Mr. Chairman and Members of the Subcommittee:

I am Dr. Charles R. Schuster, Director of the National Institute on Drug Abuse, and I am pleased to discuss the designer drug problem in America. My remarks will concentrate on three distinct types of designer drugs and the coordinated efforts of the Public Health Service (PHS) to curb their abuse. Before discussing the serious adverse health consequences caused by these substances, let me describe what we mean when we refer to designer drugs. The popular term, "designer drugs," refers to structural analogs of substances already scheduled under the Controlled Substances Act (CSA) which are prepared by underground chemists to mimic the psychoactive effects of the drugs already scheduled. Because such drugs are not structurally identical to parent compounds, their manufacture and distribution are not now a violation of that Federal law. The danger these substances pose to the health and safety of Americans is at least as serious as that posed by their analogous parent compound in terms of overdose or neuronal damage and may pose increased toxic threats as a consequence of previously unknown impurities or unusual pharmacological properties due to the subtle chemical alterations. The number of potential synthetic analogs that theoretically can be made and distributed is very large and virtually anyone with a background in college chemistry can obtain the information necessary to synthesize them. At present, there are three major types of synthetic analog drugs available through the illicit drug market in this country. These include analogs of phencyclidine (PCP), analogs of fentanyl and meperidine, both powerful synthetic narcotic analgesics, and analogs of amphetamine and methamphetamine, which have hallucinogenic and stimulant properties. Today, I will discuss what we know about the these substances and what we have done to curb their use.

PHENCYCLIDINE ANALOGS

Perhaps a prototype for the designer drug problem we now face can be found in the analogs of phencyclidine (PCP). While PCP was originally developed in the 1950's as an anesthetic for human use, its side effects, including hallucinations, gradually caused the manufacturer to limit its use to veterinary purposes. PCP itself is now controlled in Schedule II of the CSA. During the past eight years several analogs of PCP have been identified in confiscated street samples and three of these were placed in Schedule I of the CSA. Over 35 analogs of PCP have been synthesized by the National Institute on Drug Abuse (NIDA) for research purposes and abuse liability testing. Most of these analogs have been tested to determine their abuse liability or pharmacologic properties. Even though the synthesis of the PCP analogs are relatively simple, such analogs have not presented major problems. FENTANYL ANALOGS

Fentanyl is used in over 70 percent of the surgical procedures performed in the United States as a pre-anesthetic analgesic. Its medical popularity is derived from its rapid onset of action and its therapeutic efficacy and safety. Many hundreds of fentanyl analogs could theoretically be prepared from commonly available starting materials, and most of these substances

would likely have pharmacological properties similar to heroin or morphine. The fentanyl analogs are frequently hundreds of times more potent than morphine or heroin and probably present the most signficant drug abuse problem among the synthetic analogs because of the potential for overdose when dealing with such potent compounds and because economically the synthesis of such materials and its control by organized crime could significantly change the picture of traditional narcotic drug law enforcement. They produce euphoria, are strong analgesics, and create addiction similar to the classical opiate narcotics. Street names of these drugs, such as "synthetic heroin," "China White," and "new heroin," are often used interchangeably to designate a wide variety of analogs of fentanyl. In 1979 the fentanyl analog, alpha-methylfentanyl became widely available in California, and since then this substance and several other fentanyl analogs are believed to be responsible for numerous hospital emergency room visits and over 100 deaths. Because of the problems it created, alphamethylfentanyl was placed in Schedule I of the CSA on September 22, 1981.

Since the control of alpha-methylfentanyl, law enforcement laboratories have identified other fentanyl analogs clandestinely produced and distributed in California. Available information did not indicate that these analogs were causing a widespread public health and safety hazard until 1984. Additional evidence of the pervasive use of fentanyl analogs is found in the results from routine urinalysis tests of methadone clinic patients in the Los Angeles area. Estimates in 1984 by California health officials suggested that up to 20 percent of these patients may have been users of fentanyl or one of its analogs. Increased reports of the distribution, abuse, and health hazards of the fentanyl analogs coincided with the identification of 3-methyl fentanyl in 75 confiscated samples from the San Francisco bay area between 1983 and 1985 by laboratories of the Drug Enforcement Administration (DEA). One sample was obtained in Brooklyn, New York in July, 1984. Other recent anecdotal information suggests that the analogs of fentanyl were implicated in deaths in Arizona, Oregon, and Florida.

MEPERIDINE ANALOGS (MA)

Meperidine, known by the common trade name of "Demerol," is a narcotic used to control severe pain and is controlled in Schedule II of the CSA. Over the past decade, the illicit use of meperidine has increased when heroin became scarce. Two other designer drugs with pharmacological effects similar to heroin have been identified and found to be similar in structure to meperidine. These two analogs, l-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and 1-(2-phenylethyl)-4-acetyloxypiperidine (PEPAP), have been shown in analgesic tests by NIDA to be many times more potent than meperidine. Neither MPPP nor PEPAP have any legitimate medical use or manufacture in the United States. While both of these substances present significant risks to those misusing them, impurities formed during the clandestine manufacture of MPPP are causing particularly unfortunate and irreversible consequences. The abuse of MPPP was first reported in the Washington, DC area in 1976, when a 23 year old man was referred to the National Institute on Mental Health (NIMH) for evaluation after exhibiting symptoms of Parkinson's Disease. A known drug user, he had used the meperidine analogue MPPP which he himself

had manufactured. Since he was able to provide the chemical formula and procedures he had followed to produce the MPPP, it was discovered through subsequent analysis that he had inadvertently created the substance MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as a side product in the synthesis. Only the most stringent chemical controls would prevent some production of MPTP during the intended production of MPPP. The critical insight linking MPTP to the Parkinsonian syndrome was provided by Dr. J. William Langston, a grantee of the National Institutes of Health, whose studies showed that MPTP was responsible for producing the Parkinsonian syndrome which he characterized in a number of patients in California.

In 1982, several samples of clandestinely produced MPPP that contained MPTP were identified in California and one in 1985 in Florida. Some of the MPTP-containing samples had been obtained from individuals who were hospitalized with a Parkinsonian syndrome. Seven victims of MPTP-induced Parkinsonian symptoms have been under treatment since 1983, all of whom were apparently exposed to the material available in 1982 in California. Their Parkinsonian syndrome appears to be chronic and irreversible, but can be treated with the drug L-dopa. However, as in the case of idiopathic Parkinson's disease, this treatment is temporary at best. Individuals exposed to MPTP who may not now show Parkinsonian symptoms are certainly at risk for developing the syndrome at some point later in life. This is because the neurotoxic damage has already occurred and the effect may be unmasked by the aging process.

PEPAP, (1-(2-phenylethyl)-4-phenyl-4-acetyloxypiperidine), is a recent addition to the street scene, having been identified by the DEA in confiscations in California in 1985, and in the form of a precursor in a lab arrest in Texas in 1984. Its action is substantially similar to that of MPPP and, just as MPTP results from the production of MPPP, PEPTP results from the production of PEPAP although preliminary research indicates it does not have the devastating neurotoxic properties of MPTP.

AMPHETAMINE AND METHAMPHETAMINE ANALOGS

Several dozen analogs of amphetamine and methamphetamine are known, or are theoretically likely, to be hallucinogenic drugs. Some have appeared on the street and have been Scheduled under the CSA in the past, but others have not. One example of an analog of methamphetamine which currently poses a threat to the health and safety of Americans is

3,4-methylenedioxymethamphetamine, or MDMA. MDMA, and its parent compound MDA produce similar psychopharmacological effects including altered consciousness; increased acoustic, visual, and tactile sensory perceptions; and mild intoxication. MDMA was first identified in the illicit drug traffic and analyzed by DEA laboratories in 1970. Since that time it has been encountered many times by DEA laboratories, reported by forensic laboratories in 8 States, and reported routinely since 1976 by Pharm Chem Laboratory, an independent laboratory analysis firm in California. Increases in its use have been particularly alarming during the past three years. It seems particularly prevalent still in the Dallas area of Texas, although samples have been encountered in virtually all regions of the U.S.

The synthesis of MDMA is analogous to that of MDA, requires no elaborate apparatus or sophisticated techniques, and can be made from readily available materials. Recently, MDMA has received considerable attention from the media, which report that MDMA, known on the street as "Ecstasy" or "Adam," is widely used as a euphoriant among college students and to some extent by physicians as an adjunct to psychotherapy. These therapeutic applications have been carried out in humans in the absence of FDA approval or appropriate preclinical toxicity studies in animals.

The adverse health effects of amphetamines such as MDA have been known for years. One recent survey of relevant research describes studies which show that a single dose of MDA can selectively destroy serotonergic nerve terminals in the brains of a variety of animal species. More recently it has been shown that MDMA causes the same type of neuronal damage at even lower doses. The serotonergic system which is also present in man plays a role in regulating sleep, mood, sexual activity, and sensitivity to aversive stimuli. It should be noted that the doses producing MDA neurotoxicity are very close to those producing amphetamine-like and LSD-like subjective effects. This suggests that, in order to produce significant psychological effects, humans may very well be exposing themselves to neurotoxic doses of these compounds.

Because of the neurotoxic effects of structurally related compounds, an effort to place MDMA in Schedule I of the CSA was initiated on July 27, 1984. The DEA has hastened the scheduling process by placing MDMA into Schedule I on an emergency basis after receiving new reports of its widespread abuse and possible neurotoxicity.

Subsequent to the scheduling of MDMA in July of 1985, another analog appeared which was identified as 3,4-methylenedioxy-N-ethylamphetamine (MDE). Street reports indicate similar psychopharmacological effects to those reported for MDMA.

THE FEDERAL RESPONSE

In order to respond adequately to the designer drug problem, Federal law enforcement and health agencies have taken positive steps over the past several years. The overall response to the problem involves actions taken by the Department of Justice, chiefly the Drug Enforcement Administration, and several agencies of the Public Health Service in the Department of Health and Human Services. I would like to tell you what has been accomplished by the agencies of the Public Health Service.

As you know, the Public Health Service conducts health research programs and provides information and technical assistance to States on numerous health related problems. PHS efforts have been important in understanding the synthetic analog problem, and I would like to highlight specifically actions that have been taken.

One of the most important contributions of the PHS was the early identification of MPTP and the development of the animal model for Parkinson's disease. These scientific findings not only illuminated the

dangers of clandestinely produced drugs, they also provided researchers investigating Parkinson's disease with a long-needed animal model of the disease's process. Since 1982, numerous PHS sponsored research studies have begun to examine the process by which brain cells are selectively attacked and destroyed by MPTP and other substances. Last year, the Public Health Service sponsored a two-day symposium on MPTP in Bethesda, Maryland where scientists from several countries presented findings on the toxicity, clinical pathology, and epidemiology of MPTP. Other research into MPTP, and synthetic analogs in general, has been initiated.

Investigations of the nature and extent of MPTP first used in California were conducted through an interagency agreement between NIDA and CDC. In January 1985, NIDA and CDC began to interview and locate persons who may have used MPPP and MPTP. Preliminary results from the study, conducted at the request of the State of California, suggest several hundred persons may been exposed to meperidine in California based on reported symptoms similar to those reported by known users of the drug.

NIDA continues to support research projects seeking to understand basic mechanisms of action of these new synthetic analogs. In order to provide controlled substances analogs to researchers for this purpose, NIDA is synthesizing these compounds and distributing them to research laboratories for chemical and pharmacologic evaluation. În 1985, NIDA produced large quantities of MDMA and MDE in order to study its abuse liability in animal models. The production of 3-methyl fentanyl was carried out in June 1985 to provide DEA with an authentic sample of this recently controlled substance. Since October 1985, NIDA has prepared 15 fentanyl and meperidine analogs including MPPP and PEPAP, and the synthesis of an additional five are either in process or have been planned for the next few months. Five of the 15 have already been tested by NIDA for abuse liability and the remaining compounds will be tested by November. These tests indicate that the potency of some of these compounds is up to 600 times that of morphine. Additionally, NIDA has been actively soliciting, through the regular and small business grant programs, analytical methods for the detection of these drugs in human biological fluids.

PHS activities have not been limited to research. NIDA notified the drug abuse treatment and prevention community nationwide of the dangers of MPTP. Together with the National Institute on Mental Health (NIMH), NIDA prepared a report on MPTP for publication in the Morbidity and Mortality Weekly Report (MMWR). This CDC published report, which reaches a national audience of physicians, served as the basis for an article later published in the Journal of the American Medical Association, where the information reached an even wider audience. NIDA has engaged in extensive networking with State treatment programs, community-based drug abuse prevention and treatment programs, parents groups, including the National Federation of Parents for Drug Free Youth, interdisciplinary conferences involving education, law enforcement, parents, and health profession groups, and other national prevention networks.

In carrying out this responsibility, the Institute shared information with regard to the dangers associated with designer drugs through publication of