Stephen Zukin, M.D.
Director, Division of Clinical and Services Branch
National Institute on Drug Abuse
National Institutes of Health
Department of Health and Human Services
March 11, 1999
Statement for the Record
Mr. Chairman and Members of the Subcommittee, I am Dr. Stephen Zukin, Director of the Division of Clinical and Services Research at the National Institute on Drug Abuse (NIDA), one of the research institutes at the National Institutes of Health. I am here today with my colleagues to present what the science has come to show about drugs such as ketamine, rohypnol and gamma hydroxybutyrate (GHB), drugs that are reportedly being used in sexual assault incidents.
Gamma hydroxybutyrate (GHB) is the drug that I will focus much of my discussion on today, though I will be pleased to answer questions about the other drugs as well. GHB is one of a number of drugs that have been reported to be used as a "date rape" drug. These drugs are predominantly central nervous system (CNS) depressants. Because these drugs are often colorless, tasteless and odorless, they can be easily added to beverages by individuals who want to intoxicate or sedate their victims.
There is some evidence that GHB is a naturally occurring compound found in the brain. Research suggests that GHB itself may be a neurotransmitter. Brain receptor sites have been reported, as well as brain mechanisms for synthesis, release and uptake of GHB. GHB has been found to be related to the brain's major inhibitory neurotransmitter, GABA. There is also some evidence that the brain has the ability to convert GHB into GABA. However, more research needs to be conducted to determine the true physiological function of GHB.
The predominant effects of GHB are sedative, though GHB can produce a wide range of pharmacological effects depending on the dose. At lower doses GHB can relieve anxiety and produce relaxation. However, as the dose increases, the sedative effects result in sleep and eventual coma or death.
Research also shows that GHB increases dopamine levels in the striatum of the brain. Dopamine is a neurotransmitter that is intimately involved in reward and pleasure. We have come to believe that the ability to increase brain dopamine levels is a common characteristic of most drugs of abuse.
GHB also stimulates the release of growth hormone from the anterior pituitary gland. Plasma levels of growth hormones rise quickly and steadily after administration of GHB, which probably accounts for the popularity of GHB among some bodybuilders.
From the existing preclinical and clinical scientific data it is difficult to determine with precision the "abuse liability" of GHB. Abuse liability determinations, simply put, assess pharmacological and behavioral effects of drugs relative to known drugs of abuse, as well as their consequences. It is a way for scientists to assess the likelihood that a drug will be abused. Factors such as the reinforcing appetitive effects that the drug has on the individual, the possible physical dependence that may develop from using the drug, and the potential consequences associated with use of the drugs, are considered in the abuse liability determination.
Animal research has confirmed that GHB is anxiety-reducing and sedating. Other animal studies suggest that GHB may be reinforcing in self-administration studies. For example, rats given a choice between water and a solution containing GHB prefer the GHB and appear to regulate their intake to maintain a constant GHB concentration in the body. Self-administration studies of GHB in primates are more equivocal, primarily because high dose evaluations are limited due to solubility difficulties and sedation of the animals. However, some primates will also self-administer GHB but not to the same extent as other drugs such as heroin or cocaine.
There have been relatively few human or clinical studies conducted on GHB. Investigators report that some individuals experience pleasure after taking the drug. GHB's intoxicating effects are usually seen 10-20 minutes from the time the drug is taken. The effects typically last up to four hours, depending on the dosage. The behavioral and physiological effects of GHB are dose dependent. Low doses can relax an individual, whereas high doses can be lethal. The drug has a relatively short half-life, making it difficult to detect in emergency rooms and other such facilities.
Tolerance, and as I mentioned earlier physical dependence, are also factors used to determine a drug's abuse liability. Both tolerance to GHB's euphoric and sedative effects and physical dependence have been reported. These properties may contribute to continued abuse. Case studies describe the illicit purchase of GHB for abuse of its sedative, euphorigenic, and anabolic effects and also that some users tend to escalate doses. Physical dependence is evidenced by a withdrawal syndrome characterized by insomnia, muscle cramps, tremor and anxiety when GHB is discontinued. Various sources describe instances of dose escalation, compulsive use, unsuccessful efforts by individuals to decrease or discontinue use, drug-seeking, and continued use despite adverse consequences.
The available data on the actual abuse of GHB and its associated consequences is largely anecdotal. GHB is usually abused either (1) for its intoxicating/sedative/euphoriant properties or (2) for its growth hormone releasing effects.
GHB was widely available over the counter in health food stores during the 1980s, purchased largely by body builders for its ability to stimulate release of human growth hormone, which aids in fat reduction and muscle building. GHB has not been sold over-the-counter in the United States since 1992. However, products containing gamma butyrolactone (GBL), a chemical that is converted by the body into GHB, are used in a number of dietary supplements in health food stores and gymnasiums. GHB is still being marketed in Europe as a general anesthetic, a treatment for insomnia and narcolepsy, an aid to childbirth, and as a treatment for alcoholism.
GHB is relatively easy to make from common ingredients with recipes available on the Internet and in underground literature. GHB is now a popular drug with the young adults who attend "raves" or private clubs. An advance report from NIDA's Community Epidemiology Work Group (CEWG), a network of epidemiologists and researchers from 21 major U.S. metropolitan areas who meet semiannually to monitor community-level trends in drug use and abuse, found that GHB was used at "raves" in Miami, Minneapolis/St. Paul and Seattle. Overall, of the 21 areas included in the CEWG Report, 10 areas reported increased incidences of GHB use.
Poison Control Centers have documented numerous cases of acute poisonings associated with GHB. Initial symptoms of acute GHB toxicity include vomiting, drowsiness, dream-like state, decreased muscle tone, and vertigo. Loss of consciousness, irregular and depressed respiration, tremors, or myoclonus sometimes followed. Seizures, bradycardia, hypertension, and/or respiratory arrest have also been reported. Symptom severity and durations of action are dose dependent and also relate to the absence or presence of other CNS depressants.
The only systematic reporting of harm associated with GHB abuse is the data from the Drug Abuse Warning Network (DAWN), which is a surveillance system run by our colleagues at the Substance Abuse and Mental Health Services Administration. The number of emergency room (ER) mentions associated with GHB has grown from one in 1991 to 629 in 1996 for a total of 892 GHB-related ER mentions. Most of the reports involve white males. 95% of the patients are between the ages of 18-34. Most were using GHB to receive its pleasurable effects. GHB was abused most often in combination with other drugs, usually with alcohol, but also with stimulants, hallucinogens, marijuana, and sedatives. Most DAWN ER reports were from San Francisco, Dallas, Los Angeles, San Diego, and Atlanta.
The DAWN Medical Examiners have reported one GHB-related death in combination with alcohol between 1992-1995, occurring in 1995 in the Midwest. However, the Drug Enforcement Agency (DEA) has documented 32 deaths associated with GHB (4- attributed to GHB alone).
Another drug that the Subcommittee asked us to address is ketamine. Ketamine is also reportedly being used as a "date rape" drug. Ketamine is a rapid-acting general anaesthetic. It has sedative-hypnotic, analgesic, and hallucinogenic properties and is marketed in the United States and a number of foreign countries for use as a general anesthetic in both human and veterinary medical practice. Ketamine is similar to phencyclidine (PCP), although ketamine is more rapid in onset and less potent. We have quite a bit of information on this particular drug, which we would be happy to provide if that would be helpful to the members.
Given that the Food and Drug Administration has included information on Rohypnol in their testimony, I will not address this drug in my formal statement. I will be happy to provide additional information if it would be useful.
The Role of the Department of Health and Human Services
As the government's principal agency for protecting the health of all Americans, the Department of Health and Human Services is involved in making recommendations on domestic scheduling of drugs of abuse. Once the Attorney General initiates a scheduling proceeding, a request is made to the Secretary of HHS to provide a scientific and medical evaluation of the drug and a recommendation as to whether the drug should be controlled domestically. The Food and Drug Administration takes the lead role in gathering data from relevant HHS agencies.
As the world's leading research institute on drug abuse and addiction, NIDA has a memorandum of understanding with FDA (Memorandum of Understanding With the National Institute on Drug Abuse and the FDA, March 3, 1985 (50 FR 9518)) to provide expertise to the FDA in investigating and evaluating the abuse liability of drugs.
NIDA advises the FDA on the Department's "Eight Factor Analysis." The factors taken into consideration in evaluations and recommendations for each substance under consideration include: Its actual or relative potential for abuse; Scientific evidence of its pharmacological effects; The state of current science regarding the substance; Its history and current pattern of abuse; The scope, duration and significance of abuse; What, if any risk there is to the public health; Its psychic or physiological dependence liability; Whether the substance is an immediate precursor of a substance already controlled.
In conclusion, as a protector of the public's health, the Department realizes the harmful effects that drugs like GHB can have. That is why NIDA continues to support research on all drugs of abuse. In particular, NIDA will continue to support research that examines the behavioral and pharmacological mechanisms of action and relative abuse liability of drugs like GHB and Ketamine. We will share this information with our federal colleagues to ensure the best available science informs important decisions, such as scheduling, which impact the overall health of our Nation. We will also disseminate this information to the general public and policy makers to ensure that they also have the most current and accurate information about the effects of these drugs. Information that we retrieve through NIDA's drug monitoring mechanisms, particularly NIDA's Community Epidemiological Work Group (CEWG) will also be useful in alerting us to emerging drug problems. This information will also be shared as expeditiously as possible.
Thank you for the opportunity to testify before this Subcommittee.