B
Drug Abuse Research in Historical Perspective

David F. Musto, M.D.

Attempts to understand the nature of illicit drug abuse and addiction can be traced back for centuries, however, the search has always been limited by the scientific theories and social attitudes available or dominant at any one time. Dr. Benjamin Rush, a founder of the first medical school in the United States and a signer of the Declaration of Independence, was one of the pioneers of U.S. drug abuse research. However, he had few scientific resources available to attack the problem. The intricacies of cellular response to a drug could not be understood until tools were developed to measure the response and to integrate this knowledge with complex cellular biochemistry—a technology that has been developed only in the past decade. One can compare this situation with that of pneumonia. A myriad of treatments and partially effective remedies were used until the discovery of penicillin, when the old treatments became a part of medical history. It is now possible, however, to be optimistic that the tools needed to resolve the addiction problem are at hand.

BEGINNINGS OF MODERN DRUG ABUSE RESEARCH

Although the funding of drug abuse research has increased substantially since the 1960s-largely due to grants by the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH)-significant research began much earlier. The vicissitudes of this research illustrate changing popular and professional attitudes toward



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Pathways of Addiction: Opportunities in Drug Abuse Research B Drug Abuse Research in Historical Perspective David F. Musto, M.D. Attempts to understand the nature of illicit drug abuse and addiction can be traced back for centuries, however, the search has always been limited by the scientific theories and social attitudes available or dominant at any one time. Dr. Benjamin Rush, a founder of the first medical school in the United States and a signer of the Declaration of Independence, was one of the pioneers of U.S. drug abuse research. However, he had few scientific resources available to attack the problem. The intricacies of cellular response to a drug could not be understood until tools were developed to measure the response and to integrate this knowledge with complex cellular biochemistry—a technology that has been developed only in the past decade. One can compare this situation with that of pneumonia. A myriad of treatments and partially effective remedies were used until the discovery of penicillin, when the old treatments became a part of medical history. It is now possible, however, to be optimistic that the tools needed to resolve the addiction problem are at hand. BEGINNINGS OF MODERN DRUG ABUSE RESEARCH Although the funding of drug abuse research has increased substantially since the 1960s-largely due to grants by the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH)-significant research began much earlier. The vicissitudes of this research illustrate changing popular and professional attitudes toward

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Pathways of Addiction: Opportunities in Drug Abuse Research illicit drugs and drug users and also provide insights into the relationship between scientific findings and drug policy. Most of the modern problems, as well as the benefits, resulting from drug use are the outcome of scientific and technological progress. Excluding distilled spirits, the first addictive ingredient isolated from a natural product was morphine, which was extracted from crude opium by F.W.A. Serturner, a German pharmacist, in 1806. Increasingly widespread use of morphine, which constitutes roughly 10 percent of crude opium, revolutionized pain control. One of the first careful studies of morphine addiction was made in 1875 by Levinstein, who identified key elements in opiate addiction that would interest researchers: the fixation on the drug that made it the highest priority even when the user's life situation was deteriorating, and the curious phenomenon of withdrawal that could be reversed quickly by giving more opiate (Levinstein, 1878). Around the turn of the century, several new medical research issues attracted investigators: communicable diseases, bacteria, and viruses; the immune system, with its antibodies and antigens; autointoxication, or the body poisoning itself; the endocrine glands and their production of hormones; and the rapidly developing fields of biochemistry and pharmacology. A number of researchers in the United States and abroad attempted to apply those contemporary approaches to the study of illicit drug abuse, addiction (specifically, opiate addiction), and its treatment. A particularly popular line of research related to discoveries about the immune system and concerned the possible creation in the user's body of either antibodies or a toxin to morphine. This research attempted to parallel the success of antitoxins to diphtheria and tetanus. Gioffredi reported in 1897 that serum from addicted dogs could be injected into kittens, who were then protected against large doses of morphine (Gioffredi, 1897). In 1914, Valenti stated that he had extracted serum from dogs undergoing the abstinence reaction and was able to produce similar effects by injecting the serum into normal animals—giving support for the hypothesis that a toxin produced abstinence effects (Valenti, 1914). Application of the concept of ''autointoxication" to research on narcotic dependence emerged from the theories of Elie Metchnikoff, who won a Nobel Prize in medicine in 1908 for his work on toxins thought to be the product of fermentation in the large intestine (Metchnikoff, 1901). Other theories applied to drug addiction in the early 1900s included the blockage of endocrine gland passages (Sollier, 1898), changes in cell protoplasm (Cloetta, 1903), degenerative changes in brain cells (Wilcox, 1923), or changes in cell permeability (Fauser and Ottenstein, 1924). One other approach, exemplified by the New York physician Dr. Ernest S. Bishop, led to the claim that as long as the toxin or antibodies were balanced by a

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Pathways of Addiction: Opportunities in Drug Abuse Research dose of morphine, the person would feel and function normally-a theory similar to that proposed for methadone treatment today (Bishop, 1920). This early and active stage of research was characterized by optimism for medical research and the success of medical treatment. Estimates of cure ranged as high as 75-99 percent (Musto, 1987). Hope was great that the key to addiction had been found and that eventually a treatment as effective as that against diphtheria would be developed. END OF MEDICAL OPTIMISM Soon, however, this situation changed dramatically. Around the time of World War I, extensive drug use in the United States—a combination of morphine, heroin, opium, and cocaine—created a growing fear of drug abuse. The association of opium with Chinese immigrants, cocaine with African Americans, and morphine addiction with careless physicians prompted more and more restrictive legislation and an antagonism to easy access to those drugs. A six-year federal effort to control the distribution of opiates and cocaine led to the Harrison Anti-Narcotics Act of 1914. Regulations associated with the Harrison Act and promulgated by the U.S. Treasury Department in 1915 indicated that the maintenance of nonmedical addicts on narcotics to avoid withdrawal would not be considered legitimate medical practice. The federal government then began to use the act to prosecute doctors who issued prescriptions for that purpose. In 1919, the Supreme Court ratified the federal government's interpretation of the laws. The position against maintenance was controversial, however, not only because it seemed to represent an intrusion into medical practice, but also because the Gioffredi and Valenti hypotheses—that opiate use causes permanent physiological changes through creation of antibodies or a toxin—seemed to give support to those who considered addiction a medical disease. E.J. Pellini, the Assistant City Chemist of New York, actively examined the Gioffredi and Valenti claims and, in the early 1920s, published a refutation of their hypotheses (Pellini and Greenfield, 1920, 1924). The general conclusion drawn from this debate over antibodies and toxins was that there was no organic basis for addiction and withdrawal and that these phenomena were "functional" or "psychological." Thus, research into addiction and withdrawal became a controversial field after 1919 due to the fact such that research might find evidence supporting a medical model and thereby possibly challenge established government policy.

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Pathways of Addiction: Opportunities in Drug Abuse Research RESEARCH IN THE 1920s Drug abuse research in the 1920s seems to have been at a relatively low level of activity. The Public Health Service (PHS) produced some estimates of the number of addicts and general statements on the nature and treatment of drug users. Perhaps the chief scientific contribution of that decade was the demonstration of morphine dependence in monkeys. In addition to PHS, the Rockefeller Institute supported drug research. In 1913, the institute created the Bureau of Social Hygiene to study social problems generally and criminology in particular, and by the time the bureau was disbanded in 1933, 32 papers and books on addiction had been published with its support (Eddy, 1973). The vast majority described studies at Iowa State University of the effect of morphine on the gastrointestinal system and its fate in the body, as well as clinical efforts in Philadelphia to cure addicts and monitor morphine in the bodies of the patients. The foundation also supported the compendium The Opium Problem, a large anthology of information that is still in use (Terry and Pellens, 1928). NATIONAL RESEARCH COUNCIL COMMITTEE ON DRUG ADDICTION At the close of the 1920s, the Bureau of Social Hygiene decided to transfer its support of research to the National Research Council (NRC), where it was hoped greater central direction could be achieved. In 1929, the Committee on Drug Addiction was established by the NRC's Chair of the Medical Sciences Division (May and Jacobson, 1989). Its members included medical school researchers and key government scientists and administrators, including the head of the Federal Bureau of Narcotics, H. J. Anslinger. Their first task was to decide the direction of research, and their reasoning is quite instructive as to the state of research around 1930. The committee considered that further sociological studies were unlikely to help the drug situation. Given its resources, the committee felt that one drug should be targeted. Cocaine was considered but was dropped because it was no longer much of an abuse problem. Codeine appeared to be less addictive, thus posing less danger, so morphine was chosen as the target of this new research effort. The goal of studying morphine was to find substitutes that were not habit forming. Scientists were well aware that they worked in a framework of law and policy that precluded maintenance and in an atmosphere of extreme antagonism to narcotic drugs. In addition to seeking safe substitutes, the NRC committee approved three more tasks: (1) synopses of the literature on morphine and other addictive drugs were to be pre-

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Pathways of Addiction: Opportunities in Drug Abuse Research pared; (2) based on the literature search, rules and regulations governing the legitimate use of morphine and other habit-forming drugs were to be established; and (3) a determination of where gaps existed in biological knowledge was to be made. The committee proceeded to attack the problem by working in three Settings—chemical laboratories that would create possible substitutes, a pharmacology lab where these would be tested, and a clinical setting in which human subjects could be studied. New substances for trial were created first at Yale and then at Dr. L.F. Small's laboratory at the University of Virginia. The substances were then sent to a new pharmacology unit at the University of Michigan headed by Dr. Nathan Eddy, where they were tested on laboratory animals. Clinical facilities were meager until the "narcotic farms" opened in Lexington, Kentucky, in 1935 and Ft. Worth, Texas, in 1938. These institutions, dubbed farms by the sponsor of the legislation that established them, Representative Stephen G. Porter of Pennsylvania, were in fact special prisons for drug addicts, complete with cells and bars. They were officially under the control of the Treasury Department, which was charged with the enforcement of narcotic laws but were staffed by PHS officers. It was not until the late 1960s that the facility at Lexington became a true PHS hospital (Musto, 1987). Eventually the Addiction Research Center, under the leadership of C.K. Himmelsbach, was established at Lexington to determine the addictive liability of various compounds. Pharmacological research at the Lexington facility provided major contributions to the understanding of opiate and alcohol dependence and withdrawal, and included research on the quantification of opiate dependence as a physical or physiological phenomenon and on the effect of methadone on opiate withdrawal. When it became apparent that the Rockefeller funding would not be continued, the chemical and pharmacological work was transferred to the PHS. At that time—in 1941—a non-habit-forming analgesic to replace morphine had not been found. However, many drugs had been tested, and experts were hopeful that compounds with a more salutary balance of effects, although still habit forming, might be developed. Certainly, many of the pitfalls of drug testing had been recognized. Judged by today's sophisticated research, the methods were simple. Addiction liability was typically tested by substituting the test drug for a regular dose of morphine in a morphine-dependent person and observing the results. The relation of molecular composition to effect was considered but at a level that could not take into account the actual shape of the molecule or the site on which it acted. These early studies illustrate the limitations of knowledge at the molecular level, where pain relief and dependence actually occurs.

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Pathways of Addiction: Opportunities in Drug Abuse Research FROM THE CLOSE OF WORLD WAR II TO THE 1960s In 1947, the National Research Council established a successor body, the Committee on Drug Addiction and Narcotics. Prominent among the reasons for this renewed activity was the appearance of methadone from German laboratories. Methadone had been substituted for morphine to meet German needs during World War II. Researchers' considerable interest in methadone's possibilities, together with other unfunded ideas for scientific studies in the field, prompted the group to consider asking pharmaceutical manufacturers for contributions to a research fund that the committee would administer. NRC approved, and by the end of 1949, eight firms had contributed a total of $18,500. This episode reveals the paucity of funding sources and the extremely modest amounts with which basic and practical research on pain relief was conducted immediately after World War II. There were other supports for research in this area. University science departments contributed some of their own funds to these studies. Furthermore, pharmaceutical companies themselves conducted research on analgesics, although their practice of sending new drugs for testing under the committee's auspices suggests that their programs in this area were not comprehensive. In addition to its funding from pharmaceutical companies, NRC's Committee on Drug Addiction and Narcotics began to receive small annual amounts from the Veterans Administration (VA) and the World Health Organization (WHO) in 1961. Research sponsored by the committee was varied and included studies of methadone as well as the opiate antagonists nalorphine, naloxone, and naltrexone. Additionally, the committee advised the Federal Bureau of Narcotics and the Food and Drug Administration on the potential abuse liability of marketable drugs. The committee changed its name to the Committee on Problems of Drug Dependence (CPDD) in 1965 to meet the new definition of "addiction" promulgated by WHO. By 1977, CPDD had incorporated as an independent organization; it continued to grow as a locus of scientific interchange, later changing its name to the College of Problems of Drug Dependence. NATIONAL COMMISSION ON MARIHUANA AND DRUG ABUSE The era from World War I through 1960 had seen a loss of faith in the possibility of successfully treating narcotics addicts. Dr. Alexander Lambert, a leading advocate of addiction treatment since 1909, exemplified this trend with his abandonment in 1920 of the "cure" he had advocated for 11 years. Federal drug policy became concentrated on narcotics con-

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Pathways of Addiction: Opportunities in Drug Abuse Research trol through law enforcement, and prevention and treatment were deemphasized. However, this trend began to decline with time. During the 1960s, the entrenched commitment to law enforcement confronted an unprecedented rise in the nature and extent of illicit drug use. The transformation, especially in marijuana use, was associated with social and political turmoil, including the deep fissures caused by the Vietnam War, the civil rights movement, and profound demographic changes as the "baby boom" generation approached maturity. The first of several steps toward abandonment of the punitive-deterrent philosophy was the report of the President's Commission on Narcotics and Drug Abuse, which was an outgrowth of the 1962 White House Conference on Drug Abuse. The report advocated adoption of approaches more in keeping with the view of illicit drug abuse as a disease and with theories of social deviance control through medical means. This sort of thinking enjoyed widespread acceptance at that time and was the philosophy behind the establishment of federally funded community mental health centers which began the same year. Congress responded by enacting the Comprehensive Drug Abuse and Control Act of 1970. This act attempted to deal with the growing wave of drug use in the context of new attitudes and approaches by making penalties, especially for marijuana possession, less severe and more flexible and by creating categories for drugs of varying dangerousness that would allow shifts between classes to be achieved administratively rather than requiring a new statute. One of the most important initiatives of the new law was the establishment of the National Commission on Marihuana and Drug Abuse, which would report over two years (1971-1973) on the whole range of issues linked to drug use. The commission's first report, Marihuana: A Signal of Misunderstanding (NCMDA, 1972), recommended "decriminalization" as a response to the widespread use of marijuana. Although dealing in the drug would be still prohibited under this approach, users would no longer be subject to criminal punishment. This proposal was disavowed by President Nixon but influenced a number of state laws in the 1970s. Furthermore, the report urged substantial studies on marijuana, commissioned many itself, and published them in two large volumes of technical papers. The commission's second report, Drug Use in America: Problem in Perspective (NCMDA, 1973), continued the strong recommendation both for government-sponsored research and for continuation of national surveys on drug use that the commission had begun. The technical papers of the second report include studies on patterns and consequences of drug use, social responses to drug use, the legal system and drug control, and treatment and rehabilitation. The commission conceived a wide range of re-

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Pathways of Addiction: Opportunities in Drug Abuse Research search relevant to drug issues and set an example for the research programs of NIMH and NIDA. FOUNDATION SUPPORT With the exception of studies on alcoholism, foundation support for drug abuse research did not emerge until the 1960s and 1970s, when changing use patterns made drug abuse a subject of national concern. The Ford Foundation had been receiving requests for support for drug abuse research since the 1950s, but not until 1968 did it award its first grant—$17,500 for a conference to discuss the possible role of the foundation. In 1970, the Ford Foundation initiated the Drug Abuse Survey Project to pinpoint more precisely what should be done to combat drug abuse. Its final report, Dealing with Drug Abuse (Wald, 1972), analyzed in detail the great gaps in basic knowledge of drug actions within the body, psychological factors involved in deciding to use drugs, and the role of drugs in contemporary American society; it also made a strong appeal for more research. The report's practical outcome was creation of the Drug Abuse Council (DAC), which funded studies on illicit drug abuse from 1971 until 1978. General foundation support for drug abuse research increased slightly in the 1980s, rising in the late 1980s as the crack epidemic crystallized national alarm over the drug abuse problem (Renz, 1989). NIMH AND NIDA: RECENT FUNDING ON DRUG ABUSE The National Institute of Mental Health was established in 1949 as one of the National Institutes of Health. Its growth was considerable and included funding not only for research but also for training and services. As successor to the PHS Division of Mental Hygiene, concerns with alcohol and narcotics naturally fell under its mantle. For example, the Addiction Research Center (ARC) at Lexington, Kentucky, became part of NIMH. In the late 1960s, a Division of Narcotic Addiction and Drug Abuse (DNADA) was established within NIMH to oversee this responsibility. Eventually, the drug and alcohol divisions of NIMH evolved into the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). NIDA had its origins in the Drug Abuse Office and Treatment Act of 1972, which had established the Special Action Office for Drug Abuse Prevention (SAODAP) in the Executive Office of the President. SAODAP provided the first federal funding of drug abuse treatment and was part of an ambitious response to public fears of widespread drug experimentation among youth, the possibility that drug-addicted Vietnam veterans

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Pathways of Addiction: Opportunities in Drug Abuse Research would pose a danger to public order, and the general perception of a link between drug abuse and crime. This SAODAP legislation established an expiration date for the office of June 30,1975, and mandated devolution of its functions to a new institute of the Department of Health, Education, and Welfare (HEW), which was to come into existence on December 31, 1974. In fact, NIDA came into being over the summer of 1973 when HEW began a reorganization that created the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA); DNADA and SAODAP were merged under its aegis. (SAODAP had been operating on a lame duck basis since the 1972 presidential election and the resignation of its director in June 1973.) Further reorganization in 1992 divided drug abuse activities between the National Institutes of Health and the Substance Abuse and Mental Health Services Administration and assigned NIDA to the former. The creation of NIDA was itself an indication that the drug abuse problem was not expected to go away soon and that sustained research into the treatment, prevention, and biology of drug abuse was a national necessity. Over the years, however, NIDA's research budget has undergone unsettling perturbations as seen in changes of its extramural grant funding (Table B.1). The 29 percent drop in 1982 was the most severe to date in NIDA's history. Drug abuse research is supported when the nation is in a state of alarm over a new drug or an escalation in drug use, but it is quickly reduced with changes in perception of drug use or when other issues become a priority. Thus, funding levels may shift significantly and may detrimentally affect research programs that rely on ongoing support both to maintain a specific research project and to keep trained experts employed in the field. Recent expansion of NIDA's budget can be attributed primarily to funds for research on human immunodeficiency virus and AIDS. In FY 1994, $143 million (34 percent of NIDA's $425 million budget appropriation) was designated for AIDS research (NIH, 1995). It is to NIDA's credit, however, and to the credit of drug abuse researchers that even with unstable funding levels, they have sponsored and conducted an extraordinary range of research that has resulted in many of the major accomplishments in the field discussed throughout this report.

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Pathways of Addiction: Opportunities in Drug Abuse Research TABLE B.1 Annual NIDA Extramural Research Budget, 1974-1994 Fiscal Year Extramural Research Funding ($ milliona) Percentage Change from Prior Year 1974 39 -15 1975 42 7 1976 37 -13 1977 36 -1 1978 37 2 1979 40 8 1980 40 1 1981 40 -1 1982 28 -29 1983 42 10 1984 50 27 1985 57 19 1986 51 8 1987 85 67 1988 107 26 1989 158 47 1990 197 25 1991 231b   1992 228b -1 1993 220b -4 1994 224b 1 a In 1982 constant dollars. b Figures include construction funds. SOURCE: GAO (1992), NIDA (1994). REFERENCES Bishop ES. 1920. The Narcotic Drug Problem. New York: Macmillan. Cloetta M. 1903. Über das verhalten des morphins im organismus und die ursachen der angewöhnung an dasselbe. Archives of Experimental Pathology and Pharmacology 50:453-480. Eddy NB, ed. 1973. The National Research Council Involvement in the Opiate Problem, 1928-1971. Washington, DC: National Academy of Sciences. Fauser A, Ottenstein B. 1924. Chemisches und physikalisch-chemisches aum problem der "Suchten" und "Entziehungserscheinungen," insbesonders des morphinismus und cocainisums. Ztsch Neurologic Psychiatry 88:128-133. GAO (General Accounting Office). 1992. Drug Abuse Research, Federal Funding and Future Needs. Washington, DC: U.S. Government Printing Office. Gioffredi C. 1897. L'immunité artificelle par les alcaloides. Archives Italiennes de Biologie 28:402-407. Levinstein E. 1878. Morbid Craving for Morphia: A Monograph Founded on Personal Observations. Translation by Charles Harrer. London: Smith, Elder, and Co.

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Pathways of Addiction: Opportunities in Drug Abuse Research May EL, Jacobson AE. 1989. The Committee on Problems of Drug Dependence: A legacy of the National Academy of Sciences. A historical account . Drug and Alcohol Dependence 23:183-218. Metchnikoff E. 1901. L'Immunité dans les Maladies Infestieuses. Paris: Masson and Cia. Musto DF. 1987. The American Disease: Origins of Narcotic Control. New York: Oxford University Press. NCMDA (National Commission on Marihuana and Drug Abuse). 1972. Marihuana: A Signal of Misunderstanding. Washington, DC: U.S. Government Printing Office. NCMDA (National Commission on Marihuana and Drug Abuse). 1973. Drug Use in America: Problem in Perspective. Washington, DC: U.S. Government Printing Office. NIDA (National Institute on Drug Abuse). 1994. 1995 Budget Estimate. Rockville, MD: NIDA. NIH (National Institutes of Health). 1995. NIH Data Book 1994. NIH Publication No. 951261. Bethesda, MD: NIH. Pellini E, Greenfield AD. 1920. Narcotic drug addiction: I. The formation of protective substances against morphine. Archives of Internal Medicine 26:279-292. Pellini E, Greenfield AD. 1924. Narcotic drug addiction: II. The presence of toxic substances in the serum in morphine addiction. Archives of International Medicine 33:547-565. Renz L. 1989. Alcohol and Drug Abuse Funding: An Analysis of Foundation Grants. New York: The Foundation Center. Sollier P. 1898. La démorphinisation. Mécanisme physiologique. Conséquences au point de vue thérapeutique. Presse Méd 1(34):201-201; 2(56):9-10. Terry CD, Pellens M. 1928. The Opium Problem. Montclair, NJ: Patterson Smith. Valenti A. 1914. Experimentelle untersuchungen über den chronischen morphinismus. Archives of Experimental Pathology and Pharmacology 75:437-462. Wald PM. 1972. Dealing with Drug Abuse: A Report to the Ford Foundation. New York: Praeger. Wilcox WH. 1923. Norman Kerr memorial lecture on drug addiction. British Medical Journal (Dec.):1013-1018.