The notion of stages of drug use progression implies two conditions: (1) sequencing, that is, regularities in the sequential patterns of progression that are reflected in partially ordered discrete states, namely stages, and (2) association, that is, stages that are significant indicators of greater risk of progression into higher stages than the risk from any lower stage. As was noted earlier, association implies causation, when nonspuriousness has been definitely established. However, control for all spurious factors cannot be easily implemented. Although the presence of such stages would make it easier to identify individuals who are at greater risk than others for a particular kind of drug use, and thereby to design more effective intervention programs, researchers do not always agree about which conceptualization of stages is the most meaningful and what the stages are. In order to clarify the important relationship between the conceptualization of stages and their operationalization through various methods and models, this chapter discusses three methodological approaches to the study of drug use progression, and the testing of the Gateway Hypothesis in particular, that are analyzed in the present volume: structural equation models with latent variables and linear growth curve models, discussed by Bentler, Newcomb, and Zimmerman in Chapter 10 (Huba, Wingard, & Bentler, 1981; Newcomb and Bentler, 1986a, 1986b); latent transition analysis, (LTA) discussed by Collins in Chapter 11 (Graham, Collins, Wugalter, Chuny, & Hansen, 1991; Collins, 1991; Collins et al., 1994a, 1994b; Collins & Wugalter, 1992); and log linear quasi-independence models, models for parametric event sequence analysis, and hazard rate models for the analysis of drug use initiation, discussed by Yamaguchi and Kandel in Chapters 4 and 9 (Kandel & Yamaguchi, 1993; Yamaguchi & Kandel, 1984a, 1984b, 1997).

Despite extensive correlational data and discussion of the Gateway Hypothesis, there is little direct empirical evidence that addresses its potential causal mechanisms. The possible causes for initial drug use and subsequent transition from use of one drug to use and abuse of other drugs include psychological, sociological, economic, behavioral, and biological variables. It is difficult, if not impossible, directly to examine and manipulate any of these possible explanations in children. The existing literature on reasons for drug use initiation and maintenance in children is restricted to self-reports. In contrast, the literature on adult drug initiation and maintenance includes self-reports as well as experimental examination of behavioral and biological effects of drugs. Importantly, continued drug use in adults, as self-reported and as indicated in experiments, largely results from the behavioral and biological effects of the self-administered substance. Self-report studies in children also suggest that young people use drugs because of their behavioral and biological effects. It is possible that these drug effects in young people are part of the causal mechanism of the Gateway Hypothesis.

Animal models have contributed substantially to the study of drugs of abuse and allow testing of causal hypotheses regarding drug effects. Although most of these studies have examined drug effects in adult animals, the paradigms and methods are readily applicable to younger animals. Animal models to evaluate human drug use are only valuable if they parallel and predict the human condition.

The notion that there are developmental stages and sequences of involvement in drugs was first advanced a quarter of a century ago (Hamburg, Kraemer, & Jahnke, 1975; Kandel, 1975). According to this notion, there is a progressive and hierarchical sequence of stages of drug use that begins with tobacco or alcohol, two classes of drugs that are legal, and proceeds to marijuana, and from marijuana to other illicit drugs, such as cocaine, metamphetamines, and heroin. The basic premise of the developmental stage hypothesis is that involvement in various classes of drugs is not opportunistic but follows definite pathways; an individual who participates in one drug behavior is at risk of progressing to another. The notion of developmental stages in drug behavior does not imply, however, that these stages are either obligatory or universal, nor that all persons must progress through each in turn.

In the early 1980s, the term Gateway drug began to be used to refer to alcohol and cigarettes, the drugs that are used prior to the use of illicit drugs. Soon, the usage was extended to include the use of marijuana as a precursor to the use of other illicit drugs, such as cocaine or heroin, and more rarely even to cocaine as a precursor to heroin. It is not clear how the term Gateway drug originated and I could not locate any relevant literature.

The preceding chapters have described developmental patterns of use in different populations, as well as risk and protective factors for progression to various stages of use. With the exception of the research of Golub and Johnson, the studies are based on representative longitudinal school or community samples of adolescents and young adults selected from different regions or cities in the United States. The representative samples do not extend through the entire period of risk for initiation of illicit drugs. The older sample described by Golub and Johnson in Chapter 5 is of particular interest because it consists of deviant individuals. It is not clear, however, to what extent the patterns observed in that sample are affected by factors that determine criminal behavior and apprehension by the police. In all the studies, the conceptualization of stages is characterized by two features. All illicit drugs other than marijuana are aggregated into a single class and no attempt is made to determine an order among these drugs. Furthermore, with the exception of the chapter by Labouvie and White (Chapter 2), the focus is mostly on progression from one class of drugs to another; no attention is paid to progressive involvement within a particular drug class.

We take advantage of a large national data set to explore previously unexplored substantive and methodological issues related to drug use progression.

The notion that use of certain drugs is a precursor to the use of other drugs was first proposed in the 1970s. The notion derived from the empirical observation that young people progressed from the use of legal drugs, such as tobacco or alcohol, to the use of illicit drugs, such as marijuana, cocaine, and heroin. In the 1980s, the term Gateway drug was introduced and it was emphasized that certain drugs serve as gateways for other substances. Because of the theoretical and public policy implications of the Gateway Hypothesis for understanding the progression of adolescent drug use and for formulating prevention and intervention programs, a conference was organized to examine the hypothesis critically. That conference, Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis, was held in Los Angeles on June 27–30, 1998. This book derives from the conference.

To evaluate current thinking and the strengths and weaknesses of various aspects of the Gateway Hypothesis, a multidisciplinary group of scientists was brought together, representing the disciplines of sociology, psychology, epidemiology, statistics, animal behavior, molecular biology, and prevention. In addition to the authors of the chapters in this volume, several senior scholars attended the conference: Lee Robins of Washington University in St. Louis, Klaus Hurrelmann of the University of Bielefeld of the federal Republic of Germany, David Huizinga of the Institute of Behavioral Research of the University of Colorado, Charles O'Brien of the University of pennsylvania, James D. Colliver and Lucinda L. Miner of the National Institute on Drug Abuse, Vivian Faden of the National Institute on Alcohol Abuse and Alcoholism, and Herbert Simpson of the Traffic Injury Research Foundation.

We propose a new way of thinking conceptually and methodologically about drug use sequences. In terms of biopsychosocial views on drug use, such as Noble's (1996) theory on genetic variations that imply a genetically based differential rewarding effect of alcohol and drug use on the dopamine system, the effect of initial drug use on later drug use can be conceptualized as a sensitizing effect that influences the subsequent growth in use of other substances. Extensive use of a Gateway drug may serve to determine a higher initial level of use of a consequent drug or a faster trend of growth in use of the consequent drug across time. Additionally, a greater rate of growth across time in extent of use of the Gateway drug may itself serve to determine a faster trend of growth in extent of use of the consequent drug. This growth trajectory hypothesis for progression of drug use can be tested with a variant of structural equation modeling known as growth curve modeling. The more traditional cross-lag autoregressive model can be used to study lagged effects of one substance use on another. We compare these two ways of looking at drug use involvement in a sample of 679 African American and White high school youths assessed at three time points. In addition, we cross-validate our results on a previously published data set.

Both cross-sectional and longitudinal studies have demonstrated that use of illicit drugs, like cocaine, is reliably preceded by use of other drugs, like nicotine and alcohol (Yamaguchi & Kandel, 1984; Kandel & Davies, 1991; Kandel et al., 1992; Kandel & Yamaguchi, 1993; Merrill et al., 1999). The Gateway Hypothesis of drug abuse posits that the use of some drugs (Gateway drugs) increases the risk of subsequent drug abuse. If so, identification of factors that predispose to Gateway drug use may lead to early identification of those at risk for other drug use.

Several hypotheses have focused on either personality characteristics or environmental circumstances in the use of drugs and the progression of drug use (Jessor et al., 1980; Donovan et al., 1985; Donovan & Jessor, 1985; Wood et al., 1995; Costa et al., 1989; Donovan & Jesser, 1983; Swadi, 1999). For example, sensation seeking traits have been hypothesized to predict the initial foray into experimentation with psychoactive drugs (Wills et al., 1994). Because of the relative ease of procurement of nicotine and alcohol, these drugs would be most likely to be the ones used first. Initial use of other, more difficult to obtain and illicit drugs may follow as a result of a continuing search for new sensations and exposure to environmental circumstances that are more amenable to obtaining of these drugs.

This chapter, a companion to Chapter 4, clarifies the logic underlying the notion of stages of drug use progression and its relation to two related models for the analysis of progressions. These log linear models were introduced in our previous research (Yamaguchi & Kandel, 1984a; Kandel, Yamaguchi, & Chen, 1992; Kandel & Yamaguchi, 1993; Yamaguchi & Kandel, 1996) and are further refined here. The models are applied to gender/ethnic differences in progression patterns among five drugs: alcohol, cigarettes, marijuana, cocaine, and heroin. The models that underlie the substantive results presented in Chapter 4 are discussed in detail in this chapter to illustrate the use of the methods.

In order for a stage of progression in drug use to be substantiated, two conditions must be met (Yamaguchi & Kandel, 1984a; 1984b). The first condition is that of a sequential order between two states. The sequential order of initiations between a lower-stage drug A and a higher-stage drug B is such that all systematic pathways of drug use progression, except random progressions, must not include the reverse sequence B-A (Yamaguchi & Kandel, 1984a). As a result, all pathways of progression other than the random type fall into one of the following three groups: (1) reaches neither stage A nor B; (2) reaches only stage A; and (3) reaches both stages A and B, stage A first. Under these conditions, the pathways of drug use progression satisfy the condition that stage A must precede stage B.

A key element to thoughtful discussions on this topic is alluded to in the title of this book, Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis. Dr. Kandel and her colleagues do an excellent job of presenting what science has to offer on this subject. Although the verdict is still out on whether or not the Gateway Hypothesis represents a true causal progression, one point is certain: There is nothing inevitable about drug progression from alcohol and/or nicotine to drugs such as cocaine and heroin.

This notion of inevitability creates a problem in the way the Gateway Hypothesis has been used in policy formation. There is a connotation associated with this concept that the original researchers who coined the phrase probably never intended. Most of the world has interpreted the pattern or sequence of drug use as a pathway, whereas at best it is more like a funnel. According to this metaphor, everyone who has ever tried or used drugs is at the large end of the funnel, and, although events may foster more drug use for some individuals, there remains only a small subset of users who actually go on to become addicts at the other end of the funnel.

Efforts to combat the problem of drug abuse have involved a combination of strategies including education, treatment, law enforcement, and mass media campaigns. Among these, approaches intended to prevent the onset and developmental progression of drug use among adolescents have received considerable attention in recent years. A particularly fruitful area of research has involved the development and testing of school-based prevention approaches targeting youth during the early adolescent years. This research has demonstrated that at least some approaches to drug abuse prevention can produce substantial reductions in the incidence and prevalence of adolescent drug use. Moreover, this research clearly indicates that ongoing intervention during junior high school can result in durable prevention effects that last at least until the end of high school. Finally, the effectiveness of school-based prevention approaches has been demonstrated for a relatively broad range of students including White, suburban youth, and inner-city minority youth.

A necessary precondition for the development of effective prevention approaches is an understanding of both the causes of drug use and its developmental progression. Together they provide essential information concerning the nature and timing of preventive interventions. Research delineating the etiologic determinants of adolescent drug use has highlighted the importance of an array of interpersonal and intrapersonal factors for promoting and sustaining drug use and has provided guidance to program developers concerning the appropriate focus of preventive interventions.

Specific progressions or stages of drug initiation in adolescence have been identified (Collins, Graham, Rousculp, Fidler, Pan, & Hansen, 1994; Kandel, Kessler, & Margulies, 1978; Kandel & Davies, 1992; for a review, see Kandel, Yamaguchi, & Chen, 1992). The typical sequence begins with either alcohol or tobacco, followed by marijuana, which is followed by other illicit drugs. This sequence is relatively robust and has been replicated in retrospective data (Kandel et al., 1992), prospective data (Collins et al., 1994), and in international data (Adler & Kandel, 1981).

However, the determinants of this sequence are less clear. Why does the sequence begin with alcohol or tobacco? Why does marijuana initiation follow, rather than the initiation of other illicit drugs? We hypothesize that this progression reflects the normative social definitions of specific drugs in the community. Substances that are more socially acceptable, or viewed as less harmful, are more likely to be initiated first. The progression is not immutable. It reflects the norms of the society regarding the relative acceptability of different substances. Social norms of acceptability and perceived harm have frequently been cited as likely determinants in substance initiation (Bachman, Johnston, & O'Malley, 1998; Johnston, 1985; Johnston, O'Malley, & Bachman, 1994). However, the extent to which differences in the norms regarding specific substances determine the sequence of substance initiation has not been examined.

At least three different paradigmatic frameworks that guide behavioral science research (Biglan, 1995a, 1995b; Biglan & Hayes, 1996; Hayes, Hayes, & Reese, 1988) can be identified. Each is entirely defensible as an intellectual enterprise, yet each may not contribute equally to our ability to prevent or ameliorate problems of human behavior.

The most common framework guiding behavioral science research might be called mechanism, since it derives from the intellectual traditions of the physical sciences in which phenomena are conceived of as machinelike (Pepper, 1942). The key feature of this approach is the analysis of the phenomenon of interest into parts and the interrelationships of its parts. The validity of an analysis within this framework is judged by the degree to which a model of the parts and their interrelationships is confirmed by analyses of multiple samples of data. This validity or truth criterion has been labeled predictive verification. Because one can always construct a model for a given data set that perfectly fits that data set, there is a premium in this approach on showing that models are generalizable across a wide variety of samples.

A second, and somewhat less common framework has been labeled contextualism (Pepper, 1942). This approach derives from the American pragmatist philosophy. According to this approach, an analysis is said to be valid to the extent that it allows the analyst to achieve a stated goal.

Major advances in our understanding of the neurobiology of addiction have been made and have important implications for a biological component of a Gateway Hypothesis of drug addiction vulnerability. The present chapter explores the conceptual framework and animal models that guide neurobiological research in addiction and reviews these neurobiological mechanisms for different components of the addiction process. Neurobiological mechanisms for the positive reinforcing effects of drugs of abuse, the negative reinforcement associated with drug dependence, and the neurobiological substates of craving are discussed. The focus is on neurobiological elements common to all major drugs of abuse that inform the Gateway Hypothesis from a biological perspective. Activation of certain neurochemical systems contributing to the acute reinforcing effects of drugs of abuse and activation of brain stress systems during acute withdrawal, in a common brain circuitry, may be common neurobiological mechanisms that have implications for the Gateway Hypothesis of the development of drug addiction.

Drug Addiction and Animal Models

Drug addiction is a chronically relapsing disorder that can be defined as a compulsion to take a drug with loss of control over drug intake (Figure 15.1). Important challenges for neurobiological research are to understand not only how drug use proceeds to drug addiction but why some individuals have a vulnerability for the transition that occurs between controlled substance or drug use and the loss of control that defines addiction or substance dependence.

The chapters in this volume present what is currently known about the Gateway Hypothesis. Their authors have explored the hypothesis from various perspectives ranging from developmental social psychology to prevention and intervention science, and from animal models and neurobiology to analytical methodology. The presentations have elaborated the nature and extent of the empirical support for the Gateway Hypothesis at this point in time. They have also revealed the complexities embedded in the formulation of the Gateway Hypothesis. In this brief Afterword, we revisit the hypothesis in light of what our colleagues have reported, and we discuss several conclusions that derive from their presentations.

Parsing the Gateway Hypothesis

Advancing understanding of the Gateway Hypothesis requires that it be parsed into three interrelated, component propositions. All three have emerged from the research and the reviews reported in the preceding chapters.

The first proposition embedded in the Gateway Hypothesis is that among adolescents there is a developmental sequence of involvement with different classes or categories of drugs, such that initiation into drug use begins with the drugs earlier in the sequence, namely, the legal drugs, alcohol and tobacco. Involvement with illicit drugs occurs later in the developmental sequence; and marijuana is the bridge in the sequence between the licit and the other illicit drugs.