research paper about drug addiction

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• April 01, 2024 | VOL. 181, NO. 4 CURRENT ISSUE pp.255-346
• March 01, 2024 | VOL. 181, NO. 3 pp.171-254
• February 01, 2024 | VOL. 181, NO. 2 pp.83-170
• January 01, 2024 | VOL. 181, NO. 1 pp.1-82

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Substance Use Disorders and Addiction: Mechanisms, Trends, and Treatment Implications

• Ned H. Kalin , M.D.

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The numbers for substance use disorders are large, and we need to pay attention to them. Data from the 2018 National Survey on Drug Use and Health ( 1 ) suggest that, over the preceding year, 20.3 million people age 12 or older had substance use disorders, and 14.8 million of these cases were attributed to alcohol. When considering other substances, the report estimated that 4.4 million individuals had a marijuana use disorder and that 2 million people suffered from an opiate use disorder. It is well known that stress is associated with an increase in the use of alcohol and other substances, and this is particularly relevant today in relation to the chronic uncertainty and distress associated with the COVID-19 pandemic along with the traumatic effects of racism and social injustice. In part related to stress, substance use disorders are highly comorbid with other psychiatric illnesses: 9.2 million adults were estimated to have a 1-year prevalence of both a mental illness and at least one substance use disorder. Although they may not necessarily meet criteria for a substance use disorder, it is well known that psychiatric patients have increased usage of alcohol, cigarettes, and other illicit substances. As an example, the survey estimated that over the preceding month, 37.2% of individuals with serious mental illnesses were cigarette smokers, compared with 16.3% of individuals without mental illnesses. Substance use frequently accompanies suicide and suicide attempts, and substance use disorders are associated with a long-term increased risk of suicide.

Addiction is the key process that underlies substance use disorders, and research using animal models and humans has revealed important insights into the neural circuits and molecules that mediate addiction. More specifically, research has shed light onto mechanisms underlying the critical components of addiction and relapse: reinforcement and reward, tolerance, withdrawal, negative affect, craving, and stress sensitization. In addition, clinical research has been instrumental in developing an evidence base for the use of pharmacological agents in the treatment of substance use disorders, which, in combination with psychosocial approaches, can provide effective treatments. However, despite the existence of therapeutic tools, relapse is common, and substance use disorders remain grossly undertreated. For example, whether at an inpatient hospital treatment facility or at a drug or alcohol rehabilitation program, it was estimated that only 11% of individuals needing treatment for substance use received appropriate care in 2018. Additionally, it is worth emphasizing that current practice frequently does not effectively integrate dual diagnosis treatment approaches, which is important because psychiatric and substance use disorders are highly comorbid. The barriers to receiving treatment are numerous and directly interact with existing health care inequities. It is imperative that as a field we overcome the obstacles to treatment, including the lack of resources at the individual level, a dearth of trained providers and appropriate treatment facilities, racial biases, and the marked stigmatization that is focused on individuals with addictions.

This issue of the Journal is focused on understanding factors contributing to substance use disorders and their comorbidity with psychiatric disorders, the effects of prenatal alcohol use on preadolescents, and brain mechanisms that are associated with addiction and relapse. An important theme that emerges from this issue is the necessity for understanding maladaptive substance use and its treatment in relation to health care inequities. This highlights the imperative to focus resources and treatment efforts on underprivileged and marginalized populations. The centerpiece of this issue is an overview on addiction written by Dr. George Koob, the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and coauthors Drs. Patricia Powell (NIAAA deputy director) and Aaron White ( 2 ). This outstanding article will serve as a foundational knowledge base for those interested in understanding the complex factors that mediate drug addiction. Of particular interest to the practice of psychiatry is the emphasis on the negative affect state “hyperkatifeia” as a major driver of addictive behavior and relapse. This places the dysphoria and psychological distress that are associated with prolonged withdrawal at the heart of treatment and underscores the importance of treating not only maladaptive drug-related behaviors but also the prolonged dysphoria and negative affect associated with addiction. It also speaks to why it is crucial to concurrently treat psychiatric comorbidities that commonly accompany substance use disorders.

Insights Into Mechanisms Related to Cocaine Addiction Using a Novel Imaging Method for Dopamine Neurons

Cassidy et al. ( 3 ) introduce a relatively new imaging technique that allows for an estimation of dopamine integrity and function in the substantia nigra, the site of origin of dopamine neurons that project to the striatum. Capitalizing on the high levels of neuromelanin that are found in substantia nigra dopamine neurons and the interaction between neuromelanin and intracellular iron, this MRI technique, termed neuromelanin-sensitive MRI (NM-MRI), shows promise in studying the involvement of substantia nigra dopamine neurons in neurodegenerative diseases and psychiatric illnesses. The authors used this technique to assess dopamine function in active cocaine users with the aim of exploring the hypothesis that cocaine use disorder is associated with blunted presynaptic striatal dopamine function that would be reflected in decreased “integrity” of the substantia nigra dopamine system. Surprisingly, NM-MRI revealed evidence for increased dopamine in the substantia nigra of individuals using cocaine. The authors suggest that this finding, in conjunction with prior work suggesting a blunted dopamine response, points to the possibility that cocaine use is associated with an altered intracellular distribution of dopamine. Specifically, the idea is that dopamine is shifted from being concentrated in releasable, functional vesicles at the synapse to a nonreleasable cytosolic pool. In addition to providing an intriguing alternative hypothesis underlying the cocaine-related alterations observed in substantia nigra dopamine function, this article highlights an innovative imaging method that can be used in further investigations involving the role of substantia nigra dopamine systems in neuropsychiatric disorders. Dr. Charles Bradberry, chief of the Preclinical Pharmacology Section at the National Institute on Drug Abuse, contributes an editorial that further explains the use of NM-MRI and discusses the theoretical implications of these unexpected findings in relation to cocaine use ( 4 ).

Treatment Implications of Understanding Brain Function During Early Abstinence in Patients With Alcohol Use Disorder

Developing a better understanding of the neural processes that are associated with substance use disorders is critical for conceptualizing improved treatment approaches. Blaine et al. ( 5 ) present neuroimaging data collected during early abstinence in patients with alcohol use disorder and link these data to relapses occurring during treatment. Of note, the findings from this study dovetail with the neural circuit schema Koob et al. provide in this issue’s overview on addiction ( 2 ). The first study in the Blaine et al. article uses 44 patients and 43 control subjects to demonstrate that patients with alcohol use disorder have a blunted neural response to the presentation of stress- and alcohol-related cues. This blunting was observed mainly in the ventromedial prefrontal cortex, a key prefrontal regulatory region, as well as in subcortical regions associated with reward processing, specifically the ventral striatum. Importantly, this finding was replicated in a second study in which 69 patients were studied in relation to their length of abstinence prior to treatment and treatment outcomes. The results demonstrated that individuals with the shortest abstinence times had greater alterations in neural responses to stress and alcohol cues. The authors also found that an individual’s length of abstinence prior to treatment, independent of the number of days of abstinence, was a predictor of relapse and that the magnitude of an individual’s neural alterations predicted the amount of heavy drinking occurring early in treatment. Although relapse is an all too common outcome in patients with substance use disorders, this study highlights an approach that has the potential to refine and develop new treatments that are based on addiction- and abstinence-related brain changes. In her thoughtful editorial, Dr. Edith Sullivan from Stanford University comments on the details of the study, the value of studying patients during early abstinence, and the implications of these findings for new treatment development ( 6 ).

Relatively Low Amounts of Alcohol Intake During Pregnancy Are Associated With Subtle Neurodevelopmental Effects in Preadolescent Offspring

Excessive substance use not only affects the user and their immediate family but also has transgenerational effects that can be mediated in utero. Lees et al. ( 7 ) present data suggesting that even the consumption of relatively low amounts of alcohol by expectant mothers can affect brain development, cognition, and emotion in their offspring. The researchers used data from the Adolescent Brain Cognitive Development Study, a large national community-based study, which allowed them to assess brain structure and function as well as behavioral, cognitive, and psychological outcomes in 9,719 preadolescents. The mothers of 2,518 of the subjects in this study reported some alcohol use during pregnancy, albeit at relatively low levels (0 to 80 drinks throughout pregnancy). Interestingly, and opposite of that expected in relation to data from individuals with fetal alcohol spectrum disorders, increases in brain volume and surface area were found in offspring of mothers who consumed the relatively low amounts of alcohol. Notably, any prenatal alcohol exposure was associated with small but significant increases in psychological problems that included increases in separation anxiety disorder and oppositional defiant disorder. Additionally, a dose-response effect was found for internalizing psychopathology, somatic complaints, and attentional deficits. While subtle, these findings point to neurodevelopmental alterations that may be mediated by even small amounts of prenatal alcohol consumption. Drs. Clare McCormack and Catherine Monk from Columbia University contribute an editorial that provides an in-depth assessment of these findings in relation to other studies, including those assessing severe deficits in individuals with fetal alcohol syndrome ( 8 ). McCormack and Monk emphasize that the behavioral and psychological effects reported in the Lees et al. article would not be clinically meaningful. However, it is feasible that the influences of these low amounts of alcohol could interact with other predisposing factors that might lead to more substantial negative outcomes.

Increased Comorbidity Between Substance Use and Psychiatric Disorders in Sexual Identity Minorities

There is no question that victims of societal marginalization experience disproportionate adversity and stress. Evans-Polce et al. ( 9 ) focus on this concern in relation to individuals who identify as sexual minorities by comparing their incidence of comorbid substance use and psychiatric disorders with that of individuals who identify as heterosexual. By using 2012−2013 data from 36,309 participants in the National Epidemiologic Study on Alcohol and Related Conditions–III, the authors examine the incidence of comorbid alcohol and tobacco use disorders with anxiety, mood disorders, and posttraumatic stress disorder (PTSD). The findings demonstrate increased incidences of substance use and psychiatric disorders in individuals who identified as bisexual or as gay or lesbian compared with those who identified as heterosexual. For example, a fourfold increase in the prevalence of PTSD was found in bisexual individuals compared with heterosexual individuals. In addition, the authors found an increased prevalence of substance use and psychiatric comorbidities in individuals who identified as bisexual and as gay or lesbian compared with individuals who identified as heterosexual. This was most prominent in women who identified as bisexual. For example, of the bisexual women who had an alcohol use disorder, 60.5% also had a psychiatric comorbidity, compared with 44.6% of heterosexual women. Additionally, the amount of reported sexual orientation discrimination and number of lifetime stressful events were associated with a greater likelihood of having comorbid substance use and psychiatric disorders. These findings are important but not surprising, as sexual minority individuals have a history of increased early-life trauma and throughout their lives may experience the painful and unwarranted consequences of bias and denigration. Nonetheless, these findings underscore the strong negative societal impacts experienced by minority groups and should sensitize providers to the additional needs of these individuals.

Trends in Nicotine Use and Dependence From 2001–2002 to 2012–2013

Although considerable efforts over earlier years have curbed the use of tobacco and nicotine, the use of these substances continues to be a significant public health problem. As noted above, individuals with psychiatric disorders are particularly vulnerable. Grant et al. ( 10 ) use data from the National Epidemiologic Survey on Alcohol and Related Conditions collected from a very large cohort to characterize trends in nicotine use and dependence over time. Results from their analysis support the so-called hardening hypothesis, which posits that although intervention-related reductions in nicotine use may have occurred over time, the impact of these interventions is less potent in individuals with more severe addictive behavior (i.e., nicotine dependence). When adjusted for sociodemographic factors, the results demonstrated a small but significant increase in nicotine use from 2001–2002 to 2012–2013. However, a much greater increase in nicotine dependence (46.1% to 52%) was observed over this time frame in individuals who had used nicotine during the preceding 12 months. The increases in nicotine use and dependence were associated with factors related to socioeconomic status, such as lower income and lower educational attainment. The authors interpret these findings as evidence for the hardening hypothesis, suggesting that despite the impression that nicotine use has plateaued, there is a growing number of highly dependent nicotine users who would benefit from nicotine dependence intervention programs. Dr. Kathleen Brady, from the Medical University of South Carolina, provides an editorial ( 11 ) that reviews the consequences of tobacco use and the history of the public measures that were initially taken to combat its use. Importantly, her editorial emphasizes the need to address health care inequity issues that affect individuals of lower socioeconomic status by devoting resources to develop and deploy effective smoking cessation interventions for at-risk and underresourced populations.

Conclusions

Maladaptive substance use and substance use disorders are highly prevalent and are among the most significant public health problems. Substance use is commonly comorbid with psychiatric disorders, and treatment efforts need to concurrently address both. The papers in this issue highlight new findings that are directly relevant to understanding, treating, and developing policies to better serve those afflicted with addictions. While treatments exist, the need for more effective treatments is clear, especially those focused on decreasing relapse rates. The negative affective state, hyperkatifeia, that accompanies longer-term abstinence is an important treatment target that should be emphasized in current practice as well as in new treatment development. In addition to developing a better understanding of the neurobiology of addictions and abstinence, it is necessary to ensure that there is equitable access to currently available treatments and treatment programs. Additional resources must be allocated to this cause. This depends on the recognition that health care inequities and societal barriers are major contributors to the continued high prevalence of substance use disorders, the individual suffering they inflict, and the huge toll that they incur at a societal level.

Disclosures of Editors’ financial relationships appear in the April 2020 issue of the Journal .

1 US Department of Health and Human Services: Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: National Survey on Drug Use and Health 2018. Rockville, Md, SAMHSA, 2019 ( https://www.samhsa.gov/data/nsduh/reports-detailed-tables-2018-NSDUH ) Google Scholar

2 Koob GF, Powell P, White A : Addiction as a coping response: hyperkatifeia, deaths of despair, and COVID-19 . Am J Psychiatry 2020 ; 177:1031–1037 Link ,  Google Scholar

3 Cassidy CM, Carpenter KM, Konova AB, et al. : Evidence for dopamine abnormalities in the substantia nigra in cocaine addiction revealed by neuromelanin-sensitive MRI . Am J Psychiatry 2020 ; 177:1038–1047 Link ,  Google Scholar

4 Bradberry CW : Neuromelanin MRI: dark substance shines a light on dopamine dysfunction and cocaine use (editorial). Am J Psychiatry 2020 ; 177:1019–1021 Abstract ,  Google Scholar

5 Blaine SK, Wemm S, Fogelman N, et al. : Association of prefrontal-striatal functional pathology with alcohol abstinence days at treatment initiation and heavy drinking after treatment initiation . Am J Psychiatry 2020 ; 177:1048–1059 Abstract ,  Google Scholar

6 Sullivan EV : Why timing matters in alcohol use disorder recovery (editorial). Am J Psychiatry 2020 ; 177:1022–1024 Abstract ,  Google Scholar

7 Lees B, Mewton L, Jacobus J, et al. : Association of prenatal alcohol exposure with psychological, behavioral, and neurodevelopmental outcomes in children from the Adolescent Brain Cognitive Development Study . Am J Psychiatry 2020 ; 177:1060–1072 Link ,  Google Scholar

8 McCormack C, Monk C : Considering prenatal alcohol exposure in a developmental origins of health and disease framework (editorial). Am J Psychiatry 2020 ; 177:1025–1028 Abstract ,  Google Scholar

9 Evans-Polce RJ, Kcomt L, Veliz PT, et al. : Alcohol, tobacco, and comorbid psychiatric disorders and associations with sexual identity and stress-related correlates . Am J Psychiatry 2020 ; 177:1073–1081 Abstract ,  Google Scholar

10 Grant BF, Shmulewitz D, Compton WM : Nicotine use and DSM-IV nicotine dependence in the United States, 2001–2002 and 2012–2013 . Am J Psychiatry 2020 ; 177:1082–1090 Link ,  Google Scholar

11 Brady KT : Social determinants of health and smoking cessation: a challenge (editorial). Am J Psychiatry 2020 ; 177:1029–1030 Abstract ,  Google Scholar

• Cited by None

• Substance-Related and Addictive Disorders
• Addiction Psychiatry
• Transgender (LGBT) Issues

Pathways of Addiction: Opportunities in Drug Abuse Research (1996)

Chapter: 1. introduction, 1 introduction.

Drug abuse research became a subject of sustained scientific interest by a small number of investigators in the late nineteenth and early twentieth centuries. Despite their creative efforts to understand drug abuse in terms of general advances in biomedical science, the medical literature of the early twentieth century is littered with now-discarded theories of drug dependence, such as autointoxication and antibody toxins, and with failed approaches to treatment. Eventually, escalating social concern about the use of addictive drugs and the emergence of the biobehavioral sciences during the post-World War II era led to a substantial investment in drug abuse research by the federal government (see Appendix B ). That investment has yielded substantial advances in scientific understanding about all facets of drug abuse and has also resulted in important discoveries in basic neurobiology, psychiatry, pain research, and other related fields of inquiry. In light of how little was understood about drug abuse such a short time ago, the advances of the past 25 years represent a remarkable scientific accomplishment. Yet there remains a disconnect between what is now known scientifically about drug abuse and addiction, the public's understanding of and beliefs about abuse and addiction, and the extent to which what is known is actually applied in public health settings.

During its brief history, drug abuse research has been supported mainly by the federal government, with occasional investments by major private foundations. At the federal level, the lead agency for drug abuse research is the National Institute on Drug Abuse (NIDA), which supports

85 percent of the world's research on drug abuse and addiction. Other sponsoring agencies include the National Institute of Mental Health (NIMH), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Substance Abuse and Mental Health Services Administration (SAMHSA), all in the Department of Health and Human Services; as well as the Office of Justice Programs (OJP) in the Department of Justice. Throughout the federal government, the FY 1995 investment in drug abuse research and development was $542.2 million, which represents 4 percent of the $13.3 billion spent by the federal government on drug abuse (ONDCP, 1996). By comparison, $8.5 billion (64 percent of the FY 1995 budget) was spent on criminal justice programs, 1 $2.7 billion (20 percent) on treatment of drug abuse, and $1.6 billion (12 percent) on prevention efforts.

In 1992, the General Accounting Office (GAO) released a report Drug Abuse Research: Federal Funding and Future Needs, which recommended that Congress review the place of research in drug control policy and its modest 4 percent share of the drug control budget. The report questioned whether the federal commitment to research was adequate, given the enormity of research needs (GAO, 1992), and whether adequate evaluation research was being conducted to determine the efficacy of various drug control programs. In FY 1995, drug abuse research was still little more than 4 percent of the entire drug control budget.

In January 1995, NIDA requested the Institute of Medicine (IOM) to examine accomplishments in drug abuse research and provide guidance for future research opportunities. This report by the IOM Committee on Opportunities in Drug Abuse Research focuses broadly on opportunities and priorities for future scientific research in drug abuse. After a brief review of major accomplishments in drug abuse research, the remainder of this chapter discusses the vocabulary and basic concepts used in the report, highlights the importance of the nation's investment in drug abuse research, and explores some of the factors that could improve the yield from that investment.

MAJOR ACHIEVEMENTS IN DRUG ABUSE RESEARCH

There have been remarkable achievements in drug abuse research over the past quarter of a century as researchers have learned more about the biological and psychosocial aspects of drug use, abuse, and dependence. Behavioral researchers have developed animal and human mod-

els of drug-seeking behavior, that have, for example, yielded objective measures of initiation and repeated administration of drugs, thereby providing the scientific foundation for assessments of "abuse liability" (i.e., the potential for abuse) of specific drugs (see Chapter 2 ). This information is an essential predicate for informed regulatory decisions under the Food, Drug and Cosmetic Act and the Controlled Substances Act. Taking advantage of technological advances in molecular biology, neuroscientists have identified receptors or receptor types in the brain for opioids, cocaine, benzodiazepines, and marijuana and have described the ways in which the brain adapts to, and changes after, exposure to drugs. Those alterations, which may persist long after the termination of drug use, appear to involve changes in gene expression. They may explain enhanced susceptibility to future drug exposure, thereby shedding light on the enigmas of withdrawal and relapse at the molecular level (see Chapter 3 ). Epidemiologists have designed and implemented epidemiological surveillance systems that enable policymakers to monitor patterns of drug use in the population ( Chapter 4 ) and that enable researchers to investigate the causes and consequences of drug use and abuse (Chapters 5 and 7 , respectively). Paralleling broader trends in health promotion and disease prevention in the past 20 years, the field of drug abuse prevention has made significant progress in evaluating the effectiveness of interventions implemented in a range of settings including communities, schools, and families (see Chapter 6 ).

Marked gains have also been made in treatment research, including improvements in diagnostic criteria; development of a wide range of treatment interventions and sophisticated methods to assess treatment outcome; and development and approval of Leo-alpha-acetylmethadol (LAAM), a medication for the treatment of opioid dependence. Pharmacological and psychosocial treatments, alone or in combination, have been shown to be effective for drug dependencies, and treatment has been shown to reduce drug use, HIV (human immunodeficiency virus) infection rates, health care costs, and criminal activity (see Chapter 8 ).

Drug abuse researchers have also made major contributions to knowledge in adjacent fields of scientific inquiry. For example, NIDA-sponsored research was the driving force in the identification of morphine-like substances that serve as neurotransmitters in specific neurons located throughout the central and peripheral nervous systems (Orson et al., 1994). Identification of these substances represents a dramatic breakthrough in understanding the mechanisms of pain, reinforcement, and stress. Additionally, the discovery of opioid peptides as neurotransmitters played a key role in the identification of numerous other peptide neurotransmitters (Cooper et al., 1991; Goldstein, 1994; Hokfelt et al., 1995). These discoveries have broadened the understanding of brain function and now

form the basis of many current strategies in the design of new drug treatments for neuropsychiatric disorders. Additionally, drug abuse research has contributed to the development of brain imaging techniques.

Drug abuse research has also provided a major impetus for neuropharmacological research in psychiatry since the late 1950s, when it was discovered that LSD (lysergic acid diethylamide; a hallucinogen that produces psychotic symptoms) affected the brain's serotonin systems (Cooper et al., 1991). That seminal discovery stimulated decades of research in the neuropharmacological basis of behavior and psychiatric disorders. The impact on antipsychotic research has been dramatic. In addition, stimulants (e.g., cocaine and amphetamine) were found to produce a state of paranoid psychosis, resembling schizophrenia, in some people. The actions of stimulants on the brain's dopamine pathways continue to inform researchers of the potential role of those pathways in the treatment, and perhaps the pathophysiology, of schizophrenia (Kahn and Davis, 1995). Drug abuse research also has had an impact on antidepressant research (e.g., the actions of drugs of abuse on the brain's serotonin systems have provided useful models with which to investigate the role of those systems in depression and mania). Depression is a risk factor for treatment failure in smoking cessation (Glassman et al., 1993) and depression-like symptoms are dominant during cocaine withdrawal (DiGregorio, 1990). Consequently, treatment of depression in nicotine and cocaine-dependent individuals has been an area of interest for drug abuse research.

Some drugs that are abused, most notably the opioid analgesics, have essential medical uses. Since its founding, NIDA has been the major supporter of research into brain mechanisms of pain and analgesia, analgesic tolerance, and analgesic pharmacology. The resulting discoveries have led to an understanding of which brain circuits are required to generate pain and pain relief (Wall and Melzack, 1994), have revolutionized the treatment of postoperative and cancer pain (Folly and Interesse, 1986; Car et al., 1992; Jacob et al., 1994), and have led to improved treatments for many other conditions that result in chronic pain (see Chapter 3 ).

VOCABULARY OF DRUG ABUSE

Ordinarily, scientific vocabulary evolves toward greater clarity and precision in response to new empirical discoveries and reconceptualizations. That creative process is evident within each of the disciplines of drug abuse research covered in various chapters of this report. Interestingly, however, the words describing the field as a whole, and connecting each chapter to the next, seem to defy the search for clarity and precision. Does "drug" include alcohol and tobacco? What is "abuse"? Are use and

abuse mutually exclusive categories? Are abuse and dependence mutually exclusive categories? Does use of illicit drugs per se amount to abuse? Does abuse include underage use of nicotine? Is addiction synonymous with dependence?

These ambiguities have persisted for decades because the vocabulary of drug abuse is inevitably influenced by peoples' attitudes and values. If the task were solely a scientific one, precise terminology would have emerged long before now. However, because the choice of words in this field always carries a nonscientific message, scientists themselves cannot always agree on a common vocabulary.

Consider the case of nicotine; from a pharmacological standpoint, nicotine is functionally similar to other psychoactive drugs. However, many researchers and policymakers choose to exclude nicotine from the category of drug. The same is true of alcohol; for example, other terms, such as ''chemical dependency" or "substance abuse," are often used as generic terms encompassing the abuse of nicotine and alcohol as well as abuse of illicit drugs. This semantic strategy is chosen to signify the difference in legal status among alcohol, nicotine, and illicit drugs. In recent years, however, a growing number of researchers have adopted a more inclusive use of the term drug. In the case of nicotine, this move tends to reflect a policy judgment that nicotine should be classified as a drug under the federal Food, Drug and Cosmetic Act.

In the committee's view, the term drug should be understood, in its generic sense, to encompass alcohol and nicotine as well as illicit drugs. It is very important for the general public to recognize that alcohol and nicotine constitute, by far, the nation's two largest drug problems, whether measured in terms of morbidity, mortality, or social cost. Abuse of and dependence on those drugs have serious individual and societal consequences. Continued separation of alcohol, nicotine, and illicit drugs in everyday speech is an impediment to public education, prevention, and therapeutic progress.

Although the committee uses the term drug, in its generic sense, to encompass alcohol and nicotine, the report focuses, at NIDA's request, on research opportunities relating to illicit drugs; research on alcohol and nicotine is discussed only when the scientific inquiries are intertwined. Because the report sometimes ranges more broadly than illicit drugs, however, the committee has adopted several semantic conventions to promote clarity and avoid redundancy. First, the term drug, unmodified, refers to all psychoactive drugs, including alcohol and nicotine. When reference is intended solely to illicit drugs such as heroin, cocaine, and other drugs regulated by the Controlled Substances Act, the committee says so explicitly. Occasionally, to ensure that the intended meaning is clear, the report refers to "illicit drugs and nicotine" or to "illicit drugs

and alcohol," as the case may be. Additionally, the words opiate and opioid are used interchangeably, although opiates are derivative of morphine and opioids are all compounds with morphine-like properties (they may be synthetic and not resemble morphine chemically).

The report employs the standard three-stage conceptualization of drug-taking behavior that applies to all psychoactive drugs, whether licit or illicit. Each stage—use, abuse, dependence—is marked by higher levels of use and increasingly serious consequences. Thus, when the report refers to the "use" of drugs, the term is usually employed in a narrow sense to distinguish it from intensified patterns of use. Conversely, the term "abuse" is used to refer to any harmful use, irrespective of whether the behavior constitutes a "disorder'' in the DSM-IV diagnostic nomenclature (see Appendix C ). When the intent is to emphasize the clinical categories of abuse and dependence, that is made clear.

The committee also draws a clear distinction between patterns of drug-taking behavior, however described, and the harmful consequences of that behavior for the individual and for society. These consequences include the direct, acute effects of drug taking such as a drug-induced toxic psychosis or impaired driving, the effects of repeated drug taking on the user's health and social functioning, and the effects of drug-seeking behavior on the individual and society. It bears emphasizing that adverse consequences can be associated with patterns of drug use that do not amount to abuse or dependence in a clinical sense, although the focus of this report and the committee's recommendations is on the more intensified patterns of use (i.e., abuse and dependence) since they cause the majority of the serious consequences.

DEFINITIONS AND BASIC CONCEPTS

Drug use may be defined as occasional use strongly influenced by environmental factors. Drug use is not a medical disorder and is not listed as such in either of the two most important diagnostic manuals—the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV; APA, 1994); or the International Classification of Diseases (ICD-10; WHO, 1992). (See Appendix C for DSM-IV and ICD-10 diagnostic criteria.) Drug use implies intake for nonmedical purposes; it may or may not be accompanied by clinically significant impairment or distress on a given occasion.

Drug abuse is characterized in DSM-IV as including regular, sporadic, or intensive use of higher doses of drugs leading to social, legal, or interpersonal problems. Like DSM-IV, ICD-10 identifies a nondependent but problematic syndrome of drug use but calls it "harmful use" instead

of abuse. This syndrome is defined by ICD-10 as use resulting in actual physical or psychological harm.

Drug dependence (or addiction) is characterized in both DSM-IV and ICD-10 as drug-seeking behavior involving compulsive use of high doses of one or more drugs, either licit or illicit, for no clear medical indication, resulting in substantial impairment of health and social functioning. Dependence is usually accompanied by tolerance and withdrawal 2 and (like abuse) is generally associated with a wide range of social, legal, psychiatric, and medical problems. Unlike patients with chronic pain or persistent anxiety, who take medication over long periods of time to obtain relief from a specific medical or psychiatric disorder (often with resulting tolerance and withdrawal), persons with dependence seek out the drug and take it compulsively for nonmedical effects.

Tolerance occurs when certain medications are taken repeatedly. With opiates for example, it can be detected after only a few days of use for medical purposes such as the treatment of pain. If the patient suddenly stops taking the drug, a withdrawal syndrome may ensue. Physicians often confuse this phenomenon, referred to as physical dependence, with true addiction. That can lead to withholding adequate medication for the treatment of pain because of the very small risk that addiction with drug-seeking behavior may occur.

As a consequence of its compulsive nature involving the loss of control over drug use, dependence (or addiction) is typically a chronically relapsing disorder (IOM, 1990, 1995; Meter, 1996; O'Brien and McLennan, 1996; McLennan et al., in press). Although individuals with drug dependence can often complete detoxification and achieve temporary abstinence, they find it very difficult to sustain that condition and avoid relapse over time. Most persons who achieve sustained remission do so only after a number of cycles of detoxification and relapse (Dally and Marital, 1992). Relapse is caused by a constellation of biological, family, social, psychological, and treatment factors and is demonstrated by the fact that at least half of former cigarette smokers quit three or more times before they successfully achieve stable remission from nicotine addiction (Schilling, 1992). Similarly, within one year of treatment, relapse occurs in 30-50 percent of those treated for drug dependence, although the level

of drug use may not be as high as before treatment (Daley and Marlatt, 1992; McLellan et al., in press). Unlike those who use (or even abuse) drugs, individuals with addiction have a substantially diminished ability to control drug consumption, a factor that contributes to their tendency to relapse.

Another terminological issue arises in relation to the terms addiction and dependence. For some scientists, the proper terms for compulsive drug seeking is addiction, rather than dependence. In their view, addiction more clearly signifies the essential behavioral differences between compulsive use of drugs for their nonmedical effects and the syndrome of "physical dependence" that can develop in connection with repeated medical use. In response, many scientists argue that dependence has been defined in both ICD-10 and DSM-IV to encompass the behavioral features of the disorder and has become the generally accepted term in the diagnostic nomenclature. Moreover, some scientists object to the term addiction on the grounds that it is associated with stigmatizing social images and that a less pejorative term would help to promote public understanding of the medical nature of the condition. The committee has not attempted to resolve this controversy. For purposes of this report, the terms addiction and dependence are used interchangeably.

An inherent aspect of drug addiction is the propensity to relapse. Relapse should not be viewed as treatment failure; addiction itself should be considered a brain disease similar to other chronic and relapsing conditions such as hypertension, diabetes, and asthma (IOM, 1995; O'Brien and McLellan, 1996). In the latter, significant improvement is considered successful treatment even though complete remission or cure is not achieved. In the area of drug abuse, however, many individuals (both lay and professional) expect treatment programs to perform like vaccine programs, where one episode of treatment offers lifetime immunity. Not surprisingly, because of that expectation, people are inevitably disappointed in the relatively high relapse rates associated with most treatments. If, however, addiction is understood as a chronically relapsing brain disease, then—for any one treatment episode—evidence of treatment efficacy would include reduced consumption, longer abstention periods, reduced psychiatric symptoms, improved health, continued employment, and improved family relations. Most of those results are demonstrated regularly in treatment outcome studies.

The idea that drug addiction is a chronic relapsing condition, requiring long-term attention, has been resisted in the United States and in some other countries (Brewley, 1995). Many lay people view drug addiction as a character defect requiring punishment or incarceration. Proponents of the medical model, however, point to the fact that addiction is a distinct morbid process that has characteristics and identifiable signs and

symptoms that affect organ systems (Miller, 1991; Meter, 1996). Characterization of addiction as a brain disease is bolstered by evidence of genetic vulnerability to addiction, physical correlates of its clinical course, physiological changes as a result of repeated drug use, and fundamental changes in brain chemistry as evidenced by brain imaging (Volkow et al., 1993). This is not to say that behavioral, social, and environmental factors are immaterial—they all play a role in onset and outcome, just as they do in heart disease, kidney disease, tuberculosis, or other infectious diseases. Thus, the contemporary understanding of disease fully incorporates the voluntary behavioral elements that lead many people to be skeptical about the applicability of the medical model to drug addiction. In any case, the committee embraces the disease concept, not because it is indisputable but because this paradigm facilitates scientific investigation in many important areas of knowledge, without inhibiting or distorting scientific inquiry in other parts of the field.

IMPORTANCE OF DRUG ABUSE RESEARCH

The widespread prevalence of illicit drug use in the United States is well documented in surveys of households, students, and prison and jail inmates ( Chapter 4 ). Based on the National Household Survey on Drug Abuse (NHSDA), an annual survey presently sponsored by SAMHSA, it was estimated that in 1994, 12.6 million people had used illicit drugs (primarily marijuana) in the past month (SAMHSA, 1995). That figure represents 6 percent of the population 12 years of age or older. 3 The number of heavy drug users, using drugs at least once a week, is difficult to determine. It has been estimated that in 1993 there were 2.1 million heavy cocaine users and 444,000-600,000 heavy heroin users (Rhodes et al., 1995). This population represents a significant burden to society, not only in terms of federal expenditures but also in terms of costs related to the multiple consequences of drug abuse (see Chapter 7 ).

The ultimate aim of the nation's investment in drug abuse research is to enable society to take effective measures to prevent drug use, abuse, and dependence, and thereby reduce its adverse individual and social consequences and associated costs. The adverse consequences of drug abuse are numerous and profound and affect the individual's physical health and psychological and social functioning. Consequences of drug abuse include increased rates of HIV infection and tuberculosis (TB); education and vocational impairment; developmental harms to children of

drug-using parents associated with fetal exposure or maltreatment and neglect; and increased violence (see Chapter 7 ). It now appears that injection drug use is the leading risk factor for new HIV infection in the United States (Holmberg, 1996). Most (80 percent) HIV-infected heterosexual men and women who do not use injection drugs have been infected through sexual contact with HIV-infected injection drug users (IUDs). Thus, it is not surprising that the geographic distribution of heterosexual AIDS cases has been essentially the same as the distribution of male injection drug users' AIDS cases (Holmberg, 1996) Further, the IUDs-associated HIV epidemic in men is reflected in the heterosexual epidemic in women, which is reflected in HIV infection in children (CDC, 1995). Nearly all children who acquire HIV infection do so prenatal (see Chapter 7 ).

The extent of the impact of drug use and abuse on society is evidenced by its enormous economic burden. In 1990, illicit drug abuse is estimated to have cost the United States more than $66 billion. When the cost of illicit drug use and abuse is tallied with that of alcohol and nicotine ( Table 1.1 ), the collective cost of drug use and abuse exceeds the estimated annual $117 billion cost of heart disease and the estimated annual $104 billion cost of cancer (AHA, 1992; ACS, 1993; D. Rice, University of California at San Francisco, personal communication, 1995).

As noted above, the federal government accounts for a large segment of the societal expenditure on illicit drug abuse control—spending more than $13.3 billion in FY 1995 (ONDCP, 1996). About two-thirds was devoted to interdiction, intelligence, incarceration, and other law enforcement activities. Research, however, accounts for only 4 percent of federal outlays, a percentage that has remained virtually unchanged since 1981 (ONDCP, 1996) ( Figure 1.1 ). Given the social costs of illicit drug abuse and the enormity of the federal investment in prevention and control, research into the causes, consequences, treatment, and prevention of drug abuse should have a higher priority. Enhanced support for drug abuse research would be a socially sound investment, because scientific research can be expected to generate new and improved treatments, as well as prevention and control strategies that can help reduce the enormous social burden associated with drug abuse.

THE CONTEXT OF DRUG ABUSE RESEARCH

In the chapters that follow, the committee identifies research initiatives that seem most promising and most likely to lead to successful efforts to reduce drug abuse and its associated social costs. Although the yield from these initiatives will depend largely on the creativity and skill of scientists, the many contextual factors that will also have a major bear-

TABLE 1.1 Estimated Economic Costs (million dollars) of Drug Abuse, 1990

FIGURE 1.1 Federal drug control budget trends (1981-1995). NOTE: Figures are in current dollars. SOURCE: ONDCP (1996).

ing on the payoff from scientific inquiry cannot be ignored. The committee has identified six major factors that, if successfully addressed, could optimize the gains made in each area of drug abuse research: stable funding; use of a comprehensive public health framework; wider acceptance of a medical model of drug dependence; better translation of research findings into practice; raising the status of drug abuse research; and facilitating interdisciplinary research.

Stable Funding

A stable level of funding in any area of biomedical research is needed to sustain and build on research accomplishments, to retain a cadre of experts in a field, and to attract young investigators. Drug abuse research, in comparison with many other research venues, has not enjoyed consistent federal support (IOM, 1990, 1995; see also Appendix B ). The field has suffered from difficulties in recruiting and retaining young researchers and clinicians and in maintaining a stable research infrastructure (IOM, 1995). Society's capacity to contain and manage drug abuse

depends upon a stable, long-term investment in research. The vicissitudes in federal research funding often reflect changing currents in public opinion toward drugs and drug users ( Appendix B ). However, drug abuse will not disappear; it is an endemic social and public health problem. The nation must commit itself to a sustained effort. The social investment in research is an investment in "human capital" that must be sustained over the long term in order to reap the expected gains. An investment in this field is squandered if researchers who have been recruited and trained in drug abuse research are drawn to other fields because of uncertainty about the stability of future funding.

Adoption of a Comprehensive Public Health Framework

The social impact of drug abuse research can be enhanced significantly by conceptualizing goals and priorities within a comprehensive public health framework (Goldstein, 1994). All too often, public discourse about drug abuse is characterized by such unnecessary and fruitless disputes as whether drug abuse should be viewed as a social and moral problem or a health problem, whether the drug problem can best be solved by law enforcement or by medicine, whether priority should be placed on reducing supply or reducing demand, and so on. The truth is that these dichotomies oversimplify a brain disease impacted by a complex set of behaviors and a diverse array of potentially useful social responses. Forced choices of this nature also tend to inhibit or foreclose potentially useful research strategies. Confusion about social goals can lead to confusion about research priorities and can obscure the links between investigations viewing the subject through different lenses.

Some issues tend to recur. A prominent dispute centers on whether preventing drug use is important in itself or whether society should be more concerned with abuse or with the harmful consequences of use. The answer, of course, is that such a forced choice obscures, rather than clarifies, the issues. From a public health standpoint, drug use is a risk factor; the significance of use (whether of alcohol, nicotine, or illicit drugs) lies in the risk of harm associated with it (e.g., fires from smoking, impaired driving from alcohol or illicit drugs, or developmental setbacks) and in the risk that use will intensify, escalating to abuse or dependence. Those risks vary widely in relation to drug, user characteristics, social context, etc. Attention to the consequences of use and to the risk of escalation helps to set priorities (for research and policy) and provides a framework for assessing the impact of different interventions.

From a public policy standpoint, arguments about goals and priorities are fraught with controversy. From the standpoint of research strategy, however, the key lies in asking the right questions (e.g., What influ-

ences the pathways from use, to abuse, to dependence? What are the effects of needle exchange programs on illicit drug use and on HIV disease?) and in generating the knowledge required to facilitate informed policy debate. The main virtues of a comprehensive public health approach are that it helps to disentangle scientific questions from policy questions and that it encompasses all of the pertinent empirical questions, including the causes and consequences of use, abuse, and dependence, as well as the efficacy and cost of all types of interventions. In sum, the social payoff from drug abuse research can be enhanced substantially by integrating diverse strands of inquiry within a public health framework.

Acceptance of a Medical Model of Drug Dependence

Drug dependence is a chronic, relapsing brain disease that, like other diseases, can be evaluated and treated with the standard tools of medicine, including efforts in prevention, diagnosis, and treatment with medications and behavioral or psychosocial therapies. Unfortunately, the medical model of dependence is not universally accepted by health professionals and others in the treatment community; it is widely rejected within the law enforcement community and often by the public at large, which tends to view the complex and varied patterns of use, abuse, and dependence as an undifferentiated behavior rather than a medical problem.

Resistance to the medical model takes many forms. One is resistance to pharmacotherapies, such as methadone, that are seen as substituting licit drugs for illicit drugs without changing drug-taking behavior. Conversely, treatment approaches that adopt a rigid drug-free strategy preclude the use of medications for patients with other psychiatric disorders that are easily treated by pharmacotherapeutic approaches. On a subtler level, resistance to the use of pharmacotherapies is evidenced by the routine use of inadequate doses of methadone (D'Aunno and Vaughn, 1992). Finally, for others, all forms of drug abuse signify a failure of willpower or a moral weakness requiring punishment, incarceration, or moral education rather than treatment (Anglin and Hser, 1992).

Resistance to the medical model of drug dependence presents numerous barriers to research. Clinical researchers experience difficulty in soliciting participation by both treatment program administrators and patients, who are sometimes mistrustful of researchers' motives. If research involves a medication that is itself prone to abuse, there are additional regulatory requirements for drug scheduling, storage, and record keeping that act to discourage investigation (see Chapter 10 ; IOM, 1995). The ever-present threat of inappropriate intrusion by law enforcement agents has a chilling effect on treatment research (McDuff et al., 1993). All barri-

ers to inquiry, irrespective of whether they are legal or social in origin, raise the cost of research and discourage researchers from entering the field. Additionally, those barriers diminish the likelihood that a pharmaceutical company will invest in the development of antiaddiction medications (IOM, 1995). 4 Broader acceptance of the medical model of drug dependence would provide an incentive for researchers and clinicians to enter this field of research. Over time, a developing consensus in support of the medical model could facilitate common discourse, help to shape a shared research agenda within a public health framework, and diminish tensions between the research and treatment communities and the criminal justice system.

Better Translation of Research Findings into Practice and Policy

To benefit society, new research findings must be disseminated adequately to treatment providers, educators, law enforcement officials, and community leaders. In the case of prevention practices, it is often difficult for communities to change entrenched policies, particularly when combined with political imperatives for action to counteract drug abuse. In the case of treatment, technology transfer is impeded by the heterogeneity of providers and their marginalization at the outskirts of the medical community (see IOM, 1990, 1995; see also Chapter 8 ). Physicians and psychiatrists are seldom employed by specialized drug treatment facilities (approximately one-quarter employ medical doctors), and treatment is delivered by counselors whose training and supervision vary greatly and who have little access to and understanding of research results (Ball and Ross, 1991; Batten et al., 1993). These factors not only impede the transfer of research findings to the field but also impede communication from the field to the laboratory so that research designs can be modified in response to clinical realities (Pentz, 1994). Thus, there is a real need for bidirectional communication, from bench to bedside and back to the basic scientist (IOM, 1994).

The committee is aware, however, of recent technology transfer efforts in the field such as the Treatment Improvement Protocol Series, an initiative to establish guidelines for drug abuse treatment with an emphasis on incorporating research findings (SAMHSA, 1993), and the Prevention Enhancement Protocol System, a process implemented by the Center

for Substance Abuse Prevention in which scientists and practitioners develop protocols to identify and evaluate the strength of evidence on topics related to prevention interventions. Similar efforts will be invaluable for communicating and integrating research results to the treatment community.

Research frequently results in product development leading to changes in operations and an overall enhancement of the value of the enterprise. For example, in the pharmaceutical industry research often leads to the development of new medications or devices. In the public sector, however, research is often divorced from the implementation of findings and development. Research is often more basic than applied, and the fruits of research are not realized by the government, but by the private sector. Although that approach may be appropriate, it is unfortunately not always the most productive strategy for advancing research, knowledge, and product development. That is particularly true in the development of medications for opiate and cocaine addictions, where there is a great need for commitment from the private sector. However, many obstacles prevent active involvement of the pharmaceutical industry in this area of research and development (IOM, 1995).

A similar problem arises in relation to policymaking. Because debates about drug policy tend to be so highly polarized and politicized, research findings are often distorted, or selectively deployed, for rhetorical purposes. Researchers cannot prevent this practice, which is a common feature of political debate in a democratic society. However, researchers and their sponsors should not be indifferent to the disconnect between policy discourse and science. Researchers should establish and support institutional mechanisms for communicating an important message to policymakers and to the general public. Scientific research has produced a solid, and growing, body of knowledge about drug abuse and about the efficacy of various interventions that aim to prevent and control it. As long as drug abuse remains a poorly understood social problem, policy will be based mainly on wish and supposition; steps should be taken to educate policymakers about the scientific and technological advances in addiction research. Only then will it be possible for policymaking to support legislation that adequately funds new research and applies research findings. To some extent, persisting failure to reap the fruits of drug abuse research is attributable to the low visibility of the field—a problem to which the discussion now turns.

Raising the Status of Drug Abuse Research

Drug abuse research is often an undervalued area of inquiry, and most scientists and clinicians choose other disciplines in which to develop

their careers. Compared with other fields of research, investigators in drug abuse are often paid less, have less prestige among their peers, and must contend with the unique complexities of performing research in this area (e.g., regulations on controlled substances) (see IOM, 1995). The overall result is an insufficient number of basic and clinical researchers. IOM has recently begun a study, funded by the W. M. Keck Foundation of Los Angeles, to develop strategies to raise the status of drug abuse research. 5

Weak public support for this field of study is evident in unstable federal funding (see above), a lack of pharmaceutical industry investment in the development of antiaddiction medications (IOM, 1995), and inadequate funding for research training (IOM, 1995). NIDA's FY 1994 training budget, which is crucial to the flow of young researchers into the field, was about 2 percent of its extramural research budget, a percentage substantially lower than the overall National Institutes of Health (NIH) training budget, which averages 4.8 percent of its extramural research budget.

Beyond funding problems, investigators face a host of barriers to research: research subjects may pose health risks (e.g., TB, HIV/AIDS, and other infectious diseases), may be noncompliant, may deny their drug abuse problems, and may be involved in the criminal justice system. Even when research is successful and points to improvements in service delivery, the positive outcome may not be translated into practice or policy. For example, more than a year after the Food and Drug Administration's (FDA's) approval of levo-alpha-acetylmethadol (LAAM) as the first new medication for the treatment of opiate dependence in over 20 years, fewer than 1,000 patients nationwide actually had received the medication (IOM, 1995). More recently, scientific evidence regarding the beneficial effects of needle exchange programs (NRC, 1995) has received inadequate attention. Continuing indifference to scientific progress in drug abuse research inevitably depresses the status of the field, leading in turn to difficulties in recruiting new investigators.

Increasing Interdisciplinary Research

The breadth of expertise needed in drug abuse research spans many disciplines, including the behavioral sciences, pharmacology, medicine, and the neurosciences, and many fields of inquiry, including etiology, epidemiology, prevention, treatment, and health services research. Aspects of research relating to drug use tend to draw on developmental perspectives and to focus on general population samples in community settings, especially schools. Aspects of research relating to abuse and de-

pendence tend to be more clinical in nature, drawing on psychopathological perspectives. Additionally, a full account of any aspect of drug-taking behavior must also reflect an understanding of social context. The rich interplay between neuroscience and behavioral research and between basic and clinical research poses distinct challenges and opportunities.

Unfortunately, research tends to be fragmented within disciplinary boundaries. The difficulties in conducting successful interdisciplinary research are well known. Funds for research come from many separate agencies, such as the NIDA, NIMH, and SAMHSA. These agencies all have different programmatic emphases as they attempt to shape the direction of research in their respective fields. In times of funding constraints, agencies may be less inclined to fund projects at the periphery of their interests.

Additionally, NIH study sections, which rank grant proposals, are discipline specific, making it difficult for interdisciplinary proposals to ''qualify" (i.e., receive a high rank) for funding. Another problem is that the most advanced scientific literature tends to be compartmentalized within discipline or subject matter categories, making it difficult for scientists to see the whole field. The problem is exacerbated by what Tonry (1990) has called "fugitive literatures," studies carried out by private sector research firms or independent research agencies and available only in reports submitted to the sponsoring agency.

In light of lost opportunities for collaboration and interdisciplinary research, IOM (1995) previously recommended the creation and expansion of comprehensive drug abuse centers to coordinate all aspects of drug abuse research, training, and treatment. The field of drug abuse research presents a real opportunity to bridge the intellectual divide between the behavioral and neuroscience communities and to overcome the logistical impediments to interdisciplinary research.

INVESTING WISELY IN DRUG ABUSE RESEARCH

This report sets forth drug abuse research initiatives for the next decade based on a thorough assessment of what is now known and a calculated judgment about what initiatives are most likely to advance our knowledge in useful ways. This report is not meant to be a road map or tactical battle plan, but is best regarded as a strategic outline. Within each discipline of drug abuse research, the committee has highlighted priorities for future research. However, the committee did not make any attempt to prioritize recommendations across varied disciplines and fields of research. Prudent research planning must respond to newly emerging opportunities and needs while maintaining a steady commitment to the

achievement of long-term objectives. The ability to respond to new goals and needs may be the real challenge for the field of drug abuse research.

Drug abuse research is an important public investment. The ultimate aim of that investment is to reduce the enormous social costs attributable to drug abuse and dependence. Of course, drug abuse research must also compete for funding with research in other fields of public health, research in other scientific domains, and other pressing public needs. Recognizing the scarcity of resources, the committee has also considered ways in which the research effort can be harnessed most effectively to increase the yield per dollar invested. These include stable funding, use of a comprehensive public health framework, wider acceptance of a medical model of drug dependence, better translation of research findings into practice and policy, raising the status of drug abuse research, and facilitating interdisciplinary research.

The committee notes that there have been major accomplishments in drug abuse research over the past 25 years and commends NIDA for leading that effort. The committee is convinced that the field is on the threshold of significant advances, and that a sustained research effort will strengthen society's capacity to reduce drug abuse and to ameliorate its adverse consequences.

ORGANIZATION OF THE REPORT

This report sets forth a series of initiatives in drug abuse research. 6 Each chapter of the report covers a segment of the field, describes selected accomplishments, and highlights areas that seem ripe for future research. As noted, the committee has not prioritized areas for future research but, instead, has identified those areas that most warrant further exploration.

Chapter 2 describes behavioral models of drug abuse and demonstrates how the use of behavioral procedures has given researchers the ability to measure drug-taking objectively and to study the development, maintenance, and consequences of that behavior. Chapter 3 discusses drug abuse within the context of neurotransmission; it describes neurobiological advances in drug abuse research and provides the foundation for the current understanding of addiction as a brain disease. The epidemiological information systems designed to gather information on drug use in the United States are identified in Chapter 4 . The data collected from the systems provide an essential foundation for systematic study of

the etiology and consequences of drug abuse, which are addressed, respectively, in Chapters 5 and 7 . Chapter 6 addresses the efficacy of interventions designed to prevent drug abuse. The effectiveness of drug abuse treatment and the difficulties in treating special populations of drug users are discussed in Chapter 8 , while the impact of managed care on access, costs, utilization, and outcomes of treatment is addressed in Chapter 9 . Finally, Chapter 10 discusses the effects of drug control on public health and identifies areas for policy-relevant research.

Specific recommendations appear in each chapter. Although these recommendations reflect the committee's best judgment regarding priorities within the specific domains of research, the committee did not identify priorities or rank recommendations for the entire field of drug abuse research. Opportunities for advancing knowledge exist in all domains. It would be a mistake to invest too narrowly in a few fields of inquiry. At the present time, soundly conceived research should be pursued in all domains along the lines outlined in this report.

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• Published: 22 February 2021

Addiction as a brain disease revised: why it still matters, and the need for consilience

• Markus Heilig 1 ,
• James MacKillop   ORCID: orcid.org/0000-0003-4118-9500 2 , 3 ,
• Diana Martinez 4 ,
• Jürgen Rehm   ORCID: orcid.org/0000-0001-5665-0385 5 , 6 , 7 , 8 ,
• Lorenzo Leggio   ORCID: orcid.org/0000-0001-7284-8754 9 &
• Louk J. M. J. Vanderschuren   ORCID: orcid.org/0000-0002-5379-0363 10  

Neuropsychopharmacology volume  46 ,  pages 1715–1723 ( 2021 ) Cite this article

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The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.

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Introduction

Close to a quarter of a century ago, then director of the US National Institute on Drug Abuse Alan Leshner famously asserted that “addiction is a brain disease”, articulated a set of implications of this position, and outlined an agenda for realizing its promise [ 1 ]. The paper, now cited almost 2000 times, put forward a position that has been highly influential in guiding the efforts of researchers, and resource allocation by funding agencies. A subsequent 2000 paper by McLellan et al. [ 2 ] examined whether data justify distinguishing addiction from other conditions for which a disease label is rarely questioned, such as diabetes, hypertension or asthma. It concluded that neither genetic risk, the role of personal choices, nor the influence of environmental factors differentiated addiction in a manner that would warrant viewing it differently; neither did relapse rates, nor compliance with treatment. The authors outlined an agenda closely related to that put forward by Leshner, but with a more clinical focus. Their conclusion was that addiction should be insured, treated, and evaluated like other diseases. This paper, too, has been exceptionally influential by academic standards, as witnessed by its ~3000 citations to date. What may be less appreciated among scientists is that its impact in the real world of addiction treatment has remained more limited, with large numbers of patients still not receiving evidence-based treatments.

In recent years, the conceptualization of addiction as a brain disease has come under increasing criticism. When first put forward, the brain disease view was mainly an attempt to articulate an effective response to prevailing nonscientific, moralizing, and stigmatizing attitudes to addiction. According to these attitudes, addiction was simply the result of a person’s moral failing or weakness of character, rather than a “real” disease [ 3 ]. These attitudes created barriers for people with substance use problems to access evidence-based treatments, both those available at the time, such as opioid agonist maintenance, cognitive behavioral therapy-based relapse prevention, community reinforcement or contingency management, and those that could result from research. To promote patient access to treatments, scientists needed to argue that there is a biological basis beneath the challenging behaviors of individuals suffering from addiction. This argument was particularly targeted to the public, policymakers and health care professionals, many of whom held that since addiction was a misery people brought upon themselves, it fell beyond the scope of medicine, and was neither amenable to treatment, nor warranted the use of taxpayer money.

Present-day criticism directed at the conceptualization of addiction as a brain disease is of a very different nature. It originates from within the scientific community itself, and asserts that this conceptualization is neither supported by data, nor helpful for people with substance use problems [ 4 , 5 , 6 , 7 , 8 ]. Addressing these critiques requires a very different perspective, and is the objective of our paper. We readily acknowledge that in some cases, recent critiques of the notion of addiction as a brain disease as postulated originally have merit, and that those critiques require the postulates to be re-assessed and refined. In other cases, we believe the arguments have less validity, but still provide an opportunity to update the position of addiction as a brain disease. Our overarching concern is that questionable arguments against the notion of addiction as a brain disease may harm patients, by impeding access to care, and slowing development of novel treatments.

A premise of our argument is that any useful conceptualization of addiction requires an understanding both of the brains involved, and of environmental factors that interact with those brains [ 9 ]. These environmental factors critically include availability of drugs, but also of healthy alternative rewards and opportunities. As we will show, stating that brain mechanisms are critical for understanding and treating addiction in no way negates the role of psychological, social and socioeconomic processes as both causes and consequences of substance use. To reflect this complex nature of addiction, we have assembled a team with expertise that spans from molecular neuroscience, through animal models of addiction, human brain imaging, clinical addiction medicine, to epidemiology. What brings us together is a passionate commitment to improving the lives of people with substance use problems through science and science-based treatments, with empirical evidence as the guiding principle.

To achieve this goal, we first discuss the nature of the disease concept itself, and why we believe it is important for the science and treatment of addiction. This is followed by a discussion of the main points raised when the notion of addiction as a brain disease has come under criticism. Key among those are claims that spontaneous remission rates are high; that a specific brain pathology is lacking; and that people suffering from addiction, rather than behaving “compulsively”, in fact show a preserved ability to make informed and advantageous choices. In the process of discussing these issues, we also address the common criticism that viewing addiction as a brain disease is a fully deterministic theory of addiction. For our argument, we use the term “addiction” as originally used by Leshner [ 1 ]; in Box  1 , we map out and discuss how this construct may relate to the current diagnostic categories, such as Substance Use Disorder (SUD) and its different levels of severity (Fig.  1) .

Risky (hazardous) substance use refers to quantity/frequency indicators of consumption; SUD refers to individuals who meet criteria for a DSM-5 diagnosis (mild, moderate, or severe); and addiction refers to individuals who exhibit persistent difficulties with self-regulation of drug consumption. Among high-risk individuals, a subgroup will meet criteria for SUD and, among those who have an SUD, a further subgroup would be considered to be addicted to the drug. However, the boundary for addiction is intentionally blurred to reflect that the dividing line for defining addiction within the category of SUD remains an open empirical question.

Box 1 What’s in a name? Differentiating hazardous use, substance use disorder, and addiction

Although our principal focus is on the brain disease model of addiction, the definition of addiction itself is a source of ambiguity. Here, we provide a perspective on the major forms of terminology in the field.

Hazardous Substance Use

Hazardous (risky) substance use refers to quantitative levels of consumption that increase an individual’s risk for adverse health consequences. In practice, this pertains to alcohol use [ 110 , 111 ]. Clinically, alcohol consumption that exceeds guidelines for moderate drinking has been used to prompt brief interventions or referral for specialist care [ 112 ]. More recently, a reduction in these quantitative levels has been validated as treatment endpoints [ 113 ].

Substance Use Disorder

SUD refers to the DSM-5 diagnosis category that encompasses significant impairment or distress resulting from specific categories of psychoactive drug use. The diagnosis of SUD is operationalized as 2 or more of 11 symptoms over the past year. As a result, the diagnosis is heterogenous, with more than 1100 symptom permutations possible. The diagnosis in DSM-5 is the result of combining two diagnoses from the DSM-IV, abuse and dependence, which proved to be less valid than a single dimensional approach [ 114 ]. Critically, SUD includes three levels of severity: mild (2–3 symptoms), moderate (4–5 symptoms), and severe (6+ symptoms). The International Classification of Diseases (ICD) system retains two diagnoses, harmful use (lower severity) and substance dependence (higher severity).

Addiction is a natural language concept, etymologically meaning enslavement, with the contemporary meaning traceable to the Middle and Late Roman Republic periods [ 115 ]. As a scientific construct, drug addiction can be defined as a state in which an individual exhibits an inability to self-regulate consumption of a substance, although it does not have an operational definition. Regarding clinical diagnosis, as it is typically used in scientific and clinical parlance, addiction is not synonymous with the simple presence of SUD. Nowhere in DSM-5 is it articulated that the diagnostic threshold (or any specific number/type of symptoms) should be interpreted as reflecting addiction, which inherently connotes a high degree of severity. Indeed, concerns were raised about setting the diagnostic standard too low because of the issue of potentially conflating a low-severity SUD with addiction [ 116 ]. In scientific and clinical usage, addiction typically refers to individuals at a moderate or high severity of SUD. This is consistent with the fact that moderate-to-severe SUD has the closest correspondence with the more severe diagnosis in ICD [ 117 , 118 , 119 ]. Nonetheless, akin to the undefined overlap between hazardous use and SUD, the field has not identified the exact thresholds of SUD symptoms above which addiction would be definitively present.

Integration

The ambiguous relationships among these terms contribute to misunderstandings and disagreements. Figure 1 provides a simple working model of how these terms overlap. Fundamentally, we consider that these terms represent successive dimensions of severity, clinical “nesting dolls”. Not all individuals consuming substances at hazardous levels have an SUD, but a subgroup do. Not all individuals with a SUD are addicted to the drug in question, but a subgroup are. At the severe end of the spectrum, these domains converge (heavy consumption, numerous symptoms, the unambiguous presence of addiction), but at low severity, the overlap is more modest. The exact mapping of addiction onto SUD is an open empirical question, warranting systematic study among scientists, clinicians, and patients with lived experience. No less important will be future research situating our definition of SUD using more objective indicators (e.g., [ 55 , 120 ]), brain-based and otherwise, and more precisely in relation to clinical needs [ 121 ]. Finally, such work should ultimately be codified in both the DSM and ICD systems to demarcate clearly where the attribution of addiction belongs within the clinical nosology, and to foster greater clarity and specificity in scientific discourse.

What is a disease?

In his classic 1960 book “The Disease Concept of Alcoholism”, Jellinek noted that in the alcohol field, the debate over the disease concept was plagued by too many definitions of “alcoholism” and too few definitions of “disease” [ 10 ]. He suggested that the addiction field needed to follow the rest of medicine in moving away from viewing disease as an “entity”, i.e., something that has “its own independent existence, apart from other things” [ 11 ]. To modern medicine, he pointed out, a disease is simply a label that is agreed upon to describe a cluster of substantial, deteriorating changes in the structure or function of the human body, and the accompanying deterioration in biopsychosocial functioning. Thus, he concluded that alcoholism can simply be defined as changes in structure or function of the body due to drinking that cause disability or death. A disease label is useful to identify groups of people with commonly co-occurring constellations of problems—syndromes—that significantly impair function, and that lead to clinically significant distress, harm, or both. This convention allows a systematic study of the condition, and of whether group members benefit from a specific intervention.

It is not trivial to delineate the exact category of harmful substance use for which a label such as addiction is warranted (See Box  1 ). Challenges to diagnostic categorization are not unique to addiction, however. Throughout clinical medicine, diagnostic cut-offs are set by consensus, commonly based on an evolving understanding of thresholds above which people tend to benefit from available interventions. Because assessing benefits in large patient groups over time is difficult, diagnostic thresholds are always subject to debate and adjustments. It can be debated whether diagnostic thresholds “merely” capture the extreme of a single underlying population, or actually identify a subpopulation that is at some level distinct. Resolving this issue remains challenging in addiction, but once again, this is not different from other areas of medicine [see e.g., [ 12 ] for type 2 diabetes]. Longitudinal studies that track patient trajectories over time may have a better ability to identify subpopulations than cross-sectional assessments [ 13 ].

By this pragmatic, clinical understanding of the disease concept, it is difficult to argue that “addiction” is unjustified as a disease label. Among people who use drugs or alcohol, some progress to using with a quantity and frequency that results in impaired function and often death, making substance use a major cause of global disease burden [ 14 ]. In these people, use occurs with a pattern that in milder forms may be challenging to capture by current diagnostic criteria (See Box  1 ), but is readily recognized by patients, their families and treatment providers when it reaches a severity that is clinically significant [see [ 15 ] for a classical discussion]. In some cases, such as opioid addiction, those who receive the diagnosis stand to obtain some of the greatest benefits from medical treatments in all of clinical medicine [ 16 , 17 ]. Although effect sizes of available treatments are more modest in nicotine [ 18 ] and alcohol addiction [ 19 ], the evidence supporting their efficacy is also indisputable. A view of addiction as a disease is justified, because it is beneficial: a failure to diagnose addiction drastically increases the risk of a failure to treat it [ 20 ].

Of course, establishing a diagnosis is not a requirement for interventions to be meaningful. People with hazardous or harmful substance use who have not (yet) developed addiction should also be identified, and interventions should be initiated to address their substance-related risks. This is particularly relevant for alcohol, where even in the absence of addiction, use is frequently associated with risks or harm to self, e.g., through cardiovascular disease, liver disease or cancer, and to others, e.g., through accidents or violence [ 21 ]. Interventions to reduce hazardous or harmful substance use in people who have not developed addiction are in fact particularly appealing. In these individuals, limited interventions are able to achieve robust and meaningful benefits [ 22 ], presumably because patterns of misuse have not yet become entrenched.

Thus, as originally pointed out by McLellan and colleagues, most of the criticisms of addiction as a disease could equally be applied to other medical conditions [ 2 ]. This type of criticism could also be applied to other psychiatric disorders, and that has indeed been the case historically [ 23 , 24 ]. Today, there is broad consensus that those criticisms were misguided. Few, if any healthcare professionals continue to maintain that schizophrenia, rather than being a disease, is a normal response to societal conditions. Why, then, do people continue to question if addiction is a disease, but not whether schizophrenia, major depressive disorder or post-traumatic stress disorder are diseases? This is particularly troubling given the decades of data showing high co-morbidity of addiction with these conditions [ 25 , 26 ]. We argue that it comes down to stigma. Dysregulated substance use continues to be perceived as a self-inflicted condition characterized by a lack of willpower, thus falling outside the scope of medicine and into that of morality [ 3 ].

Chronic and relapsing, developmentally-limited, or spontaneously remitting?

Much of the critique targeted at the conceptualization of addiction as a brain disease focuses on its original assertion that addiction is a chronic and relapsing condition. Epidemiological data are cited in support of the notion that large proportions of individuals achieve remission [ 27 ], frequently without any formal treatment [ 28 , 29 ] and in some cases resuming low risk substance use [ 30 ]. For instance, based on data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) study [ 27 ], it has been pointed out that a significant proportion of people with an addictive disorder quit each year, and that most afflicted individuals ultimately remit. These spontaneous remission rates are argued to invalidate the concept of a chronic, relapsing disease [ 4 ].

Interpreting these and similar data is complicated by several methodological and conceptual issues. First, people may appear to remit spontaneously because they actually do, but also because of limited test–retest reliability of the diagnosis [ 31 ]. For instance, using a validated diagnostic interview and trained interviewers, the Collaborative Studies on Genetics of Alcoholism examined the likelihood that an individual diagnosed with a lifetime history of substance dependence would retain this classification after 5 years. This is obviously a diagnosis that, once met, by definition cannot truly remit. Lifetime alcohol dependence was indeed stable in individuals recruited from addiction treatment units, ~90% for women, and 95% for men. In contrast, in a community-based sample similar to that used in the NESARC [ 27 ], stability was only ~30% and 65% for women and men, respectively. The most important characteristic that determined diagnostic stability was severity. Diagnosis was stable in severe, treatment-seeking cases, but not in general population cases of alcohol dependence.

These data suggest that commonly used diagnostic criteria alone are simply over-inclusive for a reliable, clinically meaningful diagnosis of addiction. They do identify a core group of treatment seeking individuals with a reliable diagnosis, but, if applied to nonclinical populations, also flag as “cases” a considerable halo of individuals for whom the diagnostic categorization is unreliable. Any meaningful discussion of remission rates needs to take this into account, and specify which of these two populations that is being discussed. Unfortunately, the DSM-5 has not made this task easier. With only 2 out of 11 symptoms being sufficient for a diagnosis of SUD, it captures under a single diagnostic label individuals in a “mild” category, whose diagnosis is likely to have very low test–retest reliability, and who are unlikely to exhibit a chronic relapsing course, together with people at the severe end of the spectrum, whose diagnosis is reliable, many of whom do show a chronic relapsing course.

The NESARC data nevertheless show that close to 10% of people in the general population who are diagnosed with alcohol addiction (here equated with DSM-IV “dependence” used in the NESARC study) never remitted throughout their participation in the survey. The base life-time prevalence of alcohol dependence in NESARC was 12.5% [ 32 ]. Thus, the data cited against the concept of addiction as a chronic relapsing disease in fact indicate that over 1% of the US population develops an alcohol-related condition that is associated with high morbidity and mortality, and whose chronic and/or relapsing nature cannot be disputed, since it does not remit.

Secondly, the analysis of NESARC data [ 4 , 27 ] omits opioid addiction, which, together with alcohol and tobacco, is the largest addiction-related public health problem in the US [ 33 ]. This is probably the addictive condition where an analysis of cumulative evidence most strikingly supports the notion of a chronic disorder with frequent relapses in a large proportion of people affected [ 34 ]. Of course, a large number of people with opioid addiction are unable to express the chronic, relapsing course of their disease, because over the long term, their mortality rate is about 15 times greater than that of the general population [ 35 ]. However, even among those who remain alive, the prevalence of stable abstinence from opioid use after 10–30 years of observation is <30%. Remission may not always require abstinence, for instance in the case of alcohol addiction, but is a reasonable proxy for remission with opioids, where return to controlled use is rare. Embedded in these data is a message of literally vital importance: when opioid addiction is diagnosed and treated as a chronic relapsing disease, outcomes are markedly improved, and retention in treatment is associated with a greater likelihood of abstinence.

The fact that significant numbers of individuals exhibit a chronic relapsing course does not negate that even larger numbers of individuals with SUD according to current diagnostic criteria do not. For instance, in many countries, the highest prevalence of substance use problems is found among young adults, aged 18–25 [ 36 ], and a majority of these ‘age out’ of excessive substance use [ 37 ]. It is also well documented that many individuals with SUD achieve longstanding remission, in many cases without any formal treatment (see e.g., [ 27 , 30 , 38 ]).

Collectively, the data show that the course of SUD, as defined by current diagnostic criteria, is highly heterogeneous. Accordingly, we do not maintain that a chronic relapsing course is a defining feature of SUD. When present in a patient, however, such as course is of clinical significance, because it identifies a need for long-term disease management [ 2 ], rather than expectations of a recovery that may not be within the individual’s reach [ 39 ]. From a conceptual standpoint, however, a chronic relapsing course is neither necessary nor implied in a view that addiction is a brain disease. This view also does not mean that it is irreversible and hopeless. Human neuroscience documents restoration of functioning after abstinence [ 40 , 41 ] and reveals predictors of clinical success [ 42 ]. If anything, this evidence suggests a need to increase efforts devoted to neuroscientific research on addiction recovery [ 40 , 43 ].

Lessons from genetics

For alcohol addiction, meta-analysis of twin and adoption studies has estimated heritability at ~50%, while estimates for opioid addiction are even higher [ 44 , 45 ]. Genetic risk factors are to a large extent shared across substances [ 46 ]. It has been argued that a genetic contribution cannot support a disease view of a behavior, because most behavioral traits, including religious and political inclinations, have a genetic contribution [ 4 ]. This statement, while correct in pointing out broad heritability of behavioral traits, misses a fundamental point. Genetic architecture is much like organ structure. The fact that normal anatomy shapes healthy organ function does not negate that an altered structure can contribute to pathophysiology of disease. The structure of the genetic landscape is no different. Critics further state that a “genetic predisposition is not a recipe for compulsion”, but no neuroscientist or geneticist would claim that genetic risk is “a recipe for compulsion”. Genetic risk is probabilistic, not deterministic. However, as we will see below, in the case of addiction, it contributes to large, consistent probability shifts towards maladaptive behavior.

In dismissing the relevance of genetic risk for addiction, Hall writes that “a large number of alleles are involved in the genetic susceptibility to addiction and individually these alleles might very weakly predict a risk of addiction”. He goes on to conclude that “generally, genetic prediction of the risk of disease (even with whole-genome sequencing data) is unlikely to be informative for most people who have a so-called average risk of developing an addiction disorder” [ 7 ]. This reflects a fundamental misunderstanding of polygenic risk. It is true that a large number of risk alleles are involved, and that the explanatory power of currently available polygenic risk scores for addictive disorders lags behind those for e.g., schizophrenia or major depression [ 47 , 48 ]. The only implication of this, however, is that low average effect sizes of risk alleles in addiction necessitate larger study samples to construct polygenic scores that account for a large proportion of the known heritability.

However, a heritability of addiction of ~50% indicates that DNA sequence variation accounts for 50% of the risk for this condition. Once whole genome sequencing is readily available, it is likely that it will be possible to identify most of that DNA variation. For clinical purposes, those polygenic scores will of course not replace an understanding of the intricate web of biological and social factors that promote or prevent expression of addiction in an individual case; rather, they will add to it [ 49 ]. Meanwhile, however, genome-wide association studies in addiction have already provided important information. For instance, they have established that the genetic underpinnings of alcohol addiction only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors [ 50 ].

It thus seems that, rather than negating a rationale for a disease view of addiction, the important implication of the polygenic nature of addiction risk is a very different one. Genome-wide association studies of complex traits have largely confirmed the century old “infinitisemal model” in which Fisher reconciled Mendelian and polygenic traits [ 51 ]. A key implication of this model is that genetic susceptibility for a complex, polygenic trait is continuously distributed in the population. This may seem antithetical to a view of addiction as a distinct disease category, but the contradiction is only apparent, and one that has long been familiar to quantitative genetics. Viewing addiction susceptibility as a polygenic quantitative trait, and addiction as a disease category is entirely in line with Falconer’s theorem, according to which, in a given set of environmental conditions, a certain level of genetic susceptibility will determine a threshold above which disease will arise.

A brain disease? Then show me the brain lesion!

The notion of addiction as a brain disease is commonly criticized with the argument that a specific pathognomonic brain lesion has not been identified. Indeed, brain imaging findings in addiction (perhaps with the exception of extensive neurotoxic gray matter loss in advanced alcohol addiction) are nowhere near the level of specificity and sensitivity required of clinical diagnostic tests. However, this criticism neglects the fact that neuroimaging is not used to diagnose many neurologic and psychiatric disorders, including epilepsy, ALS, migraine, Huntington’s disease, bipolar disorder, or schizophrenia. Even among conditions where signs of disease can be detected using brain imaging, such as Alzheimer’s and Parkinson’s disease, a scan is best used in conjunction with clinical acumen when making the diagnosis. Thus, the requirement that addiction be detectable with a brain scan in order to be classified as a disease does not recognize the role of neuroimaging in the clinic.

For the foreseeable future, the main objective of imaging in addiction research is not to diagnose addiction, but rather to improve our understanding of mechanisms that underlie it. The hope is that mechanistic insights will help bring forward new treatments, by identifying candidate targets for them, by pointing to treatment-responsive biomarkers, or both [ 52 ]. Developing innovative treatments is essential to address unmet treatment needs, in particular in stimulant and cannabis addiction, where no approved medications are currently available. Although the task to develop novel treatments is challenging, promising candidates await evaluation [ 53 ]. A particular opportunity for imaging-based research is related to the complex and heterogeneous nature of addictive disorders. Imaging-based biomarkers hold the promise of allowing this complexity to be deconstructed into specific functional domains, as proposed by the RDoC initiative [ 54 ] and its application to addiction [ 55 , 56 ]. This can ultimately guide the development of personalized medicine strategies to addiction treatment.

Countless imaging studies have reported differences in brain structure and function between people with addictive disorders and those without them. Meta-analyses of structural data show that alcohol addiction is associated with gray matter losses in the prefrontal cortex, dorsal striatum, insula, and posterior cingulate cortex [ 57 ], and similar results have been obtained in stimulant-addicted individuals [ 58 ]. Meta-analysis of functional imaging studies has demonstrated common alterations in dorsal striatal, and frontal circuits engaged in reward and salience processing, habit formation, and executive control, across different substances and task-paradigms [ 59 ]. Molecular imaging studies have shown that large and fast increases in dopamine are associated with the reinforcing effects of drugs of abuse, but that after chronic drug use and during withdrawal, brain dopamine function is markedly decreased and that these decreases are associated with dysfunction of prefrontal regions [ 60 ]. Collectively, these findings have given rise to a widely held view of addiction as a disorder of fronto-striatal circuitry that mediates top-down regulation of behavior [ 61 ].

Critics reply that none of the brain imaging findings are sufficiently specific to distinguish between addiction and its absence, and that they are typically obtained in cross-sectional studies that can at best establish correlative rather than causal links. In this, they are largely right, and an updated version of a conceptualization of addiction as a brain disease needs to acknowledge this. Many of the structural brain findings reported are not specific for addiction, but rather shared across psychiatric disorders [ 62 ]. Also, for now, the most sophisticated tools of human brain imaging remain crude in face of complex neural circuit function. Importantly however, a vast literature from animal studies also documents functional changes in fronto-striatal circuits, as well their limbic and midbrain inputs, associated with addictive behaviors [ 63 , 64 , 65 , 66 , 67 , 68 ]. These are circuits akin to those identified by neuroimaging studies in humans, implicated in positive and negative emotions, learning processes and executive functions, altered function of which is thought to underlie addiction. These animal studies, by virtue of their cellular and molecular level resolution, and their ability to establish causality under experimental control, are therefore an important complement to human neuroimaging work.

Nevertheless, factors that seem remote from the activity of brain circuits, such as policies, substance availability and cost, as well as socioeconomic factors, also are critically important determinants of substance use. In this complex landscape, is the brain really a defensible focal point for research and treatment? The answer is “yes”. As powerfully articulated by Francis Crick [ 69 ], “You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules”. Social and interpersonal factors are critically important in addiction, but they can only exert their influences by impacting neural processes. They must be encoded as sensory data, represented together with memories of the past and predictions about the future, and combined with representations of interoceptive and other influences to provide inputs to the valuation machinery of the brain. Collectively, these inputs drive action selection and execution of behavior—say, to drink or not to drink, and then, within an episode, to stop drinking or keep drinking. Stating that the pathophysiology of addiction is largely about the brain does not ignore the role of other influences. It is just the opposite: it is attempting to understand how those important influences contribute to drug seeking and taking in the context of the brain, and vice versa.

But if the criticism is one of emphasis rather than of principle—i.e., too much brain, too little social and environmental factors – then neuroscientists need to acknowledge that they are in part guilty as charged. Brain-centric accounts of addiction have for a long time failed to pay enough attention to the inputs that social factors provide to neural processing behind drug seeking and taking [ 9 ]. This landscape is, however, rapidly changing. For instance, using animal models, scientists are finding that lack of social play early in life increases the motivation to take addictive substances in adulthood [ 70 ]. Others find that the opportunity to interact with a fellow rat is protective against addiction-like behaviors [ 71 ]. In humans, a relationship has been found between perceived social support, socioeconomic status, and the availability of dopamine D2 receptors [ 72 , 73 ], a biological marker of addiction vulnerability. Those findings in turn provided translation of data from nonhuman primates, which showed that D2 receptor availability can be altered by changes in social hierarchy, and that these changes are associated with the motivation to obtain cocaine [ 74 ].

Epidemiologically, it is well established that social determinants of health, including major racial and ethnic disparities, play a significant role in the risk for addiction [ 75 , 76 ]. Contemporary neuroscience is illuminating how those factors penetrate the brain [ 77 ] and, in some cases, reveals pathways of resilience [ 78 ] and how evidence-based prevention can interrupt those adverse consequences [ 79 , 80 ]. In other words, from our perspective, viewing addiction as a brain disease in no way negates the importance of social determinants of health or societal inequalities as critical influences. In fact, as shown by the studies correlating dopamine receptors with social experience, imaging is capable of capturing the impact of the social environment on brain function. This provides a platform for understanding how those influences become embedded in the biology of the brain, which provides a biological roadmap for prevention and intervention.

We therefore argue that a contemporary view of addiction as a brain disease does not deny the influence of social, environmental, developmental, or socioeconomic processes, but rather proposes that the brain is the underlying material substrate upon which those factors impinge and from which the responses originate. Because of this, neurobiology is a critical level of analysis for understanding addiction, although certainly not the only one. It is recognized throughout modern medicine that a host of biological and non-biological factors give rise to disease; understanding the biological pathophysiology is critical for understanding etiology and informing treatment.

Is a view of addiction as a brain disease deterministic?

A common criticism of the notion that addiction is a brain disease is that it is reductionist and in the end therefore deterministic [ 81 , 82 ]. This is a fundamental misrepresentation. As indicated above, viewing addiction as a brain disease simply states that neurobiology is an undeniable component of addiction. A reason for deterministic interpretations may be that modern neuroscience emphasizes an understanding of proximal causality within research designs (e.g., whether an observed link between biological processes is mediated by a specific mechanism). That does not in any way reflect a superordinate assumption that neuroscience will achieve global causality. On the contrary, since we realize that addiction involves interactions between biology, environment and society, ultimate (complete) prediction of behavior based on an understanding of neural processes alone is neither expected, nor a goal.

A fairer representation of a contemporary neuroscience view is that it believes insights from neurobiology allow useful probabilistic models to be developed of the inherently stochastic processes involved in behavior [see [ 83 ] for an elegant recent example]. Changes in brain function and structure in addiction exert a powerful probabilistic influence over a person’s behavior, but one that is highly multifactorial, variable, and thus stochastic. Philosophically, this is best understood as being aligned with indeterminism, a perspective that has a deep history in philosophy and psychology [ 84 ]. In modern neuroscience, it refers to the position that the dynamic complexity of the brain, given the probabilistic threshold-gated nature of its biology (e.g., action potential depolarization, ion channel gating), means that behavior cannot be definitively predicted in any individual instance [ 85 , 86 ].

Driven by compulsion, or free to choose?

A major criticism of the brain disease view of addiction, and one that is related to the issue of determinism vs indeterminism, centers around the term “compulsivity” [ 6 , 87 , 88 , 89 , 90 ] and the different meanings it is given. Prominent addiction theories state that addiction is characterized by a transition from controlled to “compulsive” drug seeking and taking [ 91 , 92 , 93 , 94 , 95 ], but allocate somewhat different meanings to “compulsivity”. By some accounts, compulsive substance use is habitual and insensitive to its outcomes [ 92 , 94 , 96 ]. Others refer to compulsive use as a result of increasing incentive value of drug associated cues [ 97 ], while others view it as driven by a recruitment of systems that encode negative affective states [ 95 , 98 ].

The prototype for compulsive behavior is provided by obsessive-compulsive disorder (OCD), where compulsion refers to repeatedly and stereotypically carrying out actions that in themselves may be meaningful, but lose their purpose and become harmful when performed in excess, such as persistent handwashing until skin injuries result. Crucially, this happens despite a conscious desire to do otherwise. Attempts to resist these compulsions result in increasing and ultimately intractable anxiety [ 99 ]. This is in important ways different from the meaning of compulsivity as commonly used in addiction theories. In the addiction field, compulsive drug use typically refers to inflexible, drug-centered behavior in which substance use is insensitive to adverse consequences [ 100 ]. Although this phenomenon is not necessarily present in every patient, it reflects important symptoms of clinical addiction, and is captured by several DSM-5 criteria for SUD [ 101 ]. Examples are needle-sharing despite knowledge of a risk to contract HIV or Hepatitis C, drinking despite a knowledge of having liver cirrhosis, but also the neglect of social and professional activities that previously were more important than substance use. While these behaviors do show similarities with the compulsions of OCD, there are also important differences. For example, “compulsive” substance use is not necessarily accompanied by a conscious desire to withhold the behavior, nor is addictive behavior consistently impervious to change.

Critics question the existence of compulsivity in addiction altogether [ 5 , 6 , 7 , 89 ], typically using a literal interpretation, i.e., that a person who uses alcohol or drugs simply can not do otherwise. Were that the intended meaning in theories of addiction—which it is not—it would clearly be invalidated by observations of preserved sensitivity of behavior to contingencies in addiction. Indeed, substance use is influenced both by the availability of alternative reinforcers, and the state of the organism. The roots of this insight date back to 1940, when Spragg found that chimpanzees would normally choose a banana over morphine. However, when physically dependent and in a state of withdrawal, their choice preference would reverse [ 102 ]. The critical role of alternative reinforcers was elegantly brought into modern neuroscience by Ahmed et al., who showed that rats extensively trained to self-administer cocaine would readily forego the drug if offered a sweet solution as an alternative [ 103 ]. This was later also found to be the case for heroin [ 103 ], methamphetamine [ 104 ] and alcohol [ 105 ]. Early residential laboratory studies on alcohol use disorder indeed revealed orderly operant control over alcohol consumption [ 106 ]. Furthermore, efficacy of treatment approaches such as contingency management, which provides systematic incentives for abstinence [ 107 ], supports the notion that behavioral choices in patients with addictions remain sensitive to reward contingencies.

Evidence that a capacity for choosing advantageously is preserved in addiction provides a valid argument against a narrow concept of “compulsivity” as rigid, immutable behavior that applies to all patients. It does not, however, provide an argument against addiction as a brain disease. If not from the brain, from where do the healthy and unhealthy choices people make originate? The critical question is whether addictive behaviors—for the most part—result from healthy brains responding normally to externally determined contingencies; or rather from a pathology of brain circuits that, through probabilistic shifts, promotes the likelihood of maladaptive choices even when reward contingencies are within a normal range. To resolve this question, it is critical to understand that the ability to choose advantageously is not an all-or-nothing phenomenon, but rather is about probabilities and their shifts, multiple faculties within human cognition, and their interaction. Yes, it is clear that most people whom we would consider to suffer from addiction remain able to choose advantageously much, if not most, of the time. However, it is also clear that the probability of them choosing to their own disadvantage, even when more salutary options are available and sometimes at the expense of losing their life, is systematically and quantifiably increased. There is a freedom of choice, yet there is a shift of prevailing choices that nevertheless can kill.

Synthesized, the notion of addiction as a disease of choice and addiction as a brain disease can be understood as two sides of the same coin. Both of these perspectives are informative, and they are complementary. Viewed this way, addiction is a brain disease in which a person’s choice faculties become profoundly compromised. To articulate it more specifically, embedded in and principally executed by the central nervous system, addiction can be understood as a disorder of choice preferences, preferences that overvalue immediate reinforcement (both positive and negative), preferences for drug-reinforcement in spite of costs, and preferences that are unstable ( “I’ll never drink like that again;” “this will be my last cigarette” ), prone to reversals in the form of lapses and relapse. From a contemporary neuroscience perspective, pre-existing vulnerabilities and persistent drug use lead to a vicious circle of substantive disruptions in the brain that impair and undermine choice capacities for adaptive behavior, but do not annihilate them. Evidence of generally intact decision making does not fundamentally contradict addiction as a brain disease.

Conclusions

The present paper is a response to the increasing number of criticisms of the view that addiction is a chronic relapsing brain disease. In many cases, we show that those criticisms target tenets that are neither needed nor held by a contemporary version of this view. Common themes are that viewing addiction as a brain disease is criticized for being both too narrow (addiction is only a brain disease; no other perspectives or factors are important) or too far reaching (it purports to discover the final causes of addiction). With regard to disease course, we propose that viewing addiction as a chronic relapsing disease is appropriate for some populations, and much less so for others, simply necessitating better ways of delineating the populations being discussed. We argue that when considering addiction as a disease, the lens of neurobiology is valuable to use. It is not the only lens, and it does not have supremacy over other scientific approaches. We agree that critiques of neuroscience are warranted [ 108 ] and that critical thinking is essential to avoid deterministic language and scientific overreach.

Beyond making the case for a view of addiction as a brain disease, perhaps the more important question is when a specific level of analysis is most useful. For understanding the biology of addiction and designing biological interventions, a neurobiological view is almost certainly the most appropriate level of analysis, in particular when informed by an understanding of the behavioral manifestations. In contrast, for understanding the psychology of addiction and designing psychological interventions, behavioral science is the natural realm, but one that can often benefit from an understanding of the underlying neurobiology. For designing policies, such as taxation and regulation of access, economics and public administration provide the most pertinent perspectives, but these also benefit from biological and behavioral science insights.

Finally, we argue that progress would come from integration of these scientific perspectives and traditions. E.O. Wilson has argued more broadly for greater consilience [ 109 ], unity of knowledge, in science. We believe that addiction is among the areas where consilience is most needed. A plurality of disciplines brings important and trenchant insights to bear on this condition; it is the exclusive remit of no single perspective or field. Addiction inherently and necessarily requires multidisciplinary examination. Moreover, those who suffer from addiction will benefit most from the application of the full armamentarium of scientific perspectives.

Funding and disclosures

Supported by the Swedish Research Council grants 2013-07434, 2019-01138 (MH); Netherlands Organisation for Health Research and Development (ZonMw) under project number 912.14.093 (LJMJV); NIDA and NIAAA intramural research programs (LL; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health); the Peter Boris Chair in Addictions Research, Homewood Research Institute, and the National Institute on Alcohol Abuse and Alcoholism grants AA025911, AA024930, AA025849, AA027679 (JM; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health).

MH has received consulting fees, research support or other compensation from Indivior, Camurus, BrainsWay, Aelis Farma, and Janssen Pharmaceuticals. JM is a Principal and Senior Scientist at BEAM Diagnostics, Inc. DM, JR, LL, and LJMJV declare no conflict of interest.

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Acknowledgements

The authors want to acknowledge comments by Drs. David Epstein, Kenneth Kendler and Naomi Wray.

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Markus Heilig

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• James MacKillop

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Heilig, M., MacKillop, J., Martinez, D. et al. Addiction as a brain disease revised: why it still matters, and the need for consilience. Neuropsychopharmacol. 46 , 1715–1723 (2021). https://doi.org/10.1038/s41386-020-00950-y

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Published : 22 February 2021

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A Conversation With …

Teen Drug Use Habits Are Changing, For the Good. With Caveats.

Dr. Nora Volkow, who leads the National Institutes of Drug Abuse, would like the public to know things are getting better. Mostly.

By Matt Richtel

Historically speaking, it’s not a bad time to be the liver of a teenager. Or the lungs.

Regular use of alcohol, tobacco and drugs among high school students has been on a long downward trend.

In 2023, 46 percent of seniors said that they’d had a drink in the year before being interviewed; that is a precipitous drop from 88 percent in 1979, when the behavior peaked, according to the annual Monitoring the Future survey, a closely watched national poll of youth substance use. A similar downward trend was observed among eighth and 10th graders, and for those three age groups when it came to cigarette smoking. In 2023, just 15 percent of seniors said that they had smoked a cigarette in their life, down from a peak of 76 percent in 1977 .

Illicit drug use among teens has remained low and fairly steady for the past three decades, with some notable declines during the Covid-19 pandemic.

In 2023, 29 percent of high school seniors reported using marijuana in the previous year — down from 37 percent in 2017, and from a peak of 51 percent in 1979.

There are some sobering caveats to the good news. One is that teen overdose deaths have sharply risen, with fentanyl-involved deaths among adolescents doubling from 2019 to 2020 and remaining at that level in the subsequent years.

Dr. Nora Volkow has devoted her career to studying use of drugs and alcohol. She has been the director of the National Institute on Drug Abuse since 2003. She sat down with The New York Times to discuss changing patterns and the reasons behind shifting drug-use trends.

What’s the big picture on teens and drug use?

People don’t really realize that among young people, particularly teenagers, the rate of drug use is at the lowest risk that we have seen in decades. And that’s worth saying, too, for legal alcohol and tobacco.

What do you credit for the change?

One major factor is education and prevention campaigns. Certainly, the prevention campaign for cigarette smoking has been one of the most effective we’ve ever seen.

Some of the policies that were implemented also significantly helped, not just making the legal age for alcohol and tobacco 21 years, but enforcing those laws. Then you stop the progression from drugs that are more accessible, like tobacco and alcohol, to the illicit ones. And teenagers don’t get exposed to advertisements of legal drugs like they did in the past. All of these policies and interventions have had a downstream impact on the use of illicit drugs.

Does social media use among teens play a role?

Absolutely. Social media has shifted the opportunity of being in the physical space with other teenagers. That reduces the likelihood that they will take drugs. And this became dramatically evident when they closed schools because of Covid-19. You saw a big jump downward in the prevalence of use of many substances during the pandemic. That might be because teenagers could not be with one another.

The issue that’s interesting is that despite the fact schools are back, the prevalence of substance use has not gone up to the prepandemic period. It has remained stable or continued to go down. It was a big jump downward, a shift, and some drug use trends continue to slowly go down.

Is there any thought that the stimulation that comes from using a digital device may satisfy some of the same neurochemical experiences of drugs, or provide some of the escapism?

Yes, that’s possible. There has been a shift in the types of reinforcers available to teenagers. It’s not just social media, it’s video gaming, for example. Video gaming can be very reinforcing, and you can produce patterns of compulsive use. So, you are shifting one reinforcer, one way of escaping, with another one. That may be another factor.

Is it too simplistic to see the decline in drug use as a good news story?

If you look at it in an objective way, yes, it’s very good news. Why? Because we know that the earlier you are using these drugs, the greater the risk of becoming addicted to them. It lowers the risk these drugs will interfere with your mental health, your general health, your ability to complete an education and your future job opportunities. That is absolutely good news.

But we don’t want to become complacent.

The supply of drugs is more dangerous, leading to an increase in overdose deaths. We’re not exaggerating. I mean, taking one of these drugs can kill you.

What about vaping? It has been falling, but use is still considerably higher than for cigarettes: In 2021, about a quarter of high school seniors said that they had vaped nicotine in the preceding year . Why would teens resist cigarettes and flock to vaping?

Most of the toxicity associated with tobacco has been ascribed to the burning of the leaf. The burning of that tobacco was responsible for cancer and for most of the other adverse effects, even though nicotine is the addictive element.

What we’ve come to understand is that nicotine vaping has harms of its own, but this has not been as well understood as was the case with tobacco. The other aspect that made vaping so appealing to teenagers was that it was associated with all sorts of flavors — candy flavors. It was not until the F.D.A. made those flavors illegal that vaping became less accessible.

My argument would be there’s no reason we should be exposing teenagers to nicotine. Because nicotine is very, very addictive.

Anything else you want to add?

We also have all of this interest in cannabis and psychedelic drugs. And there’s a lot of interest in the idea that psychedelic drugs may have therapeutic benefits. To prevent these new trends in drug use among teens requires different strategies than those we’ve used for alcohol or nicotine.

For example, we can say that if you take drugs like alcohol or nicotine, that can lead to addiction. That’s supported by extensive research. But warning about addiction for drugs like cannabis and psychedelics may not be as effective.

While cannabis can also be addictive, it’s perhaps less so than nicotine or alcohol, and more research is needed in this area, especially on newer, higher-potency products. Psychedelics don’t usually lead to addiction, but they can produce adverse mental experiences that can put you at risk of psychosis.

Matt Richtel is a health and science reporter for The Times, based in Boulder, Colo. More about Matt Richtel

Drug Addiction Research Paper

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I. introduction, academic writing, editing, proofreading, and problem solving services, get 10% off with 24start discount code, ii. drug use, misuse, abuse, and addiction, iii. drug administration, absorption, metabolism, and excretion, iv. how drugs work in the brain, v. drug safety and toxicity, vi. tolerance, dependence, and withdrawal, vii. specific psychoactive drugs, a. stimulants, 1. xanthines, 2. nicotine, 3. amphetamines, b. depressants, 3. marijuana and hashish, c. the hallucinogens lsd, mdma, and pcp, viii. summary.

IX. Bibliography

A drug is a chemical substance produced exogenously (outside of the body) that, when taken into the body, changes normal body functions. Psychologists are very interested in psychoactive drugs that change central nervous system (CNS; brain and spinal cord) activity, and thereby affect perception, thought, emotion, and behavior. Although people use many psychoactive drugs for acceptable medicinal reasons, this research paper focuses on those psychoactive drugs that people use primarily for recreational, nonmedicinal reasons (e.g., to feel good, be more alert, alter or avoid reality). An adult drinking alcohol to relax or smoking cigarettes to stop the jitters are examples of recreational use of licit (legal) drugs in this country, and smoking crack to feel euphoric or injecting heroin for the “rush” are examples of illicit (illegal) recreational drug use. Most of the information about how drugs make a person feel come from self-reports of licit and illicit users of drugs, whereas most of the data about how the body affects drugs and how drugs work in the brain comes from well-controlled experimental studies using nonhuman animals.

With pills to treat everything from the symptoms of the common cold to the positive symptoms of schizophrenia, drug use is prevalent in the United States, and pharmaceuticals are a multibillion-dollar industry. Nonetheless, society sends mixed messages about drug use, with commercials warning against the evils of illicit drug use and advertisements offering wonder treatments in a “purple pill.” Drugs in and of themselves are not “evil,” but every drug can be misused and abused. Misuse generally refers to the deviation from instructions on the label of over-the-counter drugs or the doctor’s instructions for prescription drugs. For example, taking more or fewer pills per dose or day, not using the drug the full time course as prescribed (e.g., antibiotics), using the drug past the expiration date, using the drug with other drugs (e.g., alcohol with barbiturates), or sharing prescriptions with others without a doctor’s permission are all forms of drug misuse. Although most of these acts may not seem very serious, they all can lead to very dangerous, even deadly, consequences (e.g., alcohol with other drugs, especially other CNS depressants). Drug abuse, which also can occur with licit and illicit drugs, refers here to use of a psychoactive substance to the extent that it produces some sort of physical, cognitive, behavioral, or social impairment. Keep in mind, however, that the public often thinks of drug abuse as specific to illicit drugs like methamphetamine, cocaine, heroin, and LSD (lysergic acid diethylamide), even though alcohol, for example, is a licit drug that people can abuse. What follows is an introduction to the use, misuse, and abuse of psychoactive drugs and their effects on behavior, beginning with how drugs enter the body and what happens to them once they do.

Pharmacokinetics is the study of how drugs are absorbed into the body, metabolized once in the body, and excreted from the body. The goal of drug absorption is for the drug to circulate in the blood, and more specifically for a psychoactive drug, the goal is for it to circulate in the brain. Administration for the purpose of absorption in blood and brain can take various forms depending on type of substance (lipid soluble vs. water soluble, gaseous vs. solid) and desired rate of absorption (rapid vs. slow, acute vs. continuous). Most humans administer drugs either orally (swallowed by mouth), sublingually (substance placed under the tongue), subcutaneously (injecting under the skin), intramuscularly (injecting into muscle tissue), intravenously (injecting directly into the bloodstream via a vein), transdermally (applied to outer layer of skin), intrarectally (using suppositories), intranasally (sniffed into the nostrils), or by inhalation (breathing gases and solids into the lungs). Intraperitoneal (into the peritoneal cavity), intraventricular (via a cannula into the ventricles of the brain), and intracranial (directly into a target area of the brain) injections are forms of administration used mostly in research with laboratory animals. Psychoactive drugs administered directly into the brain will have the most rapid effects because they will reach their CNS sites of action most quickly. Drugs administered through all other routes must be lipid-soluble in order to get through the formidable solid lipid barrier of the brain known as the blood brain barrier (BBB). Provided the psychoactive drugs administered directly into the bloodstream can pass the BBB, they will reach their CNS sites of action relatively quickly. Inhalation results in fast absorption into the bloodstream because gases and drugs in smoke (e.g., nicotine) are readily absorbed into the intricate network of capillaries that line the large surface area of the elaborately pocketed lungs. Although swallowing a pill is a simple, common method of drug administration, absorption is a tenuous process. Drugs taken orally must survive the harsh environment of the digestive system (e.g., stomach acids and digestive enzymes). Rates of absorption via other routes of administration are somewhere between those of inhalation and oral administration, depending somewhat on the availability of capillaries at the site of administration. Users of psychoactive drugs choose their favorite drug partially because of how quickly the drug exerts its psychoactive effects. For example, heroin is the preferred drug for some opiate addicts because it is more lipid soluble, is absorbed into the brain faster, and produces a faster, more intense “rush” than morphine does.

Before drugs can stop working in the body, they must be either broken down into other substances (metabolized) or removed from the body (excreted). Enzymes in the liver metabolize most of the psychoactive drugs described in this research paper into less lipid-soluble chemical products (metabolites). Some metabolites have their own effects on the body and brain. Several variables affect the rate of metabolism, including species, genetics, age, drug experience, and drug interactions. Regarding the latter, some drugs will inhibit or enhance the activity of enzymes responsible for metabolizing certain drugs—for example, SSRI-type antidepressants like fluoxetine inhibit some of the enzymes responsible for metabolizing codeine into the active analgesic morphine.

Subsequent to metabolism and recirculation in the blood, the kidneys excrete the more water-soluble metabolites from the body in urine, although there is excretion of small amounts of the drugs and their metabolites in exhaled breath, sweat, saliva, feces, and breast milk. Not surprisingly, urine drug tests are frequently used to determine the presence of metabolites some time after the metabolism of the original drug, rather than the presence of the original drug at time of administration.

Pharmacodynamics is the study of how drugs work in the body. Psychoactive drugs work in the CNS. The brain is made of supporting glial (fat) cells and excitable neurons. Neurons are responsible for the electrochemical transmission of information, enabling cells to communicate with one another. The structure and arrangement of neurons allows for the transmission, integration, storage, and interpretation of information received via sensory receptors, as well as the control of bodily organs and muscles. In other words, these specialized cells (neurons) are responsible for everything we think, feel, and do.

Psychoactive drugs work in the brain primarily by affecting neurotransmitter activity at the synapses. Neurons produce neurotransmitters that are stored in vesicles within the terminal buttons. When an action potential reaches the terminal buttons, vesicles release the neurotransmitter into the synaptic cleft. Neurotransmitter molecules then briefly bind to postsynaptic receptors causing ion channels to open, letting ions enter or exit, resulting in either excitatory or inhibitory postsynaptic potentials. Once released from the postsynaptic receptors, the neurotransmitter molecules undergo reuptake into the presynaptic terminal button or are destroyed by enzymes in the synaptic cleft. The effect of psychoactive drugs on synaptic activity can occur anywhere in the process of neurotransmitter production, storage, release, receptor binding, and reuptake or degradation.

More specifically, the administration of neurotransmitter precursors can increase the amount of neurotransmitter molecules available in the brain. For example, physicians prescribe L-DOPA, the precursor of dopamine, to patients with Parkinson’s disease in order to increase levels of dopamine in the brain. Other drugs can destroy or block the enzymes necessary for conversion of the precursors into neurotransmitters (e.g., p-chlorophenylalanine, PCPA, prevents the synthesis of serotonin). The vesicles that house neurotransmitters also can be the target site of drugs. Reserpine, occasionally used to treat high blood pressure, interferes with the transporter molecules that fill vesicles with neurotransmitters, thereby leaving the vesicles empty with no neurotransmitter available for release. A common target site of psychoactive drugs is the postsynaptic receptors where neurotransmitters bind. Drugs that bind to receptors and mimic the actions of a particular neurotransmitter are direct agonists (e.g., nicotine binds to nicotinic acetylcholinergic receptors). Drugs that bind to receptors without stimulating the receptor and prevent neurotransmitter molecules from occupying the receptor binding sites are direct antagonists (e.g., curare causes paralysis by binding to acetylcholinergic receptors). There are also drugs that work as agonists or antagonists by binding to sites other than where the neurotransmitter molecule binds (noncompetitive sites). Finally, drugs can affect what happens to neurotransmitters after they are released from their receptors by interfering with either the enzymes that break the neurotransmitters down (e.g., physostygmine deactivates the enzyme acetylcholinesterase, which breaks down acetylcholine) or reuptake mechanisms (e.g., cocaine deactivates the dopamine reuptake transporters).

Each type of neurotransmitter binds to a specific set of receptors that typically bear their own name (e.g., dopamine to dopaminergic receptors). The set of receptors belonging to a specific neurotransmitter can have quite different reactions to the neurotransmitter. Various drugs bind to receptor sites with different strengths, and may selectively bind to just one or a few receptor subtypes or nonselectively bind to multiple receptor subtypes. The selective serotonin reuptake inhibitors (SSRIs), used as antidepressants, bind specifically to receptor sites on the presynaptic serotonin reuptake pumps. Recent technological advances have allowed scientists to isolate the unique subtypes of receptor proteins, such that they can produce large quantities of each of the specific receptor proteins and then test the affinity of new drugs at each of the receptor subtypes. Drugs that bind to only a very specific receptor subtype or have greatly enhanced affinities for very specific subtypes of receptors will have fewer side effects as compared to drugs that bind less discriminately to an entire set of receptors. A good example is the drugs used to treat Parkinson’s disease. Some of the older drugs (e.g., bromocriptine) that are structurally more similar to dopamine have more negative side effects than the newer developed drugs (e.g., ropinerole) that have more discriminate receptor affinity for D3 than D2 receptors.

Clearly, not all drugs are equal. Scientists who study drugs, pharmacologists, typically measure many participants’ responses to doses so low that they cause no measurable effect to doses so high that they cease to cause any additional effect. They then plot the number (or percent) of participants who respond to the drug at each of the doses tested (dose response curve). The plot indicates the drug’s potency (number of drug molecules required to elicit a given response), efficacy (the maximum effect of the drug, with additional amounts resulting in no increase in response), and variability (individual differences in responsiveness to the drug).

The federal Food and Drug Administration (FDA) has extremely specific guidelines in place for the testing of a new drug’s effectiveness and safety. Safety refers to the drug’s potential to produce everything from predictable, tolerable, unpleasant side effects to unpredictable, intolerable, severe toxicities. Unfortunately, all drugs have multiple effects, with some effects less desirable. Given that undesirable side effects are unavoidable, the goal is the most favorable combination of the most desired drug effects and the least unwanted side effects. The ED50 is the effective dose that produces the desired effect in 50 percent of the participants. The LD50 is the lethal dose that produces death in 50 percent of the subjects. Typically, the ED50 and LD50 are determined in several species and over many trials to reduce the risk of toxicity in humans. The greater the distance between the ED50 and LD50, the less the risk of drug-induced toxicity at beneficial dosages. The margin of safety is the ratio of LD1 to ED99 (effective dose in 99 percent of the participants). Ratios of one or greater suggest greater safety. Be cautious, though—this margin of safety is under the best of controlled testing conditions, far from the circumstances under which many humans may take the drug (e.g., mixing drugs). One drug can alter the effects of another drug in many different ways. A second drug can have an additive effect, a synergistic effect (a greater effect than would be expected when just adding the two drugs), or an antagonistic effect (the second drug reduces or blocks the effect of the target drug). Even drugs not meant to have any effect (placebos) can influence a target drug’s effects because of the user’s expectations.

Tolerance is the need to take increasing doses of a drug in order to achieve the same effects as previously achieved with lower doses. Likewise, when the same dose of drug has less and less of an effect with repeated administrations, tolerance has occurred. A good example is the tolerance that some people have for the caffeine in coffee. A novice coffee drinker may feel the stimulatory effects of coffee after a single cup of coffee containing about 100 mg of caffeine. After drinking coffee daily for a few weeks, it may take two or three cups of caffeinated coffee to feel that same excitation. There are several types of tolerance including metabolic tolerance, cellular tolerance, and behavioral tolerance. Metabolic tolerance occurs when, with repeated administrations of the drug, the body produces more and more metabolic enzymes, thereby speeding up the rate of metabolism of that drug. Thus, one must take more and more drug with each administration to maintain the same concentration of drug in the body as during previous episodes. Cellular tolerance is down regulation (reduction in numbers) of the receptors in the brain or reduced sensitivity of those receptors to the drug because of the continuous or repetitive presence of the drug. The result is the need for more drug in order to get the same level of effect in the brain. Behavioral tolerance involves learning. Behavioral tolerance can be observed in the presence of conditioned drug-taking cues and be absent in novel environments or situations. The drug serves as the unconditioned stimulus (US) and the drug effect as an unconditioned response (UR). Drug administering paraphernalia (e.g., white uniform, syringe and needle, bong and roach clips) and a specific location (e.g., doctor’s office, nightclub, crack house) where the drug is administered can serve as conditioned stimuli (CSs) that, when paired with the drug (US), come to elicit conditioned responses (CRs) that are similar to the UR or opposite the UR (compensatory responses). For example, when Siegel (1975) gave rats morphine (US), they showed reduced sensitivity (UR analgesia) to heat applied to their paws, but with repetitive administrations of morphine in the presence of the same environmental cues (CS), the rats showed increased sensitivity (CR hyperalgesia) to those environmental cues.

A drug may develop different types of tolerance, and to all, some, or none of its effects. Some effects of a drug may even show acute tolerance, which occurs during a single administration of the drug. As a drug is absorbed into the blood, there is a gradual increase in the blood drug concentration, the ascending portion of the blood concentration curve. As long as drug administration has ceased, the blood concentration will eventually reach a peak level. When more metabolism than absorption is occurring, the concentration of drug in the blood begins to decline, depicted as the descending portion of the blood concentration. Acute tolerance is evident when, during a single administration, the measured effect is stronger on the ascending portion of the blood concentration curve than at the same concentration on the descending portion of the curve. Some effects of alcohol show acute tolerance in humans and rats. Finally, cross-tolerance is tolerance that occurs to one specific drug and subsequently tolerance occurs to the first administration of a different drug.

Drug dependence sometimes accompanies tolerance but does not require it. Dependence exists when a person must continue taking a drug in order to function normally and avoid the symptoms of withdrawal (physiological changes associated with the cessation of the drug). In other words, to determine dependence requires one to stop taking the drug. Physical dependence signifies that the body has adjusted physiologically to the repeated or continued presence of the drug. Removing the drug upsets the balance the body has established with the drug present, and results in often-unpleasant symptoms opposite those produced by the drug (e.g., heroin causes constipation whereas withdrawal from heroin causes diarrhea). Interestingly, long-term alcohol consumption can produce considerable tolerance without causing physical dependence; however, abstention from chronic alcoholism can cause life-threatening tremors, nausea, seizures, and delirium. Although the public tends to associate aversive withdrawal symptoms with drug “addiction” (e.g., chills, runny nose, fever, increased sensitivity to pain with opiate addiction), dependence and withdrawal are not unique to illicit drugs. Many legally prescribed and appropriately used therapeutic drugs result in dependence (e.g., SSRI-type antidepressants). It takes the body from several days to several weeks to readjust to the absence of a previously administered drug that has produced dependence. Thus, physiological dependence and withdrawal promote drug-taking behaviors, as people continue to take the drug, at least partially, to avoid the terrible effects of withdrawal. Several drugs that do not cause physiological dependence (e.g., cocaine, marijuana) do, however, produce psychological dependence. That is, an individual may be dependent on a drug for its pleasurable effects (i.e., positive reinforcement). Rats prefer to lever press for cocaine over food, even to the point of starvation.

Psychoactive agents are categorized a number of different ways. For example, drugs are categorized according to their chemical structure (e.g., amphetamines), whether they are legal or illegal (e.g., caffeine and nicotine vs. cocaine and amphetamines), how they affect the CNS (e.g., stimulants and depressants), and the type of behavioral, affective, and/or cognitive effects they produce (e.g., hallucinogens, analgesics). What follows is a description of a few of the most well-studied drugs with emphasis on the use of the drug; behavioral, cognitive, and mood-related effects of the drug; and the CNS mechanisms by which the drug produces its effects on behavior.

Stimulants produce behavioral excitation, increased motor activity, and increased alertness by enhancing excitation at neuronal synapses. The most commonly used stimulants include caffeine (a xanthine), nicotine, amphetamines, and cocaine. Many consider caffeine and nicotine to be “minor” stimulants and amphetamines and cocaine to be “major” stimulants. These stimulants have medicinal purposes, but most people are more familiar with their recreational uses. Stimulants vary greatly in the degree to which they affect behavior and in their potential for dependence and abuse.

Xanthines are a family of stimulants that includes caffeine, theobromine, and theophylline, the most widely used stimulants in the world. Caffeine is in many products (e.g., over-the-counter medications, baked goods, candy) but most commonly is associated with coffee and soft drinks. Tea contains caffeine, theophylline, and trace amounts of theobromine, and both caffeine and theobromine are in chocolate. Caffeine and theophylline are approximately equal with regard to stimulatory effects, but theobromine is only about one-tenth as strong as the other two.

How much caffeine is in coffee depends on the type of coffee bean (coffea robusta having twice the caffeine content of coffee Arabica) and how it is brewed (caffeine in a 5-ounce cup: instant about 60 mg, percolated about 85 mg, drip-brewed about 112 mg). Caffeine content in 12-ounce soft drinks ranges from about 38 mg (Diet Pepsi) to 54 mg (Mountain Dew), and as high as about 110 mg in special “energy” sodas (Red Bull). A 5-ounce cup of medium brewed black tea has about 60 mg of caffeine, and a strong brew of tea contains as much as 100 mg of caffeine. A 5- ounce cup of brewed tea contains a much smaller amount of theophylline (< 1 mg). A 1-ounce piece of milk chocolate contains 1 to 6 mg caffeine and about 40 mg of the 10 times less stimulating theobromine. There is 75 to 150 mg of xanthines in a cup of hot cocoa, and cocoa products contain enough caffeine and theobromine to affect behavior.

Orally consumed caffeine is absorbed in the stomach and mostly intestines, with peak blood levels occurring at 30 to 60 minutes. Caffeine easily crosses the blood brain and placenta barriers. Some foods, alcohol, smoking, hormones, age, and species affect the metabolism of caffeine. Xanthines are antagonists at adenosine A1 and A2a receptors, affecting the release of several neurotransmitters. When activated by adenosine, receptors located on presynaptic terminals inhibit spontaneous and stimulated neurotransmitter release. By blocking activation of adenosine receptors, xanthines lead to increased neurotransmitter release and increased excitation. At high concentrations, xanthines also block benzodiazepine receptors located on the GABA receptor complex, which may account for some of the increased anxiety after consumption of enormous amounts of coffee. Because outside of the CNS theophylline is particularly good at causing smooth muscles to relax, theophylline is useful therapeutically to dilate the bronchi of the lungs in the treatment of asthma.

Often people consume products containing moderate levels of caffeine because of their subjective experiences of increased alertness, improved attention, reduced fatigue, and more clear cognition. Experimental evidence suggests the most prominent effect of caffeine is enhancing performance of noncognitive tasks, like athletic and perceptual tasks, by reducing fatigue and boredom (see review by Weiss & Laties, 1962). Additionally, caffeine augments brainstem reflexes, enhances some visual processing, improves reaction time and self-reported alertness, reduces the detrimental effects of sleep deprivation on psychomotor performance, increases wakefulness, and produces insomnia.

Tolerance develops to some of the subjective effects of caffeine. Small and moderate, but not large, doses of caffeine appear to have reinforcing properties. Most people manage their caffeine intake, avoiding the anxiety, tremors, rapid breathing, and insomnia associated with high doses of caffeine. Within 12 to 24 hours of cessation, caffeine withdrawal often causes mild to severe headaches, drowsiness, muscle aches, and irritability, suggesting caffeine has some potential for producing limited physiological dependence. However, after reviewing caffeine studies, Nehlig (1999) concluded that caffeine does not affect the dopaminergic CNS centers for reward and motivation, as do cocaine and amphetamines.

Nicotine is one of the most-used psychoactive drugs in the world. The primary psychoactive active ingredient in tobacco is nicotine. According to the 2005 National Survey on Drug Use and Health (Department of Health and Human Services, 2006), about 71.5 million Americans (> 12 years old) used a tobacco product within the previous month. Only 30.6 percent of full-time college students ages 18 to 22 reported using in the previous month, as compared to 42.7 percent of same-aged part-time and noncollege students. Many of the toxic chemical compounds, other than nicotine, in tobacco products are the source of serious health problems (e.g., emphysema, chronic lung disease, cancer, cardiovascular disease) and death.

Nicotine is easily absorbed into the body. When inhaled, nicotine in cigarette smoke particles (tar) is quickly absorbed into the bloodstream via the capillaries lining the lungs. Smokers experience a sudden “rush” with that first cigarette of the day because the nicotine-saturated blood rapidly reaches the brain and crosses the BBB. Even though cigarettes contain about 0.5 to 2.0 mg of nicotine, smokers absorb only about 20 percent of that nicotine into blood. Smokers easily avoid nicotine toxicity by controlling the depth and rate of smoke inhalation. The liver metabolizes about 90 percent of the nicotine in the bloodstream before excretion. Urine tests measuring nicotine’s major metabolite cotinine do not distinguish between tobacco use and environmental exposure.

Nicotine is an agonist at acetylcholinergic nicotinic receptors. Peripherally, nicotine’s activation of receptors increases blood pressure, heart rate, and adrenal gland release of adrenaline. Nicotine activation of CNS nicotinic receptors located on presynaptic terminal buttons facilitates release of dopamine, acetylcholine, and glutamate throughout the brain. Physiological and psychological dependence of nicotine is due to nicotinic-induced release of dopamine from neurons projecting from the ventral tegmental area to forebrain regions (mesolimbic system) and prefrontal cortex (mesocortical system), brain areas responsible for reinforcement. Nicotine-induced release of acetylcholine is the likely cause of improved cognition and memory, as well as increased arousal. Increased glutamatergic activity due to nicotinic presynaptic facilitation contributes to enhanced memory of nicotine users.

Plenty of evidence exists regarding nicotine’s facilitating effects on cognition and memory in humans and animals (for reviews see Levin, McClernon, & Rezvani, 2006; Levin & Simon, 1998). Individual differences in the cognitive effects of nicotine may be due to genetic variations in dopaminergic activity. Nicotine administered via a patch to adult carriers of the 957T allele (alters D2 receptor binding in humans) impaired working verbal memory performance and reduced processing efficiency in brain regions important for phonological rehearsal (Jacobsen, Pugh, Mencl, & Gelernter, 2006). Additionally, nicotine stimulates activity in brain regions involved in attention, motivation, mood, motor activity, and arousal.

Tolerance appears to develop to the subjective mood effects of nicotine, but not to nicotine-induced changes in physiology or behavioral performance (for review see Perkins, 2002). However, most smokers do develop both physiological and psychological dependence on nicotine. Typically, withdrawal from cigarettes causes intense persistent cravings, irritability, apprehension, irritation, agitation, fidgeting, trouble concentrating, sleeplessness, and weight gain. Even people deprived of smoking just overnight report higher stress, irritability, and lower pleasure (e.g., Parrott & Garnham, 1998). Abstinence symptoms can last for several months, and many smokers find the cravings to be so intense that they relapse. It is common for smokers to quit smoking many times. Decreased activity in reward brain areas (e.g., dopaminergic mesolimbic system) that occurs during nicotine withdrawal may be responsible for the motivation of cravings, relapse, and continued smoking.

In 1932 amphetamine, a synthetic drug similar in structure to ephedrine, was patented. That amphetamine is a potent dilator of nasal and bronchial passages easily administered as an inhalant made it a viable treatment for asthma in the early 1900s. During World War I and World War II, governments gave amphetamines to soldiers to prevent fatigue and improve mood. Subsequently, college students used amphetamines to stay awake studying for exams, and truck drivers for staying awake on crosscountry hauls. It did not take long for word to spread that amphetamines (speed) caused euphoria, quickly making them an abused recreational drug. As Schedule II drugs, amphetamines have high potential for abuse and dependence, but also have accepted medicinal use with strict restrictions. Currently, treatments for narcolepsy and attention deficit hyperactivity disorder (ADHD) are accepted uses of amphetamines and amphetamine-like drugs (methylphenidate).

Amphetamines are a group of similarly structured synthetic chemicals that cause euphoria and behavioral stimulation. The d form of amphetamine is more potent than the 1 form. Administration is typically oral for current medicinal purposes, and inhalation or injection with a freebase form of methamphetamine (ice, crank) for a faster recreational “rush.” Amphetamines easily cross the BBB and readily disperse throughout the brain. The liver metabolizes about 60 percent of methamphetamine, amphetamine being the major active metabolite, and then the kidneys excrete the metabolites and unchanged methamphetamine.

Amphetamines work both in the periphery and in the CNS. In the CNS, these drugs increase activity at synapses that release epinephrine, norepinephrine, and dopamine by either causing the neurotransmitters to leak out of their vesicles into the synaptic cleft and/or blocking reuptake into presynaptic terminal buttons. Recreational users typically prefer methamphetamine to other amphetamines because it has fewer unpleasant peripheral effects (e.g., increased heart rate, increased blood pressure, dry mouth, headaches) and stronger, longer-lasting CNS.

Amphetamines improve mood, decrease fatigue, increase vigilance, energize, impair ability to estimate time, and diminish the desire for food and drink. “Fen-Phen,” a combination of fenfluramine and the amphetamine phentermine, was widely prescribed as an effective appetite suppressant in the 1990s, at least until it was removed from the market in late 1997 because of its association with heart valve problems and lung disease. Most of the performanceenhancing effects of amphetamines are limited to tasks that are routine, well-rehearsed, and well-practiced activities. Intravenously or intranasally administered high doses of amphetamine cause a “rush” of intense exhilaration and pleasure. The euphoria and strong reinforcing properties of amphetamines are due to increased dopamine activity in the mesolimbic system. Increased repetitive movements (stereotypy in laboratory rats) and behaviors (punding in humans) to the exclusion of eating, grooming, and sleeping are probably due to amphetamine stimulation in the nigrostriatal dopamine system. High acute doses and chronic use probably over stimulate the mesolimbic dopamine system, producing violently aggressive paranoia and amphetamine psychosis, delusions, hallucinations, and a split from reality. The sensation that insects are crawling under the skin (formication) may be the basis for the self-mutilation observed in laboratory animals. Long-term chronic use of methamphetamines is particular neurotoxic, leading to irreversible brain damage and psychosis.

Acute and chronic tolerance to amphetamines’ desired effects of enhanced mood and euphoria occurs rapidly. The positively rewarding feelings associated with intravenously injected amphetamine, especially methamphetamine, leads to overwhelming psychological dependence. Physiological dependence on amphetamines is evident from the withdrawal symptoms of ravenous hunger, fatigue, lethargy, depression, and suicidal tendencies. Many of the characteristics of amphetamines are similar to those of cocaine.

For thousands of years, the natives of the South American Andes have increased endurance and stamina as they traveled the harsh mountain terrain by chewing the leaves of the coca plant. The plant became of interest to Europeans and Americans in the mid to late 1800s when entrepreneurs began adding the extract of the coca leaves to many products (e.g., wine, nerve tonics, home remedies, teas, and colas). In the 1860s Dr. W. S. Halstead discovered cocaine’s local anesthetic properties. Because cocaine is readily absorbed in mucous membranes, it is still a local anesthetic of choice in some surgeries (e.g., nasal, esophageal). Currently, U.S. federal law categorizes cocaine as a Schedule II drug (high potential for abuse and dependence, but has currently accepted medicinal use with strict restrictions). In 2005 an estimated 2.4 million people were using cocaine, and about 2,400 persons per day used cocaine for the first time (Department of Health and Human Services, 2006).

Cocaine administration takes several forms, all with fairly quick but short-lived results (1 to 2 hours’ duration). Users snort the powdered hydrochloride salt form of cocaine, and when they dissolve that in water, they can inject the drug. In the 1970s users developed a smokeable free-base form of cocaine by extracting the hydrochloride with the very volatile gas ether. The safer smokeable rock crystal crack cocaine forms when producers treat cocaine with baking soda and water. The crack user inhales the vapors as the rock heats and makes a crackling sound. When inhaled, cocaine is rapidly absorbed by capillaries in the lungs, whereas snorted cocaine hydrochloride is absorbed more slowly into mucous membranes. Cocaine readily crosses the BBB and quickly distributes throughout the brain, where it remains for as long as 8 hours. The major metabolite benzoylecgonine is inactive and, when excreted by the kidneys in urine, is detectable for 48 hours, even as long as 2 weeks in chronic cocaine users. Cometabolism of cocaine and alcohol produces the pharmacologically active, longer-lasting, and toxic metabolite cocaethylene.

Cocaine blocks presynaptic reuptake transporters for dopamine, epinephrine, norepinephrine, and serotonin. This blockade prolongs the presence of these neurotransmitters in the synapse, allowing the neurotransmitters to bind repetitively to postsynaptic receptors. Cocaine’s enhancement of dopaminergic activity in the reward/reinforcement centers of the brain (e.g., the nucleus accumbens and other mesolimbic systems) is responsible for the highly addictive nature and powerful psychological dependence of cocaine. Serotonin receptors also play a role in the reinforcing effects of cocaine.

Cocaine is an extremely addictive psychostimulant that in low to moderate doses produces euphoria and increases alertness, mental acuity, self-consciousness, talkativeness, and motor behavior. Moderate to high doses cause more intense confusion, agitation, paranoia, restlessness, tremors, and seizures. Chronic use of cocaine produces impulsive and repetitive behavior. High-dose cocaine use can cause cocaine-induced psychosis characterized by extreme agitation and anxiety; exaggerated compulsive motor behaviors; delusions of paranoia and persecution; visual, auditory and tactile hallucinations; loss of touch with reality; and permanent brain damage. Medical risks associated with cocaine use include increased risk of cerebral ischemia, intracranial bleeding, heart attack and heart complications due to cocaine’s vasoconstrictive properties, respiratory failure, strokes, seizures, and risks with snorting that include nasal lesions, perforations, bleeding, and infections.

Tolerance to cocaine’s effects and physiological dependence to high doses of cocaine can occur. Regarding withdrawal syndrome, as the stimulatory CNS effects of cocaine subside, the user experiences depression, anxiety, lingering sleepiness, boredom, reduced motivation, and an intense craving for the drug. Much more powerful is the development of psychological dependence, because of cocaine’s strong reinforcing properties, and therefore relapse.

Depressants decrease CNS neuronal activity such that behavior is depressed, anxiety is lessened, and sedation and sleep are increased. This group of drugs includes barbiturates, benzodiazepines, some abused inhalants, and alcohol. Many of these drugs work at the GABA receptor complex, and all have potential for misuse, abuse, and dependence.

Alcohol (ethanol) is a CNS depressant used throughout the world and history. In the United States, alcohol sales are an important part of the economy, with Americans spending over a hundred billion dollars annually on beer, wines, and distilled liquors. Based on alcohol sales in the Unites States, total ethanol consumption in 2004 was 377,002,000 gallons, including 4,368,000 gallons of ethanol and 97,065,000 gallons of beer (National Institute on Alcohol Abuse and Alcoholism, n.d.). Alcohol consumption in the United States costs in terms of increased risky behavior, injuries on the job, relational strain, and hospitalization. Chronic users develop vitamin deficiencies because alcohol is high in calories and not nutritious, and they are at risk for pancreatitis, chronic gastritis, gastric ulcers, stomach and intestinal cancers (alcohol is a gastric irritant), as well as death due to cirrhosis of the liver. Alcohol is involved in costly traffic-related injuries and fatalities. According to the National Highway Traffic Safety Administration, automobile crashes involving alcohol in 2000 cost the public almost $115 billion, with an estimated 513,000 people injured and 16,792 killed (Pacific Institute for Research and Evaluation, n.d.).

People typically absorb alcohol orally, and ethanol is easily absorbed via the gastrointestinal system. Generally, beers have 3.2 to 5 percent ethanol, wines 12 to 14 percent, and hard liquors (distilled spirits) 40 to 50 percent. An adult can metabolize the amount of ethanol contained in a 12-ounce, 3.2 percent beer, a 3 ½-ounce, 12 percent wine, or 1-ounce, 40 percent (80 proof) hard liquor in approximately one hour. The enzyme alcohol dehydrogenase metabolizes about 95 percent of the ethanol consumed into acetaldehyde at a constant rate of 0.25 ounces/hour, and that metabolizes to acetyl-coenzyme, which then converts to water and carbon dioxide. The other 5 percent is excreted unchanged mostly through breath (hence the use of Breathalyzers to estimate alcohol concentration). Women have less ethanol-metabolizing enzyme in their stomach wall and therefore absorb more ethanol than men do. Water and fat-soluble ethanol easily crosses the BBB and placental barriers. Ethanol diffuses rapidly throughout the brain, and ethanol concentrations in a fetal brain reach those of the alcohol-drinking mother.

Ethanol nonspecifically affects neuronal membranes and directly affects synaptic activity and ionic channels of several neurotransmitters. Ethanol dose dependently inhibits NMDA-type glutamate receptors (reduces postsynaptic excitation) and enhances inhibition produced by GABAA receptor-mediated influx of chloride ions (increases postsynaptic inhibition). Ethanol also induces synaptic release of opioids that trigger dopamine release in the brain reinforcement areas, explaining how the antagonist naltrexone reduces cravings for alcohol and relapse in alcoholdependent persons attempting to abstain. Specific serotonin receptors (5HT2, 5HT3) located in the nucleus accumbens may also be a site of ethanol action. Antagonists of those receptors reduce ethanol consumption in some persons with alcoholism. Additionally, ethanol leads to a decrease in the number of cannabinoid receptors (down-regulation) affecting the craving of alcohol.

Water excretion in urine increases (diuretic) as the blood alcohol concentration (BAC) rises, and water is retained (antidiuretic) as the BAC declines, causing swelling in the extremities. Although it makes the drinker feel warmer to the touch, ethanol actually causes hypothermia. Because ethanol causes blood vessels in skin to dilate, persons with white skin appear flushed. Behaviorally, ethanol has a biphasic effect, with low doses inhibiting inhibitions (disinhibition), and high doses depressing all behaviors. Alcohol reduces the latency to fall to sleep and inhibits REM sleep. Generally, low to moderate doses increase rate and tone of speech, impair visual perception, disrupt balance, worsen reaction time, exaggerate mood, reduce fear and apprehension (anxiolytic), and affect learning and memory in a state-dependent manner. However, there are huge individual differences in ethanol-induced effects because genetics, motivation, environment, experience with alcohol, and tolerance vary greatly. Chronic consumption of higher doses of alcohol can lead to memory storage problems, with heavy drinkers experiencing blackouts, periods during which they cannot remember events even though they were awake and active. Long-term heavy drinking can cause irreversible neuronal damage, producing dementia and severe cognitive deficits known as Korsakoff’s Syndrome.

Each of the forms of tolerance can develop to some of the effects of ethanol (e.g., depression of REM) depending on pattern of drinking and amount consumed, with tolerance more apparent in regular and heavy drinkers. Physiological dependence is evident when withdrawal from ethanol results in agitation, confusion, tremors, cramps, sweating, nausea, and vomiting. Persons with severe alcoholism may experience delirium tremens (DTs) characterized by disorientation, hallucinations, and life threatening seizures.

The opiates, also known as narcotics, are a class of potent analgesics that have similar behavioral effects, including opium, opium extracts (e.g., morphine, codeine), several opiate derivatives (e.g., heroin), and several chemically unrelated synthetic opiates (e.g., methadone). Opium is harvested from the opium poppy, and has been used for centuries. In the 1800s, women and children alike ingested opium in everything from cure-alls to cough syrups. In the mid-1800s morphine as a medical analgesic increased with the invention of the hypodermic needle during the Civil War. When heroin was put on the market in the late 1890s it was considered a powerful and safe cough suppressant, and it was at least a decade before its full potential for abuse and dependence was realized. In the United States, opium, morphine, codeine, and methadone are all Schedule II drugs (high potential for abuse and dependence with acceptable medicinal uses with strict restrictions), whereas heroin is a Schedule I drug (high potential for abuse and dependence with no acceptable medicinal use). Although it is illegal in this country, it is widely used as a recreational drug. An estimated 108,000 persons age 12 and older used heroin for the first time in 2005 (Department of Health and Human Services, 2006).

Opiates are administered orally, as rectal suppositories, or as is most common with medicinal and recreational use, via injection. Morphine, because it is more water than fat soluble, crosses the BBB slowly, whereas more lipid soluble heroin crosses the BBB much more rapidly and produces a faster more intense “rush.” Metabolism of morphine in the liver produces the metabolite morphine- 6-glucuronide that is an even more potent analgesic. Heroin, which is three times more potent than morphine, metabolizes to monoacetylmorphine, which then converts to morphine. Urine tests detect the opiates as well as their metabolites, and therefore are not useful in determining the exact form of the drug used. Furthermore, poppy seeds and cough syrups contain ingredients that metabolize and test positive for opiate metabolites.

Exogenous opioids (produced outside of the body) bind to opioid receptors and mimic the actions of endogenous opioids (endorphins). Most of their analgesic effects are due to their presynaptic inhibition of pain-producing neurotransmitter release. There are Mu, Kappa, and Delta opiate receptors. Morphine is an agonist at Mu receptors located in several brain areas including the nucleus accumbens (addiction and abuse), thalamus, striatum, and brainstem (respiratory depression, nausea and vomiting), in the spinal cord (analgesia), and periphery. In the brain, Delta receptors in the nucleus accumbens and limbic system are involved in opioid-related emotional responses, and Kappa receptors may be Mu receptor–antagonists.

Opiates alter the perception of pain without affecting consciousness. They also produce a feeling of drowsiness, putting the person in a sort of mental fog that impairs cognitive processing. Opiates cause the user to feel carefree, content, and euphoric. Respiration becomes slow, shallow, and irregular, at therapeutic doses, and breathing may stop with high doses. Combined use of opiates and depressants can be particularly hazardous. Other physiological effects of opiate use include constricted pupils, histamine-induced red eyes and itching, lowered blood pressure, constipation, cough suppression, nausea and vomiting, and changes in the immune system.

Key features of frequent repetitive opiate use are tolerance to analgesia and euphoria, and cross-tolerance to other opiates. The severity of the withdrawal symptoms— anxiety, agitation, despair, irritability, physical pain, cramping, and diarrhea—depends on how long, how often, and how much of the opiate was used. Depression and intense cravings for the drug last for several months after the individual has stopped using heroin, for example.

For centuries, people in many parts of the world have used some form of the Cannabis sativa hemp plant as a recreational drug. The plant grows as a weed in many parts of the United States, and is cultivated in other countries. Marijuana production consists of drying and shredding the leaves of the plant, whereas hashish is a dried form of the resin from the flowers of the plant. Marijuana and hashish are both Schedule I drugs in the United States. Each day in 2005, an estimated 6,000 persons, 59.1 percent under 18, used marijuana for the first time (Department of Health and Human Services, 2006). The main psychoactive substance in these products is delta-9- tetrahydocaanabinol (THC). Most marijuana has a THC content of about 4 to 8 percent.

Often THC is ingested via hand-rolled marijuana cigarettes called joints or reefers, but it is also consumed in cookies and brownies. Only about half of the THC in a marijuana cigarette is absorbed, but absorption via the capillaries in the lining of the lungs is very rapid. Peak blood levels of THC occur within 10 minutes of the beginning of smoking, and detectable blood levels continue for 12 hours after a single cigarette. Absorption and onset of effects after oral ingestion is slower, with peak THC blood levels not occurring for at least 2 hours. THC easily crosses the BBB and placenta barrier, and collects in fatty parts of the body. It slowly metabolizes into active 11-hydroxy-delta- 9-THC, which then converts into inactive metabolites detectable in urine tests for as long as a month in heavy or chronic smokers.

The actions of THC in the brain were unknown until the 1990s identification of the weaker and shorter-lasting endogenous THC-like substance, anandamide, and the cannabinoid receptor. THC is an anandamide agonist that, when bound to cannabinoid receptors, inhibits the release of other neurotransmitters at those synapses, especially GABA. These g-protein-linked receptors are located mostly on presynaptic terminals and exist in large numbers throughout the brain, but not in the brainstem. That there are none of these receptors in the brainstem, where regulations of major life-support functions are controlled (e.g., heart rate, respiration), is probably why even high doses of marijuana are not likely lethal, although they can peripherally affect the cardiovascular and immune systems.

The psychoactive effects of THC are dependent upon type of administration, experience with the drug, environment, and expectations. Interestingly, the effects of marijuana on appetite and sexual behavior are culturally dependent, with Americans experiencing “the munchies” and Jamaicans decreased appetite, Americans enhanced sexual responsiveness and persons of India reduced sexual interest. Generally, people use marijuana because it has a mellowing, mildly euphoric effect. Other psychoactive effects include poorer attention, distorted perception of time and colors, altered auditory and gustatory perceptions, diminished anxiety, slowed reaction time, and impaired cognitive processing. Poor learning and memory are due to the numerous cannabinoid receptors in the hippocampus. Impaired balance and abnormal movements occur because of THC’s activation of receptors in the basal ganglia, and the cognitive effects are due to receptors in the cerebral cortex. Poor reaction time, decreased attention to peripheral visual stimuli, difficulty concentrating, and impairment of complex motor tasks under the influence of marijuana hinders driving ability. High doses of marijuana produce panic and anxiety, and extremely high doses produce additional disorientation, delusions, and hallucinations.

Tolerance, receptor-down regulation with repeated use, develops to THC. Withdrawal symptoms, which begin about 48 hours after the last marijuana use, include restlessness, irritability, despair, apprehension, difficulty sleeping, nausea, cramping, and poor appetite. Withdrawal symptoms are mild as compared to those that occur with most other drugs (e.g., alcohol, opiates) and occur for only about half of regular users. Thus, physiological dependence does occur for many, and most experience craving for marijuana when they stop using the drug.

Although the hallucinogens lysergic acid diethylamide (LSD), methylene-dioxy-methamphetamine (MDMA; Ecstasy), and phencyclidine (PCP; Angel Dust) affect very different neurotransmitter systems, they are grouped here because of their similar psychological effects at nontoxic doses. The commonality among hallucinogens (psychedelic drugs) is their ability to cause users to disconnect from reality and hallucinate. Although there are a large number of natural hallucinogenics, LSD, MDMA, and PCP are all synthetic drugs originally synthesized with hopes of medicinal value. Albert Hoffman accidentally experienced a “psychedelic trip” in 1943, and since then LSD has become one of the most widely known hallucinogens. PCP was used as an anesthetic prior to being taken off the market in 1965, when it made it to the streets as a recreational drug, and MDMA became a club drug in the 1960s. Estimates of first time users of hallucinogens for each year from 2000 to 2005 have been close to one million people age 12 and older per year, with about 615,000 first-time Ecstasy users in 2005 (Department of Health and Human Services, 2006).

Users ingest LSD orally, and the drug is absorbed in about 60 minutes with peak blood levels within 3 hours. LSD easily crosses both brain and placenta barriers. Metabolism takes place in the liver, where LSD is converted to 2-oxo-3phydroxy-LSD, and then excreted in urine. People use MDMA orally, snort it, smoke it, and inject it, with absorption being slowest with oral use. Most of MDMA metabolizes to 3,4-dihydroxymethamphetamine (DHMA), and urine tests detect metabolites for up to 5 days. People either take PCP orally (peak blood levels in 2 hours) or smoke the drug (peak blood levels in 15 minutes), and it is well absorbed into blood with both methods. Urine tests detect PCP for as long as a week after use.

LSD is a serotonergic receptor agonist, and most of the psychoactive effects of LSD are thought to be due to agonist actions at serotonin receptors in the pontine raphe (filters sensory stimuli). MDMA is structurally similar to but more potent than mescaline and metamphetamine, and stimulates release of both serotonin and dopamine in the CNS. Prolonged use of MDMA results in serotonergic neurotoxicity, and can lead to long-term verbal and visual memory loss. PCP blocks the ionic channels of glutamatergic-NMDA receptors, preventing calcium ions from entering into the dendrites of postsynaptic neurons when glutamate binds to these receptors, and blocking synaptic excitation.

Very small doses of LSD cause vivid visual hallucinations like colorful kaleidoscope lights and distorted images, lights to be heard and sounds to be seen, moods that oscillate from jubilation to dread, and frightening cognitions that surface. The LSD “trip” is often unpleasant, resulting in panic and confusion. A unique feature of LSD use is the infamous “flashback,” a reoccurrence of the drug’s effects without warning, even a long time after LSD use. At low doses MDMA has behavioral effects similar to those of methamphetamines, but at higher doses it has the psychoactive effects of LSD. Low doses of PCP produce agitation, dissociation from self and others, a “blank stare,” and major alterations in mood and cognition. Higher doses of PCP can cause the user to have violent reactions to stimuli in his or her environment, along with analgesia and memory loss. Extremely high doses of PCP result in coma.

Tolerance and cross-tolerance develops to the psychological and physiological effects of most hallucinogens rather quickly, making it difficult to stay repetitively “high” on these drugs. Furthermore, there are few if any withdrawal symptoms and therefore little or no physiological dependence with LSD, MDMA, and PCP in most users.

Psychoactive drugs change cognitions, emotions, and behavior. Drugs, per se, are neither good nor bad. People use psychoactive drugs for medicinal and recreational reasons. Regardless of the initial reason for using a drug, some people misuse and even abuse some psychoactive drugs because of the drugs’ effects on mood, thought, and behavior. How people administer the drug (by ingestion, injection, inhalation, or absorption through the skin) affects how fast and intense the drug’s effects are. The route of administration can affect how quickly the drug is absorbed into the bloodstream, how rapidly it is broken down, and how long it takes to be excreted from the body. The primary site of action for psychoactive drugs is the synapse of neurons in the brain. Often drugs work by either mimicking or blocking the actions of one or more neurotransmitters in the CNS. All drugs have multiple effects, and most are toxic at some dose. Dependence, withdrawal, and/or tolerance develop to some of the effects of most, but not all, psychoactive drugs.

Psychoactive drugs can be categorized many different ways. For example, by chemical structure, whether their use is legal or illegal, or the type of CNS or behavioral effects they produce. Stimulants, like cocaine and amphetamines, increase neuronal and behavioral activity. Depressants, like alcohol, reduce neuronal and behavioral activity. Opiates, some having legal uses (e.g., morphine) and others not (e.g., heroin), reduce pain and, in high enough doses, cause an addictive “rush.” Low doses of marijuana have a mellowing, mildly euphoric effect, whereas very high doses can cause hallucinations. Drugs like LSD, MDMA, and PCP are all classified as hallucinogens because at even low doses they cause sensory and perceptual distortions. Although a great deal is known about how many psychoactive drugs act in the brain and affect behavior, researchers continue to identify the most effective pharmacological, cognitive, and behavioral treatments for persons who abuse these drugs.

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9 facts about americans and marijuana.

The use and possession of marijuana is illegal under U.S. federal law, but about three-quarters of states have legalized the drug for medical or recreational purposes. The changing legal landscape has coincided with a decades-long rise in public support for legalization, which a majority of Americans now favor.

Here are nine facts about Americans’ views of and experiences with marijuana, based on Pew Research Center surveys and other sources.

As more states legalize marijuana, Pew Research Center looked at Americans’ opinions on legalization and how these views have changed over time.

Data comes from surveys by the Center,  Gallup , and the  2022 National Survey on Drug Use and Health  from the U.S. Substance Abuse and Mental Health Services Administration. Information about the jurisdictions where marijuana is legal at the state level comes from the  National Organization for the Reform of Marijuana Laws .

More information about the Center surveys cited in the analysis, including the questions asked and their methodologies, can be found at the links in the text.

Around nine-in-ten Americans say marijuana should be legal for medical or recreational use,  according to a January 2024 Pew Research Center survey . An overwhelming majority of U.S. adults (88%) say either that marijuana should be legal for medical use only (32%) or that it should be legal for medical  and  recreational use (57%). Just 11% say the drug should not be legal in any form. These views have held relatively steady over the past five years.

Views on marijuana legalization differ widely by age, political party, and race and ethnicity, the January survey shows.

While small shares across demographic groups say marijuana should not be legal at all, those least likely to favor it for both medical and recreational use include:

• Older adults: 31% of adults ages 75 and older support marijuana legalization for medical and recreational purposes, compared with half of those ages 65 to 74, the next youngest age category. By contrast, 71% of adults under 30 support legalization for both uses.
• Republicans and GOP-leaning independents: 42% of Republicans favor legalizing marijuana for both uses, compared with 72% of Democrats and Democratic leaners. Ideological differences exist as well: Within both parties, those who are more conservative are less likely to support legalization.
• Hispanic and Asian Americans: 45% in each group support legalizing the drug for medical and recreational use. Larger shares of Black (65%) and White (59%) adults hold this view.

Support for marijuana legalization has increased dramatically over the last two decades. In addition to asking specifically about medical and recreational use of the drug, both the Center and Gallup have asked Americans about legalizing marijuana use in a general way. Gallup asked this question most recently, in 2023. That year, 70% of adults expressed support for legalization, more than double the share who said they favored it in 2000.

Half of U.S. adults (50.3%) say they have ever used marijuana, according to the 2022 National Survey on Drug Use and Health . That is a smaller share than the 84.1% who say they have ever consumed alcohol and the 64.8% who have ever used tobacco products or vaped nicotine.

While many Americans say they have used marijuana in their lifetime, far fewer are current users, according to the same survey. In 2022, 23.0% of adults said they had used the drug in the past year, while 15.9% said they had used it in the past month.

While many Americans say legalizing recreational marijuana has economic and criminal justice benefits, views on these and other impacts vary, the Center’s January survey shows.

• Economic benefits: About half of adults (52%) say that legalizing recreational marijuana is good for local economies, while 17% say it is bad. Another 29% say it has no impact.

• Criminal justice system fairness: 42% of Americans say legalizing marijuana for recreational use makes the criminal justice system fairer, compared with 18% who say it makes the system less fair. About four-in-ten (38%) say it has no impact.
• Use of other drugs: 27% say this policy decreases the use of other drugs like heroin, fentanyl and cocaine, and 29% say it increases it. But the largest share (42%) say it has no effect on other drug use.
• Community safety: 21% say recreational legalization makes communities safer and 34% say it makes them less safe. Another 44% say it doesn’t impact safety.

Democrats and adults under 50 are more likely than Republicans and those in older age groups to say legalizing marijuana has positive impacts in each of these areas.

Most Americans support easing penalties for people with marijuana convictions, an October 2021 Center survey found . Two-thirds of adults say they favor releasing people from prison who are being held for marijuana-related offenses only, including 41% who strongly favor this. And 61% support removing or expunging marijuana-related offenses from people’s criminal records.

Younger adults, Democrats and Black Americans are especially likely to support these changes. For instance, 74% of Black adults  favor releasing people from prison  who are being held only for marijuana-related offenses, and just as many favor removing or expunging marijuana-related offenses from criminal records.

Twenty-four states and the District of Columbia have legalized small amounts of marijuana for both medical and recreational use as of March 2024,  according to the  National Organization for the Reform of Marijuana Laws  (NORML), an advocacy group that tracks state-level legislation on the issue. Another 14 states have legalized the drug for medical use only.

Of the remaining 12 states, all allow limited access to products such as CBD oil that contain little to no THC – the main psychoactive substance in cannabis. And 26 states overall have at least partially  decriminalized recreational marijuana use , as has the District of Columbia.

In addition to 24 states and D.C.,  the U.S. Virgin Islands ,  Guam  and  the Northern Mariana Islands  have legalized marijuana for medical and recreational use.

More than half of Americans (54%) live in a state where both recreational and medical marijuana are legal, and 74% live in a state where it’s legal either for both purposes or medical use only, according to a February Center analysis of data from the Census Bureau and other outside sources. This analysis looked at state-level legislation in all 50 states and the District of Columbia.

In 2012, Colorado and Washington became the first states to pass legislation legalizing recreational marijuana.

About eight-in-ten Americans (79%) live in a county with at least one cannabis dispensary, according to the February analysis. There are nearly 15,000 marijuana dispensaries nationwide, and 76% are in states (including D.C.) where recreational use is legal. Another 23% are in medical marijuana-only states, and 1% are in states that have made legal allowances for low-percentage THC or CBD-only products.

The states with the largest number of dispensaries include California, Oklahoma, Florida, Colorado and Michigan.

Note: This is an update of a post originally published April 26, 2021, and updated April 13, 2023.  

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Americans overwhelmingly say marijuana should be legal for medical or recreational use

Religious americans are less likely to endorse legal marijuana for recreational use, four-in-ten u.s. drug arrests in 2018 were for marijuana offenses – mostly possession, two-thirds of americans support marijuana legalization, most popular.

About Pew Research Center Pew Research Center is a nonpartisan fact tank that informs the public about the issues, attitudes and trends shaping the world. It conducts public opinion polling, demographic research, media content analysis and other empirical social science research. Pew Research Center does not take policy positions. It is a subsidiary of The Pew Charitable Trusts .

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• Indian J Psychiatry
• v.52(Suppl1); 2010 Jan

Substance use and addiction research in India

Pratima murthy.

Department of Psychiatry, De-Addiction Centre, National Institute of Mental Health and Neuro Sciences, Bangalore - 560 029, India

N. Manjunatha

B. n. subodh, prabhat kumar chand, vivek benegal.

Substance use patterns are notorious for their ability to change over time. Both licit and illicit substance use cause serious public health problems and evidence for the same is now available in our country. National level prevalence has been calculated for many substances of abuse, but regional variations are quite evident. Rapid assessment surveys have facilitated the understanding of changing patterns of use. Substance use among women and children are increasing causes of concern. Preliminary neurobiological research has focused on identifying individuals at high risk for alcohol dependence. Clinical research in the area has focused primarily on alcohol and substance related comorbidity. There is disappointingly little research on pharmacological and psychosocial interventions. Course and outcome studies emphasize the need for better follow-up in this group. While lack of a comprehensive policy has been repeatedly highlighted and various suggestions made to address the range of problems caused by substance use, much remains to be done on the ground to prevent and address these problems. It is anticipated that substance related research publications in the Indian Journal of Psychiatry will increase following the journal having acquired an ‘indexed’ status.

INTRODUCTION

Substance use has been a topic of interest to many professionals in the area of health, particularly mental health. An area with enormous implications for public health, it has generated a substantial amount of research. In this paper we examine research in India in substance use and related disorders. Substance use includes the use of licit substances such as alcohol, tobacco, diversion of prescription drugs, as well as illicit substances.

METHODOLOGY

For this review, we have carried out a systematic web-based review of the Indian Journal of Psychiatry (IJP). The IJP search included search of both the current and archives section and an issue-to-issue search of articles with any title pertaining to substance use. This has included original articles, reviews, case series and reports with significant implications. Letters to editor and abstracts of annual conference presentations have not been included.

Publications in other journals were accessed through a Medlar search (1992-2009) and a Pubmed search (1950-2009). Other publications related to substance use available on the websites of international and national agencies have also been reviewed. In this review, we focus mainly on publications in the IJP and have selectively reviewed the literature from other sources.

For the sake of convenience, we discuss the publications under the following areas: Epidemiology, clinical issues (diagnosis, psychopathology, comorbidity), biological studies (genetics, imaging, electrophysiology, and vulnerability), interventions and outcomes as well as community interventions and policies. There is a vast amount of literature on tobacco use and consequences in international and national journals, but this is outside the scope of this review. Tobacco is mentioned in this review of substance use to highlight that it should be remembered as the primary licit substance of abuse in our country.

The number of articles (area wise) available from IJP, other Indian journals and international journals are indicated in Figures ​ Figures1 1 and ​ and2. 2 . A majority of the publications in international journals relate to tobacco, substance use co-morbidity and miscellaneous areas like animal studies.

Publications in the area of substance use and related disorders

Break up of areas of publication

EPIDEMIOLOGY

Much of the earlier epidemiological research has been regional and it has been very difficult to draw inferences of national prevalence from these studies.

Regional studies

Studies between 1968 until 2000 have been primarily on alcohol use [ Table 1 ]. They have varied in terms of populations surveyed (ranged from 115 to 16,725), sampling procedures (convenient, purposive and representative), focus of enquiry (alcohol use, habitual excessive use, alcohol abuse, alcoholism, chronic alcoholism, alcohol and drug abuse and alcohol dependence), location (urban, rural or both, Slums), in the screening instruments used (survey questionnaires and schedules, semi-structured interviews, quantity frequency index, Michigan Alcohol Screening Test (MAST) etc). Alcohol ‘use/abuse’ prevalence in different regions has thus varied from 167/1000 to 370/1000; ‘alcohol addiction’ or ‘alcoholism’ or ‘chronic alcoholism’ from 2.36/1000 to 34.5/1000; alcohol and drug use/abuse from 21.4 to 28.8/1000. A meta-analysis by Reddy and Chandrashekhar[ 26 ] (1998) revealed an overall substance use prevalence of 6.9/1000 for India with urban and rural rates of 5.8 and 7.3/1000 population. The rates among men and women were 11.9 and 1.7% respectively.

Regional epidemiological studies in substance use: A summary

U - Urban; R - Rural; Sl - Slum; SR - Semi-rural; NM - Not mentioned

Regional studies between 2001 and 2007 continue to reflect this variability. Currently, the interest is to look at hazardous alcohol use. A study in southern rural India[ 27 ] showed that 14.2% of the population surveyed had hazardous alcohol use on the AUDIT. A similar study in the tertiary hospital[ 28 ] showed that 17.6% admitted patients had hazardous alcohol use.

The only incidence study on alcohol use from Delhi[ 17 ] found that annual incidence of nondependent alcohol use and dependent alcohol use among men was 3 and 2 per 1000 persons in a total cohort of 2,937 households.

National Studies

The National Household Survey of Drug Use in the country[ 29 ] is the first systematic effort to document the nation-wide prevalence of drug use [ Table 2 ]. Alcohol (21.4%) was the primary substance used (apart from tobacco) followed by cannabis (3.0%) and opioids (0.7%). Seventeen to 26% of alcohol users qualified for ICD 10 diagnosis of dependence, translating to an average prevalence of about 4%. There was a marked variation in alcohol use prevalence in different states of India (current use ranged from a low of 7% in the western state of Gujarat (officially under Prohibition) to 75% in the North-eastern state of Arunachal Pradesh. Tobacco use prevalence was high at 55.8% among males, with maximum use in the age group 41-50 years.

Nationwide studies on substance use prevalence

H-H - House to house survey; M - Male; F - Female; A - Alcohol, C - Cannabis; O - Opioids; T - Tobacco

The National Family Health Survey (NFHS)[ 30 ] provides some insights into tobacco and alcohol use. The changing trends between NFHS 2 and NFHS 3 reflect an increase in alcohol use among males since the NFHS 2, and an increase in tobacco use among women.

The Drug Abuse Monitoring System,[ 29 ] which evaluated the primary substance of abuse in inpatient treatment centres found that the major substances were alcohol (43.9%), opioids (26%) and cannabis (11.6%).

Patterns of substance use

Rapid situation assessments (RSA) are useful to study patterns of substance use. An RSA by the UNODC in 2002[ 31 ] of 4648 drug users showed that cannabis (40%), alcohol (33%) and opioids (15%) were the major substances used. A Rapid Situation and Response Assessment (RSRA) among 5800 male drug users[ 32 ] revealed that 76% of the opioid users currently injected buprenorphine, 76% injected heroin, 70% chasing and 64% using propoxyphene. Most drug users concomitantly used alcohol (80%). According to the World Drug Report,[ 33 ] of 81,802 treatment seekers in India in 2004-2005, 61.3% reported use of opioids, 15.5% cannabis, 4.1% sedatives, 1.5% cocaine, 0.2% amphetamines and 0.9% solvents.

Special populations

In the last decade, there has been a shift in viewing substance use and abuse as an exclusive adult male phenomenon to focusing on the problem in other populations. In the GENACIS study[ 34 ] covering a population of 2981 respondents [1517 males; 1464 females], across five districts of Karnataka, 5.9% of all female respondents (N =87) reported drinking alcohol at least once in the last 12 months, compared to 32.7% among male respondents (N = 496). Special concerns with women’s drinking include the fetal alcohol spectrum effects described with alcohol use during pregnancy.[ 35 ]

Abuse of other substances among women has largely been studied through Rapid Assessment Surveys. A survey of 1865 women drug users by 110 NGOs across the country[ 36 ] revealed that 25% currently were heroin users, 18% used dextropropoxyphene, 11% opioid containing cough syrups and 7% buprenorphine. Eighty seven per cent concomitantly used alcohol and 83% used tobacco. Twenty five per cent of respondents had lifetime history of injecting drug use and 24% had been injecting in the previous month. There are serious sexually transmitted disease risks, including HIV that women partners and drug users face.[ 36 , 37 ]

Substance use in medical fraternity

As early as 1977, a drug abuse survey in Lucknow among medical students revealed that 25.1% abused a drug at least once in a month. Commonly abused drugs included minor tranquilizers, alcohol, amphetamines, bhang and non barbiturate sedatives. In a study of internees on the basis of a youth survey developed by the WHO in 1982,[ 38 ] 22.7% of males ‘indulged in alcohol abuse’ at least once in a month, 9.3% abused cannabis, followed by tranquilizers. Common reasons cited were social reasons, enjoyment, curiosity and relief from psychological stress. Most reported that it was easy to obtain drugs like marijuana and amphetamines. Substance use among medical professionals has become the subject of recent editorials.[ 39 , 40 ]

Substance use among children

The Global Youth Tobacco Survey[ 41 ] in 2006 showed that 3.8% of students smoke and 11.9% currently used smokeless tobacco. Tobacco as a gateway to other drugs of abuse has been the topic of a symposium.[ 42 ]

A study of 300 street child laborers in slums of Surat in 1993[ 43 ] showed that 135 (45%) used substances. The substances used were smoking tobacco, followed by chewable tobacco, snuff, cannabis and opioids. Injecting drug use[ 44 ] is also becoming apparent among street children as are inhalants.[ 45 ]

A study in the Andamans[ 46 ] shows that onset of regular use of alcohol in late childhood and early adolescence is associated with the highest rates of consumption in adult life, compared to later onset of drinking.

Studies in other populations

A majority of 250 rickshaw pullers interviewed in New Delhi[ 47 ] in 1986 reported using tobacco (79.2%), alcohol (54.4%), cannabis (8.0%) and opioids (0.8%). The substances reportedly helped them to be awake at night while working. In a study of prevalence of psychiatric illness in an industrial population[ 48 ] in 2007, harmful use/dependence on substances (42.83%) was the most common psychiatric condition. A study among industrial workers from Goa on hazardous alcohol use using the AUDIT and GHQ 12 estimated a prevalence of 211/1000 with hazardous drinking.[ 19 ]

Hospital-based studies

These studies have basically described profiles of substance use among patients and include patterns of alcohol use,[ 49 – 53 ] opioid use,[ 54 – 56 ] pediatric substance use,[ 57 ] female substance use,[ 58 ] children of alcoholics[ 59 ] and geriatric substance use.[ 60 ]

Alcohol misuse has been implicated in 20% of brain injuries[ 61 ] and 60% of all injuries in the emergency room setting.[ 62 ] In a retrospective study of emergency treatment seeking in Sikkim between 2000 and 2005,[ 63 ] substance use emergencies constituted 1.16% of total psychiatric emergencies. Alcohol withdrawal was the commonest cause for reporting to the emergency (57.4%).

Effects of substance use disorders

Mortality and morbidity due to alcohol and tobacco have been extensively reviewed elsewhere[ 35 , 64 – 66 ] and are beyond the scope of this review. The effects of cannabis have also been reviewed.[ 67 ] Mortality with injecting drug use is a serious concern with increase in crude mortality rates to 4.25 among injecting drug users compared to the general population.[ 68 ] Increased susceptibility to HIV/AIDS and other sexually transmitted diseases has been reported with alcohol[ 69 ] as well as injecting drug use.[ 70 ]

Clinical issues

Harmful alcohol use patterns among admitted patients in general hospital has highlighted the importance of routine screening and intervention in health care settings.[ 71 ]

Peer influence is a significant factor for heroin initiation.[ 72 ] Precipitants of relapse (dysfunction, stress and life events) differ among alcohol and opioid dependents.[ 73 ] Chronologies in the development of dependence have been evaluated in alcohol dependence.[ 74 , 75 ]

Craving a common determinant of relapse has been shown to reduce with increase in length of period of abstinence.[ 76 ]

Alcohol dependence constitutes a significant group among the psychiatric population in the Armed Forces.[ 77 ] A study of personality factors[ 78 ] among 100 alcohol dependent persons showed significantly high neuroticism, extroversion, anxiety, depression, psychopathic deviation, stressful life events and significantly low self-esteem as compared with normal control subjects. Alcohol dependence causes impairment in set shifting, visual scanning and response inhibition abilities and relative abstinence has been found to improve this deficit.[ 79 , 80 ] Alcohol use has had a significant association with head injury and cognitive deficits.[ 81 , 82 ] Persistent drinking is associated with persisting memory deficits in head injured alcohol dependent patients.[ 82 ] Mild intellectual impairment has been demonstrated in patients with bhang and ganja dependence.[ 83 – 86 ]

Kumar and Dhawan[ 87 ] found that health related reasons like death/physical complications due to drug use in peers and patients themselves, knowledge of HIV and difficulties in accessing veins were the main reason for reverse transition (shift from parenteral to inhalation route).

Evaluation and assessment

Diagnostic issues have focused on cross-system agreement[ 88 ] between ICD-10 and DSM IV, variability in diagnostic criteria across MAST, RDC, DSM and ICD[ 89 ] and suitability of MAST as a tool for detecting alcoholism.[ 90 ] The CIWA-A was found useful in monitoring alcohol withdrawal syndrome.[ 91 ]

The utility of liver functions for diagnosis of alcoholism and monitoring recovery has been demonstrated in clinical settings.[ 92 – 94 ] A range of hepatic dysfunction has been demonstrated through liver biopsies.[ 95 ]

A few studies have focused on scale development for motivation[ 96 , 97 ] and addiction related dysfunction[ 98 ] (Brief Addiction Rating Scale). An evaluation of two psychomotor tests comparing smokers and non-smokers found no differences across the two groups.[ 99 ]

Typology research has included validation of Babor’s[ 100 ] cluster A and B typologies, age of onset typology,[ 101 ] and a review on typology of alcoholism.[ 102 ]

Craving plays an important role in persistence of substance use and relapse. Frequency of craving has been shown to decrease with increase in length of abstinence among heroin dependent patients. Socio-cultural factors did not influence the subjective experience of craving.[ 76 ]

In a study of heroin dependent patients, their self-report moderately agreed with urinalysis using thin layer chromatography (TLC), gas liquid chromatography (GLC) and high performance liquid chromatography (HPLC).[ 103 ] The authors, however, recommend that all drug dependence treatment centers have facilities for drug testing in order to validate self-report.

Comorbidity/dual diagnosis

Cannabis related psychopathology has been a favorite topic of enquiry in both retrospective[ 104 , 105 ] and prospective studies[ 106 ] and vulnerability to affective psychosis has been highlighted. The controversial status of a specific cannabis withdrawal syndrome and cannabis psychosis has been reviewed.[ 67 ]

High life time prevalence of co-morbidity (60%) has been demonstrated among both opioid and alcohol dependent patients.[ 107 ] In alcohol dependence, high rates of depression and cluster B personality disorders[ 54 , 108 ] and phobia[ 109 ] have been demonstrated, but the need to revaluate for depressive symptoms after detoxification has been highlighted.[ 110 ] It is necessary to evaluate for ADHD, particularly in early onset alcohol dependent patients.[ 111 ] Seizures are overrepresented in subjects with alcohol and merit detailed evaluation.[ 112 ] Delirium and convulsions can also complicate opioid withdrawal states.[ 113 , 114 ] Skin disease,[ 115 ] and sexual dysfunction[ 116 ] have also been the foci of enquiry. Phenomenological similarities between alcoholic hallucinosis and paranoid schizophrenia have been discussed.[ 117 ] Opioid users with psychopathology[ 118 ] have diverse types of psychopathology as do users of other drugs.[ 119 ]

In a study of 22 dual diagnosed schizophrenia patients, substance use disorder preceded the onset of schizophrenic illness in the majority.[ 120 ] While one study found high rates of comorbid substance use (54%) in patients with schizophrenia with comorbid substance users showing more positive symptoms[ 121 ] which remitted more rapidly in the former group,[ 122 ] other studies suggest that substance use comorbidity in schizophrenia is low, and is an important contributor to better outcome in schizophrenia in developing countries like India.[ 123 , 124 ]

The diagnosis and management of dual diagnosis has been reviewed in detail.[ 125 ]

Social factors

Co-dependency has been described in spouses of alcoholics and found to correlate with the Addiction Severity scores of their husbands.[ 126 ] Coping behavior described among wives of alcoholics include avoidance, indulgence and fearful withdrawal.[ 127 ] These authors did not find any differences in personality between wives of alcoholics compared to controls.[ 128 ] Delusional jealousy and fighting behavior of substance abusers/dependents are important determinants of suicidal attempts among their spouses.[ 129 ] Parents of narcotic dependent patients, particularly mothers also show significant distress.[ 130 ]

BIOLOGY OF ADDICTION

An understanding of the cellular and molecular mechanisms of drug dependence has led to a reformulation of the etiology of this complex disorder.[ 131 ] An understanding of specific neurotransmitter systems has led to the development of specific pharmacotherapies for these disorders.

Cellular and molecular mechanisms

Altered alcohol metabolism due to polymorphisms in the alcohol metabolizing enzymes may influence clinical and behavioral toxicity due to alcohol. Erythrocyte aldehyde dehydrogenase was demonstrated to be suitable as a peripheral trait marker for alcohol dependence.[ 132 ] Single nucleotide polymorphism of the ALDH 2 gene has been studied in six Indian populations and provides the baseline for future studies in alcoholism.[ 133 ] An evaluation of ADH 1B and ALDH 2 gene polymorphism in alcohol dependence showed a high frequency of the ALDH2*2/*2 genotype among alcohol-dependent subjects.[ 134 ] DRD2 polymorphisms have been studied in patients with alcohol dependence, but a study in an Indian population failed to show a positive association. Genetic polymorphisms of the opioid receptor µ1 has been associated with alcohol and heroin addiction in a population from Eastern India.[ 135 ]

Neuro-imaging and electrophysiological studies

Certain individuals may develop early and severe problems due to alcohol misuse and be poorly responsive to treatment. Such vulnerability has been related to individual differences in brain functioning [ Figure 3 ]. Individuals with a high family history of alcoholism (specifically of the early-onset type, developing before 25 years of age) display a cluster of disinhibited behavioral traits, usually evident in childhood and persisting into adulthood.[ 136 ]

Brain volume differences between children and adolescents at high risk and low risk for alcohol dependence

Early onset drinking may be influenced by delayed brain maturation. Alcohol-naïve male offspring of alcohol-dependent fathers have smaller (or slowly maturing) brain volumes compared to controls in brain areas responsible for attention, motivation, judgment and learning.[ 137 , 138 ] The lag is hypothesized to work through a critical function of brain maturation-perhaps delayed myelination (insulation of brain pathways).

Functionally, this is thought to create a state of central nervous system hyperexcitability or disinhibition.[ 139 ] Individuals at risk have also been shown to have specific electro-physiological characteristics such as reduced amplitude of the P300 component of the event related potential.[ 140 , 141 ] Auditory P300 abnormalities have also been demonstrated among opiate dependent men and their male siblings.[ 142 ]

Such brain disinhibition is manifest by a spectrum of behavioral abnormalities such as inattention (low boredom thresholds), hyperactivity, impulsivity, oppositional behaviors and conduct problems, which are apparent from childhood and persist into adulthood. These brain processes not only promote impulsive risk-taking behaviors like early experimentation with alcohol and other substances but also appear to increase the reinforcement from alcohol while reducing the subjective appreciation of the level of intoxication, thus making it more likely that these individuals are likely not only to start experimenting with alcohol use at an early age but are more likely to have repeated episodes of bingeing.[ 143 ]

INTERVENTIONS, COURSE AND OUTCOME

Although there are a few review articles on pharmacological treatment of alcoholism,[ 144 , 145 ] there is a dearth of randomized studies on relapse prevention treatment in our setting.

Treatment of complications of substance use has been confined to case reports. A case report of thiamine resistant Wernicke Korsakoff Syndrome[ 146 ] successfully treated with a combination of magnesium sulphate and thiamine. Another case of subclinical psychological deterioration[ 147 ] (alcoholic dementia) improved with thiamine and vitamin B supplementation.

Pharmacological intervention

A randomized double blind study compared the effectiveness of detoxification with either lorazepam or chlordiazepoxide among hundred alcohol dependent inpatients with simple withdrawal. Lorazepam was found to be as effective as the more traditional drug chlordiazepoxide in attenuating alcohol withdrawal symptoms as assessed using the revised Clinical Institute Withdrawal Assessment for Alcohol scale.[ 148 ] This has implications for treatment in peripheral settings where liver function tests may not be available. However, benzodiazepines must be used carefully and monitored as dependence is very common.[ 149 ]

In a study closer to the real-world situation from Mumbai, 100 patients with alcohol dependence with stable families were randomized to receive disulfiram or topiramate. At the end of nine months, though patients on topiramate had less craving, a greater proportion of patients on disulfiram were abstinent (90% vs. 56%). Patients in the disulfiram group also had a longer time to their first drink and relapse.[ 150 ] Similar studies by the same authors and with similar methodology had earlier found that disulfiram was superior to acamprosate and Naltrexone. Though the study lacked blinding, it had an impressively low (8%) dropout rate.[ 151 , 152 ] A chart based review has shown there was no significant difference with regard to abstinence among the patients prescribed acamprosate, naltrexone or no drugs. Although patients on acamprosate had significantly better functioning, lack of randomization and variations in base line selection parameters may have influenced these findings.[ 153 ] Short term use of disulfiram among alcohol dependence patients with smoking was not associated with decrease pulmonary function test (FEV 1 ) and airway reactivity.[ 154 ]

Usefulness of clonidine for opioid detoxification has been described by various authors. These studies date back to 1980 when there was no alternative treatment for opioid dependence and clonidine emerged as the treatment of choice for detoxification in view of its anti adrenergic activity.[ 155 – 157 ] Sublingual buprenorphine for detoxification among these patients was reported as early as 1992. At that time the dose used was much lower, i.e. 0.6 -1.2 mg/ day which is in contrast to the current recommended dose of 6-16 mg/day. Comparison of buprenorphine (0.6-1.2 mg/ day) and clonidine (0.3-0.9 mg/day) for detoxification found no difference among treatment non completers. Maximum drop out occurred on the fifth day when withdrawal symptoms were very high.[ 158 ] A 24- week outcome study of buprenorphine maintenance in opiate users showed high retention rates of 81.5%, reduction in Addiction Severity Index scores and injecting drug use. Use of slow release oral morphine for opioid maintenance has also been reported.[ 159 ] Effectiveness of baclofen in reducing withdrawal symptoms among three patients with solvent dependence is reported.[ 160 ]

Psychosocial

Psychoeducational groups have been found to facilitate recovery in alcohol and drug dependence.[ 161 ] Family intervention therapy in addition to pharmacotherapy was shown to reduce the severity of alcohol intake and improve the motivation to stop alcohol in a case-control design study.[ 162 ] Several community based models of care have been developed with encouraging results.[ 163 ]

Course and outcome

An evaluation after five years, of 800 patients with alcohol dependence treated at a de-addiction center, found that 63% had not utilized treatment services beyond one month emphasizing the need to retain patients in follow-up.[ 164 ]

In a follow-up study on patients with alcohol dependence, higher income and longer duration of in-patient treatment were found to positively correlate with improved outcome at three month follow up. Outcome data was available for 52% patients; 81% of those maintained abstinence.[ 165 ] Maximum attrition was between three to six months. In a similar study among in-patients, 46% were abstinent. The drop out rate was 10% at the end of one year.[ 101 ] Studies done in the community setting have shown the effectiveness of continued care in predicting better outcome in alcohol dependence. In one study the patient group from a low socio-economic status who received weekly follow up or home visit at a clinic located within the slum showed improvement at the end of month 3, 6 and 9, and one year, in comparison with a control group that received no active follow-up intervention.[ 166 ] In a one-year prospective study of outcome following de-addiction treatment, poor outcome was associated with higher psychosocial problems, family history of alcoholism and more follow-up with mental health services.[ 167 ]

COMMUNITY INTERVENTIONS AND POLICIES

The camp approach for treatment of alcohol dependence was popularized by the TTK hospital camp approach at Manjakkudi in Tamil Nadu.[ 168 ] Treatment of alcohol and drug abuse in a camp setting as a model of drug de-addiction in the community through a 10 day camp treatment was found to have good retention rates and favorable outcome at six months.

Community perceptions of substance related problems are useful to understand for policy development. In a 1981 study in urban and rural Punjab of 1031 respondents, 45% felt people could not drink without producing bad effects on their health, 26.2% felt they could have one or two drinks per month without affecting their health. About one third felt it was alright to have one or two drinks on an occasion. 16.9% felt it was normal to drink ‘none at all’. Alcoholics were identified by behavior such as being dead drunk, drinking too much, having arguments and fights and creating public nuisance. Current users gave the most permissive responses and non-users the most restrictive responses regarding the norms for drinking.[ 169 ] The influence of cultural norms[ 170 ] has led the tendency to view drugs as ‘good’ and ‘bad’.

Simulations done in India have demonstrated that implementing a nationwide legal drinking age of 21 years in India, can achieve about 50-60 % of the alcohol consumption reducing effects compared to prohibition.[ 171 ] However, recently there are attempts to increase the permissible legal alcohol limit. This kind of contrarian approach does not make for coherent policy.

It has been argued that the 1970s saw an overzealous implementation of a simplistic model of supply and demand.[ 171 ] A presidential address[ 172 ] in 1991 emphasized the need for a multipronged approach to addressing alcohol-related problems. Existing programs have been identified as being patchy, poorly co-ordinated and poorly funded. Primary, secondary and tertiary approaches were discussed. The address highlighted the need for supply and demand side measures to address this significant public health problem. It highlighted the political and financial power of the alcohol industry and the social ambivalence to drinking. More recently, the need to have interventions for harmful and hazardous use, the need to develop evidence based combinations of pharmacotherapy and psychosocial interventions and stepped care solutions have been highlighted.[ 173 ] Standard treatment guidelines for alcohol and other drug use disorders have suggested specific measures at the primary, secondary and tertiary health care level, including at the solo physician level.[ 174 ] An earlier report in 1988 on training general practitioners on management of alcohol related problems[ 175 ] suggests that their involvement in alcohol and health education was modest, involvement in control and regulatory activities minimal, and they perceived no role in the development of a health and alcohol policy.

There have been reviews of the National Master Plan 1994, which envisaged different responsibilities for the Ministries of Health and the Ministry of Welfare (presently Social Justice and Empowerment) and the Drug Dependence Program 1996.[ 176 , 177 ] A proposal for adoption of a specialty section on addiction medicine[ 178 ] includes the development of a dedicated webpage, co-ordinated CMEs, commissioning of position papers, promoting demand reduction strategies and developing a national registry.

SUMMARY AND CONCLUSIONS

While epidemiological research has now provided us with figures for national-level prevalence, it would be prudent to recognize that there are regional differences in substance use prevalence and patterns. It is also prudent to recognize the dynamic nature of substance use. There is thus a need for periodic national surveys to determine changing prevalence and incidence of substance use. Substance use is associated with significant mortality and morbidity. Substance use among women and children is increasingly becoming the focus of attention and merits further research. Pharmaceutical drug abuse and inhalant use are serious concerns. For illicit drug use, rapid assessment surveys have provided insights into patterns and required responses. Drug related emergencies have not been adequately studied in the Indian context.

Biological research has focused on two broad areas, neurobiology of vulnerability and a few studies on molecular genetics. There is a great need for translation research based on the wider body of basic and animal research in the area.

Clinical research has primarily focused on alcohol. An area which has received relatively more attention in substance related comorbidity. There is very little research on development and adaptation of standardized tools for assessment and monitoring, and a few family studies. Ironically, though several evidence based treatments have now become available in the country, there are very few studies examining the utilization and effectiveness of these treatments, given that most treatment is presently unsubsidized and dependent on out of pocket expenditure. Both pharmacological and psychosocial interventions have disappointingly attracted little research. Course and outcome studies emphasize the need for better follow-up in this group.

While a considerable number of publications have lamented the lack of a coherent policy, the need for human resource enhancement and professional training and recommended a stepped-care multipronged approach, much remains to be done on the ground.

Finally, publication interest in the Indian Journal of Psychiatry in the area of substance use will undoubtedly increase, with the journal having become indexed.

Source of Support: Nil

Conflict of Interest: None declared