manslaughter carries a maximum sentence of 15 years in prison, and poisoning carries a maximum sentence of life imprisonment.

Both the FDA and the U.S. Department of Justice have ongoing criminal enforcement actions against GHB. As of 2000, the government had investigated 850 incidents involving GHB, including 124 cases of largescale interstate manufacture and distribution of GHB, 150 clandestine laboratories, and 500 seized and analyzed laboratory exhibits. There have been more than 33 GHB-related convictions.

Legal history

In 1990, based on more than 30 reports of illness linked to GHB, the FDA banned its use except in the carefully controlled environment of agency-approved drug studies. In January 1999, the FDA requested a voluntary recall of all GBL-containing products sold in health food stores and warned the public of its abuse potential and danger to public health. It is now illegal to sell anything for human consumption that contains GBL, GHB, or BD.

Federal guidelines, regulations, and penalties

GHB is already classified as a controlled substance by more than 20 states, and some other states also impose criminal penalties for possession of GHB. If Congress classifies GHB as a controlled substance, marketing the drug illegally would subject the offender to federal penalties, including imprisonment and fines.

GBL became a Schedule II substance in California effective January 1, 2000. In that state, possession of GBL or GHB is an alternate felony/misdemeanor, punishable by 16 months or two or three years in the state prison, or up to one year in the county jail. Possession for sale is a felony, punishable by 16 months, two years, or three years in state prison. Sale or transportation is a felony punishable by a state prison term of two, three, or four years. Transportation between non-neighboring counties is a felony punishable by incarceration in state prison for three, six, or nine years.

On February 18, 2000, GBL became a List I chemical, subject to the criminal, civil, and administrative sanctions of the CSA. This legislation, Public Law 106-172, was named the Hillary Farias and Samantha Reid Date-Rape Prohibition Act of 1999 for the two Michigan girls poisoned with GBL, one fatally.

See also Alcohol; Ecstasy (MDMA); GHB; Rohypnol

RESOURCES

Periodicals

"Adverse Events Associated with Ingestion of Gamma-Butyrolac-tone Minnesota, New Mexico, and Texas, 1998-1999." Morbidity and Mortality Weekly Report 48 (February 26, 1999): 137-140.

Catalano, Maria C., et al. "GBL Withdrawal Syndromes." Psychosomatics 42 (February 2001): 83-88.

Nordenberg, Tamar. "California Man Imprisoned after fX Drinks Injure Partygoers." FDA Investigators' Reports—FDA Consumer Magazine (July–August 1998).

Nordenberg, Tamar. "The Death of the Party: All the Rave, GHB's Hazards Go Unnoticed." FDA Consumer Magazine (March–April 2000).

Winickoff, J. P., et al. "Verve and Jolt: Deadly New Internet Drugs." Pediatrics 106, no. 4 (October 2000): 829-830.

Other

Food and Drug Administration website. <http://www.fda.gov>. July 5, 2002 (July 8, 2002).

FDA Talk Paper T99-5: FDA Warns about Products Containing Gamma Butyrolactone or GBL and Asks Companies to Issue a Recall (January 21, 1999). <http:www.fda.gov/bbs/topics/ANSWERS/ANS00937.html>. Accessed 3/25/02.

FDA Talk Paper T99-21: U.S. FDA Warns about GBL-Related Products (May 11, 1999). <http://old.healthnet.org/programs/e-drug-hma/e-drug.199905/msg00021.html. Accessed 3/25/02>.

Neuroscience for Kids: 1,4-Butanediol (BD): Danger! <http://faculty.washington.edu/chudler/14b.html>. April 17, 2001 (March 30, 2002).

Neuroscience for Kids: Gamma hydroxybutyrate (GHB) = Bad News. <http://faculty.washington.edu/chudler/ghb.html>. April 16, 2001 (March 30, 2002).

Project GHB website. <http://www.projectghb.org>. Accessed March 29, 2002.

Supplement Watch: GBL. <http://www.supplementwatch.com/supatoz/supplement.asp?supplementId=137>. July 8, 2002 (July 8, 2002).

U.S. Department of Justice, DEA Diversion Control Program. Drugs and Chemicals of Concern: Gamma Hydroxybutyric Acid. (August 2001). http://www.deadiversion.usdoj.gov/drugs_ concern/ghb/summary.htm. Accessed March 30, 2002.

Organizations

National Institute on Drug Abuse (NIDA), National Institutes of Health, 6001 Executive Boulevard, Room 5213, Bethesda, MD, USA, 20892-9561, (301) 443-1124, (888) 644-6432, [email protected], <http://www.nida.nih.gov/AboutNIDA.html>.

Laurie L. Barclay, MD