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• June 01, 2024 | VOL. 181, NO. 6 CURRENT ISSUE pp.461-564
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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 Link ,  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

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Article Contents

Introduction.

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Understanding reasons for drug use amongst young people: a functional perspective

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Annabel Boys, John Marsden, John Strang, Understanding reasons for drug use amongst young people: a functional perspective, Health Education Research , Volume 16, Issue 4, August 2001, Pages 457–469, https://doi.org/10.1093/her/16.4.457

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This study uses a functional perspective to examine the reasons young people cite for using psychoactive substances. The study sample comprised 364 young poly-drug users recruited using snowball-sampling methods. Data on lifetime and recent frequency and intensity of use for alcohol, cannabis, amphetamines, ecstasy, LSD and cocaine are presented. A majority of the participants had used at least one of these six drugs to fulfil 11 of 18 measured substance use functions. The most popular functions for use were using to: relax (96.7%), become intoxicated (96.4%), keep awake at night while socializing (95.9%), enhance an activity (88.5%) and alleviate depressed mood (86.8%). Substance use functions were found to differ by age and gender. Recognition of the functions fulfilled by substance use should help health educators and prevention strategists to make health messages about drugs more relevant and appropriate to general and specific audiences. Targeting substances that are perceived to fulfil similar functions and addressing issues concerning the substitution of one substance for another may also strengthen education and prevention efforts.

The use of illicit psychoactive substances is not a minority activity amongst young people in the UK. Results from the most recent British Crime Survey show that some 50% of young people between the ages of 16 and 24 years have used an illicit drug on at least one occasion in their lives (lifetime prevalence) ( Ramsay and Partridge, 1999 ). Amongst 16–19 and 20–24 year olds the most prevalent drug is cannabis (used by 40% of 16–19 year olds and 47% of 20–24 year olds), followed by amphetamine sulphate (18 and 24% of the two age groups respectively), LSD (10 and 13%) and ecstasy (8 and 12%). The lifetime prevalence for cocaine hydrochloride (powder cocaine) use amongst the two age groups is 3 and 9%, respectively. Collectively, these estimates are generally comparable with other European countries ( European Monitoring Centre for Drugs and Drug Addiction, 1998 ) and the US ( Johnston et al ., 1997 , 2000 ).

The widespread concern about the use of illicit drugs is reflected by its high status on health, educational and political agendas in many countries. The UK Government's 10-year national strategy on drug misuse identifies young people as a critical priority group for prevention and treatment interventions ( Tackling Drugs to Build a Better Britain 1998 ). If strategies to reduce the use of drugs and associated harms amongst the younger population are to be developed, particularly within the health education arena, it is vital that we improve our understanding of the roles that both licit and illicit substances play in the lives of young people. The tendency for educators, practitioners and policy makers to address licit drugs (such as alcohol) separately from illegal drugs may be unhelpful. This is partly because young illicit drug users frequently drink alcohol, and may have little regard for the illicit and licit distinction established by the law. To understand the roles that drug and alcohol use play in contemporary youth culture, it is necessary to examine the most frequently used psychoactive substances as a set.

It is commonplace for young drug users to use several different psychoactive substances. The terms `poly-drug' or `multiple drug' use have been used to describe this behaviour although their exact definitions vary. The term `poly-drug use' is often used to describe the use of two or more drugs during a particular time period (e.g. over the last month or year). This is the definition used within the current paper. However, poly-drug use could also characterize the use of two or more psychoactive substances so that their effects are experienced simultaneously. We have used the term `concurrent drug use' to denote this pattern of potentially more risky and harmful drug use ( Boys et al. 2000a ). Previous studies have reported that users often use drugs concurrently to improve the effects of another drug or to help manage its negative effects [e.g. ( Power et al ., 1996 ; Boys et al. 2000a ; Wibberley and Price, 2000 )].

The most recent British Crime Survey found that 5% of 16–29 year olds had used more than one drug in the last month ( Ramsay and Partridge, 1999 ). Given that 16% of this age band reported drug use in the month prior to interview, this suggests that just under a third of these individuals had used more than one illicit substance during this time period. With alcohol included, the prevalence of poly-drug use is likely to be much higher.

There is a substantial body of literature on the reasons or motivations that people cite for using alcohol, particularly amongst adult populations. For example, research on heavy drinkers suggested that alcohol use is related to multiple functions for use ( Edwards et al ., 1972 ; Sadava, 1975 ). Similarly, research with a focus on young people has sought to identify motives for illicit drug use. There is evidence that for many young people, the decision to use a drug is based on a rational appraisal process, rather than a passive reaction to the context in which a substance is available ( Boys et al. 2000a ; Wibberley and Price, 2000 ). Reported reasons vary from quite broad statements (e.g. to feel better) to more specific functions for use (e.g. to increase self-confidence). However, much of this literature focuses on `drugs' as a generic concept and makes little distinction between different types of illicit substances [e.g. ( Carman, 1979 ; Butler et al ., 1981 ; Newcomb et al ., 1988 ; Cato, 1992 ; McKay et al ., 1992 )]. Given the diverse effects that different drugs have on the user, it might be proposed that reasons for use will closely mirror these differences. Thus stimulant drugs (such as amphetamines, ecstasy or cocaine) will be used for reasons relating to increased nervous system arousal and drugs with sedative effects (such as alcohol or cannabis), with nervous system depression. The present study therefore selected a range of drugs commonly used by young people with stimulant, sedative or hallucinogenic effects to examine this issue further.

The phrase `instrumental drug use' has been used to denote drug use for reasons specifically linked to a drug's effects ( WHO, 1997 ). Examples of the instrumental use of amphetamine-type stimulants include vehicle drivers who report using to improve concentration and relieve tiredness, and people who want to lose weight (particularly young women), using these drugs to curb their appetite. However, the term `instrumental substance use' seems to be used when specific physical effects of a drug are exploited and does not encompass use for more subtle social or psychological purposes which may also be cited by users. In recent reports we have described a `drug use functions' model to help understand poly-substance use phenomenology amongst young people and how decisions are made about patterns of consumption ( Boys et al ., 1999a , b , 2000a ). The term `function' is intended to characterize the primary or multiple reasons for, or purpose served by, the use of a particular substance in terms of the actual gains that the user perceives that they will attain. In the early, 1970s Sadava suggested that functions were a useful means of understanding how personality and environmental variables impacted on patterns of drug use ( Sadava, 1975 ). This work was confined to functions for cannabis and `psychedelic drugs' amongst a sample of college students. To date there has been little research that has examined the different functions associated with the range of psychoactive substances commonly used by young poly-drug users. It is unclear if all drugs with similar physical effects are used for similar purposes, or if other more subtle social or psychological dimensions to use are influential. Work in this area will help to increase understanding of the different roles played by psychoactive substances in the lives of young people, and thus facilitate health, educational and policy responses to this issue.

Previous work has suggested that the perceived functions served by the use of a drug predict the likelihood of future consumption ( Boys et al ., 1999a ). The present study aims to develop this work further by examining the functional profiles of six substances commonly used by young people in the UK.

Patterns of cannabis, amphetamine, ecstasy, LSD, cocaine hydrochloride and alcohol use were examined amongst a sample of young poly-drug users. Tobacco use was not addressed in the present research.

Sampling and recruitment

A snowball-sampling approach was employed for recruitment of participants. Snowball sampling is an effective way of generating a large sample from a hidden population where no formal sampling frame is available ( Van Meter, 1990 ). A team of peer interviewers was trained to recruit and interview participants for the study. We have described this procedure in detail elsewhere and only essential features are described here ( Boys et al. 2000b ). Using current or ex-drug users to gather data from hidden populations of drug using adults has been found to be successful ( Griffiths et al ., 1993 ; Power, 1995 ).

Study participants

Study participants were current poly-substance users with no history of treatment for substance-related disorders. We excluded people with a treatment history on the assumption that young people who have had substance-related problems requiring treatment represent a different group from the general population of young drug users. Inclusion criteria were: aged 16–22 years and having used two or more illegal substances during the past 90 days. During data collection, the age, gender and current occupation of participants were recorded and monitored to ensure that sufficient individuals were recruited to the groups to permit subgroup analyses. If an imbalance was observed in one of these variables, the interviewers were instructed to target participants with specific characteristics (e.g. females under the age of 18) to redress this imbalance.

Study measures

Data were collected using a structured interviewer-administered questionnaire developed specifically for the study. In addition to recording lifetime substance use, questions profiled consumption patterns of six substances in detail. Data were collected between August and November 1998. Interviews were audiotaped with the interviewee's consent. This enabled research staff to verify that answers had been accurately recorded on the questionnaire and that the interview had been conducted in accordance with the research protocol. Research staff also checked for consistency across different question items (e.g. the total number of days of drug use in the past 90 days should equal or exceed the number of days of cannabis use during the same time period). On the few occasions where inconsistencies were identified that could not be corrected from the tape, the interviewer was asked to re-contact the interviewee to verify the data.

Measures of lifetime use, consumption in the past year and past 90 days were based on procedures developed by Marsden et al . ( Marsden et al ., 1998 ). Estimated intensity of consumption (amount used on a typical using day) was recorded verbatim and then translated into standardized units at the data entry stage.

Functions for substance use scale

The questionnaire included a 17-item scale designed to measure perceived functions for substance use. This scale consisted of items developed in previous work ( Boys et al ., 1999a ) in addition to functions derived from qualitative interviews ( Boys et al ., 1999b ), new literature and informal discussions with young drug users. Items were drawn from five domains (Table I ).

Participants were asked if they had ever used a particular drug in order to fulfil each specific function. Those who endorsed the item were then invited to rate how frequently they had used it for this purpose over the past year, using a five-point Likert-type scale (`never' to `always'; coded 0–4). One item differed between the function scales used for the stimulant drugs and for alcohol and cannabis. For the stimulant drugs (amphetamines, cocaine and ecstasy) the item `have you ever used [named drug] to help you to lose weight' was used, for cannabis and alcohol this item was replaced with `have you ever used [drug] to help you to sleep?'. (The items written in full as they appeared in the questionnaire are shown in Table III , together with abbreviations used in this paper.)

Statistical procedures

The internal reliability of the substance use functions scales for each of the six substances was judged using Chronbach's α coefficient. Chronbach's α is a statistic that reflects the extent to which each item in a measurement scale is associated with other items. Technically it is the average of correlations between all possible comparisons of the scale items that are divided into two halves. An α coefficient for a scale can range from 0 (no internal reliability) to 1 (complete reliability). Analyses of categorical variables were performed using χ 2 statistic. Differences in scale means were assessed using t -tests.

The sample consisted of 364 young poly-substance users (205 males; 56.3%) with a mean age of 19.3 years; 69.8% described their ethnic group as White-European, 12.6% as Black and 10.1% were Asian. Just over a quarter (27.5%) were unemployed at the time of interview; a third were in education, 28.8% were in full-time work and the remainder had part-time employment. Estimates of monthly disposable income (any money that was spare after paying for rent, bills and food) ranged from 0 to over £1000 (median = £250).

Substance use history

The drug with the highest lifetime prevalence was cannabis (96.2%). This was followed by amphetamine sulphate (51.6%), cocaine hydrochloride (50.5%) (referred to as cocaine hereafter) and ecstasy (48.6%). Twenty-five percent of the sample had used LSD and this was more common amongst male participants (χ 2 [1] = 9.68, P < 0.01). Other drugs used included crack cocaine (25.5%), heroin (12.6%), tranquillizers (21.7%) and hallucinogenic mushrooms (8.0%). On average, participants had used a total of 5.2 different psychoactive substances in their lives (out of a possible 14) (median = 4.0, mode = 3.0, range 2–14). There was no gender difference in the number of different drugs ever used.

Table II profiles use of the six target drugs over the past year, and the frequency and intensity of use in the 90 days prior to interview.

There were no gender differences in drug use over the past year or in the past 90 days with the exception of amphetamines. For this substance, females who had ever used this drug were more likely to have done so during the past 90 days than males (χ 2 [1] = 4.14, P < 0.05). The mean number of target drugs used over the past 90 days was 3.2 (median = 3.0, mode = 3.0, range 2–6). No gender differences were observed. Few differences were also observed in the frequency and intensity of use. Males reported drinking alcohol more frequently during the three months prior to interview ( t [307] = 2.48, P < 0.05) and using cannabis more intensively on a `typical using day' ( t [337] = 3.56, P < 0.001).

Perceived functions for substance use

There were few differences between the functions endorsed for use of each drug `ever' and those endorsed for use during `the year prior to interview'. This section therefore concentrates on data for the year prior to interview. We considered that in order to use a drug for a specific function, the user must have first hand knowledge of the drug's effects before making this decision. Consequently, functions reported by individuals who had only used a particular substance on one occasion in their lives (i.e. with no prior experience of the drug at the time they made the decision to take it) were excluded from the analyses. Table III summarizes the proportion of the sample who endorsed each of the functions for drugs used in the past year. Roman numerals have been used to indicate the functions with the top five average scores. Table III also shows means for the total number of different items endorsed by individual users and the internal reliability of the function scales for each substance using Chronbach's α coefficients. There were no significant gender differences in the total number of functions endorsed for any of the six substances.

The following sections summarize the top five most popular functions drug-by-drug together with any age or gender differences observed in the items endorsed.

Cannabis use ( n = 345)

Overall the most popular functions for cannabis use were to `RELAX' (endorsed by 96.8% of people who had used the drug in the last year), to become `INTOXICATED' (90.7%) and to `ENHANCE ACTIVITY' (72.8%). Cannabis was also commonly used to `DECREASE BOREDOM' (70.1%) and to `SLEEP' (69.6%) [this item was closely followed by using to help `FEEL BETTER' (69.0%)]. Nine of the 17 function items were endorsed by over half of those who had used cannabis on more than one occasion in the past year. There were no significant gender differences observed, with the exception of using to `KEEP GOING', where male participants were significantly more likely to say that they had used cannabis to fulfil this function in the past year (χ 2 [1] = 6.10, P < 0.05).

There were statistically significant age differences on four of the function variables: cannabis users who reported using this drug in the past year to help feel `ELATED/EUPHORIC' or to help `SLEEP' were significantly older than those who had not used cannabis for these purposes (19.6 versus 19.0; t [343] = 3.32, P < 0.001; 19.4 versus 19.0; t [343] = 2.01, P < 0.05). In contrast, those who had used cannabis to `INCREASE CONFIDENCE' and to `STOP WORRYING' tended to be younger than those who did not (19.0 versus 19.4; t [343] = –2.26, P < 0.05; 19.1 versus 19.5; t [343] = –1.99, P < 0.05).

Amphetamines ( n = 160)

Common functions for amphetamine use were to `KEEP GOING' (95.6%), to `STAY AWAKE' (91.3%) or to `ENHANCE ACTIVITY' (66.2%). Using to help feel `ELATED/EUPHORIC' (60.6%) and to `ENJOY COMPANY' (58.1%) were also frequently mentioned. Seven of the 17 function items were endorsed by over half of participants who had used amphetamines in the past year. As with cannabis, gender differences were uncommon: females were more likely to use amphetamines to help `LOSE WEIGHT' than male participants (χ 2 [1] = 21.67, P < 0.001).

Significant age differences were found on four function variables. Individuals who reported using amphetamines in the past year to feel `ELATED/EUPHORIC' were significantly older than those who did not (19.9 versus 19.0; t [158] = 2.87, P < 0.01). In contrast, participants who used amphetamines to `STOP WORRYING' (18.8 versus 19.8; t [158] = –2.77, P < 0.01), to `DECREASE BOREDOM' (19.2 versus 19.9; t [158] = –2.39, P < 0.05) or to `ENHANCE ACTIVITY' (19.3 versus 20.1; t [158] = –2.88, P < 0.01) were younger than those who had not.

Ecstasy ( n = 157)

The most popular five functions for using ecstasy were similar to those for amphetamines. The drug was used to `KEEP GOING' (91.1%), to `ENHANCE ACTIVITY' (79.6%), to feel `ELATED/EUPHORIC' (77.7%), to `STAY AWAKE' (72.0%) and to get `INTOXICATED' (68.2%). Seven of the 17 function items were endorsed by over half of those who had used ecstasy in the past year. Female users were more likely to use ecstasy to help `LOSE WEIGHT' than male participants (Fishers exact test, P < 0.001).

As with the other drugs discussed above, participants who reported using ecstasy to feel `ELATED/EUPHORIC' were significantly older than those who did not (19.8 versus 18.9; t [155] = 2.61, P < 0.01). In contrast, those who had used ecstasy to `FEEL BETTER' (19.3 versus 20.0; t [155] = –2.29, P < 0.05), to `INCREASE CONFIDENCE' (19.2 versus 19.9; t [155] = –2.22, P < 0.05) and to `STOP WORRYING' (19.0 versus 19.9; t [155] = –2.96, P < 0.01) tended to be younger.

LSD ( n = 58)

Of the six target substances examined in this study, LSD was associated with the least diverse range of functions for use. All but two of the function statements were endorsed by at least some users, but only five were reported by more than 50%. The most common purpose for consuming LSD was to get `INTOXICATED' (77.6%). Other popular functions included to feel `ELATED/EUPHORIC' and to `ENHANCE ACTIVITY' (both endorsed by 72.4%), and to `KEEP GOING' and to `ENJOY COMPANY' (both endorsed by 58.6%). Unlike the other substances examined, no gender or age differences were observed.

Cocaine ( n = 168)

In common with ecstasy and amphetamines, the most widely endorsed functions for cocaine use were to help `KEEP GOING' (84.5%) and to help `STAY AWAKE' (69.0%). Consuming cocaine to `INCREASE CONFIDENCE' and to get `INTOXICATED' (both endorsed by 66.1%) were also popular. However, unlike the other stimulant drugs, 61.9% of the cocaine users reported using to `FEEL BETTER'. Ten of the 17 function items were endorsed by over half of those who had used cocaine in the past year.

Gender differences were more common amongst functions for cocaine use than the other substances surveyed. More males reported using cocaine to `IMPROVE EFFECTS' of other drugs (χ 2 [1] = 4.00, P < 0.05); more females used the drug to help `STAY AWAKE' (χ 2 [1] = 12.21, P < 0.001), to `LOSE INHIBITIONS' (χ 2 [1] = 9.01, P < 0.01), to `STOP WORRYING' (χ 2 [1] = 8.11, P < 0.01) or to `ENJOY COMPANY' of friends (χ 2 [1] = 4.34, P < 0.05). All participants who endorsed using cocaine to help `LOSE WEIGHT' were female.

Those who had used cocaine to `FEEL BETTER' (18.9 versus 19.8; t [166] = –3.06, P < 0.01), to `STOP WORRYING' (18.6 versus 19.7; t [166] = –3.86, P < 0.001) or to `DECREASE BOREDOM' (18.9 versus 19.6; t [166] = –2.52, P < 0.05) were significantly younger than those who did not endorse these functions. Similar to the other drugs, participants who had used cocaine to feel `ELATED/EUPHORIC' in the past year tended to be older than those who had not (19.6 versus 18.7; t [166] = 3.16, P < 0.01).

Alcohol ( n = 312)

The functions for alcohol use were the most diverse of the six substances examined. Like LSD, the most commonly endorsed purpose for drinking was to get `INTOXICATED' (89.1%). Many used alcohol to `RELAX' (82.7%), to `ENJOY COMPANY' (74.0%), to `INCREASE CONFIDENCE' (70.2%) and to `FEEL BETTER' (69.9%). Overall, 11 of the 17 function items were endorsed by over 50% of those who had drunk alcohol in the past year. Male participants were more likely to report using alcohol in combination with other drugs either to `IMPROVE EFFECTS' of other drugs (χ 2 [1] = 4.56, P < 0.05) or to ease the `AFTER EFFECTS' of other substances (χ 2 [1] = 7.07, P < 0.01). More females than males reported that they used alcohol to `DECREASE BOREDOM' (χ 2 [1] = 4.42, P < 0.05).

T -tests revealed significant age differences on four of the function variables: those who drank to feel `ELATED/EUPHORIC' were significantly older (19.7 versus 19.0; t [310] = 3.67, P < 0.001) as were individuals who drank to help them to `LOSE INHIBITIONS' (19.6 versus 19.0; t [310] = 2.36, P < 0.05). In contrast, participants who reported using alcohol just to get `INTOXICATED' (19.2 versus 20.3; t [310] = –3.31, P < 0.001) or to `DECREASE BOREDOM' (19.2 versus 19.6; t [310] = –2.25, P < 0.05) were significantly younger than those who did not.

Combined functional drug use

The substances used by the greatest proportion of participants to `IMPROVE EFFECTS' from other drugs were cannabis (44.3%), alcohol (41.0%) and amphetamines (37.5%). It was also common to use cannabis (64.6%) and to a lesser extent alcohol (35.9%) in combination with other drugs in order to help manage `AFTER EFFECTS'. Amphetamines, ecstasy, LSD and cocaine were also used for these purposes, although to a lesser extent. Participants who endorsed the combination drug use items were asked to list the three main drugs with which they had combined the target substance for these purposes. Table IV summarizes these responses.

Overall functions for drug use

In order to examine which functions were most popular overall, a dichotomous variable was created for each different item to indicate if one or more of the six target substances had been used to fulfil this purpose during the year prior to interview. For example, if an individual reported that they had used cannabis to relax, but their use of ecstasy, amphetamines and alcohol had not fulfilled this function, then the variable for `RELAX' was scored `1'. Similarly if they had used all four of these substances to help them to relax in the past year, the variable would again be scored as `1'. A score of `0' indicates that none of the target substances had been used to fulfil a particular function. Table V summarizes the data from these new variables.

Over three-quarters of the sample had used at least one target substance in the past year for 11 out of the 18 functions listed. The five most common functions for substance use overall were to `RELAX' (96.7%); `INTOXICATED' (96.4%); `KEEP GOING' (95.9%); `ENHANCE ACTIVITY' (88.5%) and `FEEL BETTER' (86.8%). Despite the fact that `SLEEP' was only relevant to two substances (alcohol and cannabis), it was still endorsed by over 70% of the total sample. Using to `LOSE WEIGHT' was only relevant to the stimulant drugs (amphetamines, ecstasy and cocaine), yet was endorsed by 17.3% of the total sample (almost a third of all female participants). Overall, this was the least popular function for recent substance use, followed by `WORK' (32.1%). All other items were endorsed by over 60% of all participants.

Gender differences were identified in six items. Females were significantly more likely to have endorsed the following: using to `INCREASE CONFIDENCE' (χ 2 [1] = 4.41, P < 0.05); `STAY AWAKE' (χ 2 [1] = 5.36, P < 0.05), `LOSE INHIBITIONS' (χ 2 [1] = 4.48, P < 0.05), `ENHANCE SEX' (χ 2 [1] = 5.17, P < 0.05) and `LOSE WEIGHT' (χ 2 [1] = 29.6, P < 0.001). In contrast, males were more likely to use a substance to `IMPROVE EFFECTS' of another drug (χ 2 [1] = 11.18, P < 0.001).

Statistically significant age differences were identified in three of the items. Those who had used at least one of the six target substances in the last year to feel `ELATED/EUPHORIC' (19.5 versus 18.6; t [362] = 4.07, P < 0.001) or to `SLEEP' (19.4 versus 18.9; t [362] = 2.19, P < 0.05) were significantly older than those who had not used for this function. In contrast, participants who had used in order to `STOP WORRYING' tended to be younger (19.1 versus 19.7; t [362] = –2.88, P < 0.01).

This paper has examined psychoactive substance use amongst a sample of young people and focused on the perceived functions for use using a 17-item scale. In terms of the characteristics of the sample, the reported lifetime and recent substance use was directly comparable with other samples of poly-drug users recruited in the UK [e.g. ( Release, 1997 )].

Previous studies which have asked users to give reasons for their `drug use' overall instead of breaking it down by drug type [e.g. ( Carman, 1979 ; Butler et al ., 1981 ; Newcomb et al ., 1988 ; Cato, 1992 ; McKay et al ., 1992 )] may have overlooked the dynamic nature of drug-related decision making. A key finding from the study is that that with the exception of two of the functions for use scale items (using to help sleep or lose weight), all of the six drugs had been used to fulfil all of the functions measured, despite differences in their pharmacological effects. The total number of functions endorsed by individuals for use of a particular drug varied from 0 to 15 for LSD, and up to 17 for cannabis, alcohol and cocaine. The average number ranged from 5.9 (for LSD) to 9.0 (for cannabis). This indicates that substance use served multiple purposes for this sample, but that the functional profiles differed between the six target drugs.

We have previously reported ( Boys et al. 2000b ) that high scores on a cocaine functions scale are strongly predictive of high scores on a cocaine-related problems scale. The current findings support the use of similar function scales for cannabis, amphetamines, LSD and ecstasy. It remains to be seen whether similar associations with problem scores exist. Future developmental work in this area should ensure that respondents are given the opportunity to cite additional functions to those included here so that the scales can be further extended and refined.

Recent campaigns that have targeted young people have tended to assume that hallucinogen and stimulant use is primarily associated with dance events, and so motives for use will relate to this context. Our results support assumptions that these drugs are used to enhance social interactions, but other functions are also evident. For example, about a third of female interviewees had used a stimulant drug to help them to lose weight. Future education and prevention efforts should take this diversity into account when planning interventions for different target groups.

The finding that the same functions are fulfilled by use of different drugs suggests that at least some could be interchangeable. Evidence for substituting alternative drugs to fulfil a function when a preferred drug is unavailable has been found in other studies [e.g. ( Boys et al. 2000a )]. Prevention efforts should perhaps focus on the general motivations behind use rather than trying to discourage use of specific drug types in isolation. For example, it is possible that the focus over the last decade on ecstasy prevention may have contributed inadvertently to the rise in cocaine use amongst young people in the UK ( Boys et al ., 1999c ). It is important that health educators do not overlook this possibility when developing education and prevention initiatives. Considering functions that substance use can fulfil for young people could help us to understand which drugs are likely to be interchangeable. If prevention programmes were designed to target a range of substances that commonly fulfil similar functions, then perhaps this could address the likelihood that some young people will substitute other drugs if deterred from their preferred substance.

There has been considerable concern about the perceived increase in the number of young people who are using cocaine in the UK ( Tackling Drugs to Build a Better Britain 1998 ; Ramsay and Partridge, 1999 ; Boys et al. 2000b ). It has been suggested that, for a number of reasons, cocaine may be replacing ecstasy and amphetamines as the stimulant of choice for some young people ( Boys et al ., 1999c ). The results from this study suggest that motives for cocaine use are indeed similar to those for ecstasy and amphetamine use, e.g. using to `keep going' on a night out with friends, to `enhance an activity', `to help to feel elated or euphoric' or to help `stay awake'. However, in addition to these functions which were shared by all three stimulants, over 60% of cocaine users reported that they had used this drug to `help to feel more confident' in a social situation and to `feel better when down or depressed'. Another finding that sets cocaine aside from ecstasy and amphetamines was the relatively common existence of gender differences in the function items endorsed. Female cocaine users were more likely to use to help `stay awake', `lose inhibitions', `stop worrying', `enjoy company of friends' or to help `lose weight'. This could indicate that women are more inclined to admit to certain functions than their male counterparts. However, the fact that similar gender differences were not observed in the same items for the other five substances, suggests this interpretation is unlikely. Similarly, the lack of gender differences in patterns of cocaine use (both frequency and intensity) suggests that these differences are not due to heavier cocaine use amongst females. If these findings are subsequently confirmed, this could point towards an inclination for young women to use cocaine as a social support, particularly to help feel less inhibited in social situations. If so, young female cocaine users may be more vulnerable to longer-term cocaine-related problems.

Many respondents reported using alcohol or cannabis to help manage effects experienced from another drug. This has implications for the choice of health messages communicated to young people regarding the use of two or more different substances concurrently. Much of the literature aimed at young people warns them to avoid mixing drugs because the interactive effects may be dangerous [e.g. ( HIT, 1996 )]. This `Just say No' type of approach does not take into consideration the motives behind mixing drugs. In most areas, drug education and prevention work has moved on from this form of communication. A more sophisticated approach is required, which considers the functions that concurrent drug use is likely to have for young people and tries to amend messages to make them more relevant and acceptable to this population. Further research is needed to explore the motivations for mixing different combinations of drugs together.

Over three-quarters of the sample reported using at least one of the six target substances to fulfil 11 out of the 18 functions. These findings provide strong evidence that young people use psychoactive drugs for a range of distinct purposes, not purely dependent on the drug's specific effects. Overall, the top five functions were to `help relax', `get intoxicated', `keep going', `enhance activity' and `feel better'. Each of these was endorsed by over 85% of the sample. Whilst all six substances were associated to a greater or lesser degree with each of these items, there were certain drugs that were more commonly associated with each. For example, cannabis and alcohol were popular choices for relaxation or to get intoxicated. In contrast, over 90% of the amphetamine and ecstasy users reported using these drugs within the last year to `keep going'. Using to enhance an activity was a common function amongst users of all six substances, endorsed by over 70% of ecstasy, cannabis and LSD users. Finally, it was mainly alcohol and cannabis (and to a lesser extent cocaine) that were used to `feel better'.

Several gender differences were observed in the combined functions for recent substance use. These findings indicate that young females use other drugs as well as cocaine as social supports. Using for specific physical effects (weight loss, sex or wakefulness) was also more common amongst young women. In contrast, male users were significantly more likely to report using at least one of the target substances to try to improve the effects of another substance. This indicates a greater tendency for young males in this sample to mix drugs than their female counterparts. Age differences were also observed on several function items: participants who had used a drug to `feel elated or euphoric' or to `help sleep' tended to be older and those who used to `stop worrying about a problem' were younger. If future studies confirm these differences, education programmes and interventions might benefit from tailoring their strategies for specific age groups and genders. For example, a focus on stress management strategies and coping skills with a younger target audience might be appropriate.

Some limitations of the study need to be acknowledged. The sample for this study was recruited using a snowball-sampling methodology. Although it does not yield a random sample of research participants, this method has been successfully used to access hidden samples of drug users [e.g. ( Biernacki, 1986 ; Lenton et al ., 1997 )]. Amongst the distinct advantages of this approach are that it allows theories and models to be tested quantitatively on sizeable numbers of subjects who have engaged in a relatively rare behaviour.

Further research is now required to determine whether our observations may be generalized to other populations (such as dependent drug users) and drug types (such as heroin, tranquillizers or tobacco) or if additional function items need to be developed. Future studies should also examine if functions can be categorized into primary and subsidiary reasons and how these relate to changes in patterns of use and drug dependence. Recognition of the functions fulfilled by substance use could help inform education and prevention strategies and make them more relevant and acceptable to the target audiences.

Structure of functions scales

Profile of substance use over the past year and past 90 days ( n = 364)

Proportion (%) of those who have used [substance] more than once, who endorsed each functional statement for their use in the past year

Combined functional substance use reported by the sample over the past year

Percentage of participants who reported having used at least one of the target substances to fulfil each of the different functions over the past year ( n = 364)

We gratefully acknowledge research support from the Health Education Authority (HEA). The views expressed in this paper are those of the authors and do not necessarily reflect those of the HEA. We would also like to thank the anonymous referees for helpful comments and suggestions on an earlier draft of this paper.

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Burden of drug use disorders in the United States from 1990 to 2021 and its projection until 2035: results from the GBD study

• Tongchao Zhang 1 , 2   na1 ,
• Lin Sun 3   na1 ,
• Xiaolin Yin 1 , 2 ,
• Hui Chen 1 , 2 ,
• Lejin Yang 4 &
• Xiaorong Yang 1 , 2  

BMC Public Health volume  24 , Article number:  1639 ( 2024 ) Cite this article

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Metrics details

Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic progress. The United States (US) also suffers a heavy burden, it is necessary to figure out the situation from multiple perspectives and take effective measures to deal with it. Therefore, using the data from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, we evaluated this topic.

Annual data on DUDs-related burden were collected from the GBD study 2021. We calculated the indicator of estimated annual percentage change (EAPC) to evaluate the changing trend of burden. The Bayesian model for age-period-cohort was introduced to forecast the burden.

In 2021, the number and age-standardized rate of prevalence were particularly prominent, with 12,146.95 thousand and 3821.43 per 100,000, respectively. Higher burden was also observed in males, 15–45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia; and the national death-related burden with the highest increase (EAPC = 7.96). Other significant inverse associations were seen between EAPC, age-standardized rates, and socio-demographic index (SDI). Moreover, in the next 14 years, the projected DUDs burden remains exigent.

Conclusions

The burden of DUDs in the US is heavy and has been enlarging. This study proposes that greater attention should be paid to the strategies in males, the younger population, opioid use disorders, and low-SDI states implemented by decision-makers to achieve goals such as reducing burden.

Peer Review reports

Drug use disorders (DUDs), refer to the forced and endless use of certain drugs with dependency characteristics in the pursuit of special psychological effects rather than medical purposes, can cause serious psychological, physiological consequences, and social problems [ 1 , 2 , 3 ], including cognitive impairment, suicidal tendencies, decreased quality of life, and risk of infectious diseases [ 4 , 5 , 6 , 7 ]. DUDs continue to be a heavy burden globally, according to the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019, DUDs were in the top 20 leading causes of disability-adjusted life years (DALYs) in the 10–49-year age groups in 2019 [ 8 ]. Meanwhile, the World Drug Report 2023 indicated that, in 2021, over 296 million people worldwide used drugs; and the number of people suffering from DUDs has soared to 39.5 million, an increase of 45% in the past 10 years [ 9 ]. However, only one-fifth of people with drug-related disorders received medication treatment, and the gap in access to treatment among regions continued to widen [ 9 ].

Notably, the United States (US) is one of the countries with a heavy DUDs-related burden [ 1 , 8 ]. According to the GBD study, in 2019, over half of the death cases due to DUDs worldwide occurred in the US [ 1 , 8 ]. The GBD database has the advantage of systematic analysis and integration of global disease and health data, and the adoption of the GBD data can provide policymakers, researchers, and the public with comprehensive insights into the status of DUD in the US. Therefore, in this study, we retrieved detailed data on the latest burden of DUDs from the GBD study (2021) to fully investigate the magnitude and temporal trends of burden due to DUDs in the US from 1990 to 2021 by age, sex, state, and drug categories; and attempted to predict the burden in the next 14 years. Our results can be helpful for the country to develop more effective population-specific policies and methods.

Materials and methods

Data collection and case definition.

Similar to the GBD study 2019, the data collection, processing, and overall analysis methods of the GBD study (2021) have been reported in detail previously [ 10 , 11 , 12 ]. We collected the data on DUDs-related burden from the Institute for Health Metrics and Evaluation (IHME, https://vizhub.healthdata.org/gbd-results/ ). We obtained the data on DUDs-related burden about the numbers (in thousands), rates (per 100,000 population), and age-standardized rates (per 100,000 population) of incidence, prevalence, deaths, and DALYs by age, sex, and state from 1990 to 2021. Meanwhile, the information about the socio-demographic index (SDI, an indicator that was calculated based on the fertility rate, education, and income) for the states was also collected [ 10 , 11 , 12 ].

In the GBD study (2021), the DUDs were defined based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or the International Classification of Diseases (ICD-10) diagnostic criteria, including opioid use disorders, cocaine use disorders, cannabis use disorders, amphetamine use disorders, and other DUDs [ 10 , 11 ]. Other DUDs included hallucinogen dependence, inhalant or solvent dependence, sedative dependence, tranquiliser dependence, and other medicines, drugs, substance dependence [ 10 ].

Evaluation of DUDs-related burden

The prevalence, incidence, mortality, and burden of DUDs (by age, sex, year, and subtype) were generally evaluated in the following ways: Firstly, based on the input raw data of vital registration, verbal autopsy, and surveillance databases, a cause of death database was generated through standardization, ICD mapping, age-sex division, garbage code redistribution, and noise reduction [ 10 , 11 ]. Secondly, based on this cause of death database, the estimation of DUDs-related burden followed the general Cause of Death Ensemble model (CODEm) strategy [ 10 , 11 ]. The CODEm strategy mainly included two models: linear mixed-effects regression (LMER) models and spatiotemporal Gaussian process regression (ST-GPR) [ 10 , 11 ]. With the progress of the CODEm strategy (covariates adjusted), the mortality rate of DUDs and the years of life lost (YLLs) were primarily evaluated [ 10 , 11 ]. In the GBD 2021 study, the covariate included additional data and increased time smoothing, which improved the stability of the results, especially for the estimates of the US and Western Europe [ 10 , 11 ]. Thirdly, based on the cause of death database and systematic reviews of epidemiological survey data, using the Bayesian meta-regression method DisMod-MR 2.1, the prevalence, incidence, and years of life lived with disability (YLDs, fully considering the disability weights and comorbidity) was further generated by age, sex, year, and subtype [ 10 , 11 ]. DisMod-MR 2.1 is a Bayesian meta-regression tool, which gathers data points across multiple sources and accounts for recognized variability factors such as disparities in case definitions and sampling methods to generate internal consistent estimates [ 10 , 11 ]. And lastly, the DALYs (by age, sex, year, and subtype) were obtained by adding YLLs and YLDs [ 10 , 11 ]. Based on the global standard population of the GBD study (2021), age-standardized rates were also estimated [ 13 ].

Statistical analysis

Data were described as absolute numbers with 95% uncertainty intervals (UIs) by age, sex, year, state, and drug categories. 95% UI was generated by the 2.5th and 97.5th percentiles of the ordered estimate values for the CODEm process of 1,000 draws [ 11 ]. When assessing the temporal trends, we introduced the indicator of estimated annual percentage change (EAPC) [ 14 , 15 , 16 ]. The EAPC was calculated based on a regression model, that is, [ln (age-standardized rate) = α + β × (calendar year) + ε]. The EAPC and its 95% confidence interval (CI) were calculated from the model of [100 × (exp (β)-1)] [ 14 , 15 , 16 ]. The trends were recognized as a decrease when the upper boundary of 95% CI of EAPC was < 0; while if the lower boundary of 95% CI of EAPC was > 0, the upward trends of burden were defined; otherwise, the trends represented stable [ 14 , 15 , 16 ].

Meanwhile, using the Pearson or Spearman rank test, associations between EAPC, DUDs-related burden, and SDI were determined, and the expected associations between them were estimated using the locally weighted regression (LOESS) model [ 17 ]. Additionally, we implemented the Bayesian model for age-period-cohort (BAPC) to forecast the burden until 2030 [ 18 , 19 , 20 ]. The BAPC model is expressed as n ij  = log(λ ij ) = μ + α i  + β j  + γ k , where λ ij denotes the count of cases, μ denotes the intercept, and α i , β j , and γ k signify the effect of age, period, and cohort, respectively [ 18 , 19 , 20 ]. To account for overdispersion, we utilized the BAPC model, which was implemented using the INLA and BAPC packages in R software [ 18 , 19 , 20 ]. The predicted population was obtained from the World Population Prospects 2022 [ 21 ].

All statistical analyses and visualization of results were conducted using the R software (Version 4.0.3; https://www.R-project.org/ ), and the two-tailed P value < 0.05 was considered statistically significant.

The burden of DUDs in the US in 2021 along with the temporal trend

Nationally, in 2021, the numbers of DUDs-related incident cases, prevalent cases, deaths, and DALYs were 1583.45 (95%UI: 1384.48, 1793.91), 12,146.95 (95%UI: 11,024.58, 13,461.04), 70.89 (95%UI: 64.05, 78.96), and 6484.69 (95%UI: 5471.72, 7481.32) thousand, respectively; accounting for 11.64%, 22.87%, 51.64%, and 41.67% of global numbers, respectively (Additional File 1: Tables S1-S8). Meanwhile, the age-standardized rates of incidence, prevalence, mortality, and DALYs (ASIR, ASPR, ASMR, and ASDR) of the DUDs were 531.19 (95%UI: 462.11, 605.02), 3821.43 (95%UI: 3450.13, 4257.62), 19.52 (95%UI: 17.73, 21.61), and 1944.08 (95%UI: 1632.99, 2249.41) per 100,000, respectively (Additional File 1: Tables S1-S4). It could be observed that the ASIR, ASPR, ASMR, and ASDR were significantly higher in the US than those in the world (3.14 times, 5.76 times, 11.83 times, and 10.18 times, respectively) (Additional File 1: Tables S1-S8). At the state level, the highest absolute number of DUDs-related burden was observed in California, Texas, Florida, New York, Pennsylvania, and Ohio also observed higher numbers (Additional File 1: Tables S1-S4). Meanwhile, West Virginia had the highest age-standardized rates, followed by Kentucky (Additional File 1: Tables S1-S4; Fig.  1 A, 1C, 1E, and 1G). From 1990 to 2021, the ASIR, ASPR, ASMR, and ASDR increased in the US, with EAPCs of 1.27 (95%CI: 1.05, 1.48), 2.17 (95%CI: 1.81, 2.53), 7.96 (95%CI: 7.64, 8.29), and 6.12 (95%CI: 5.83, 6.40), respectively (Additional File 1: Tables S1-S4). While a slight increase was only observed in ASMR worldwide (Additional File 1: Tables S5-S8). It could be observed that the burden of DUDs increased in all states from 1990 to 2021, with the highest growth in West Virginia (Additional File 1: Tables S1-S4; Fig.  1 B, 1D, 1F, and 1H). The burden and changing trend of DUDs for each sex and type of DUDs was presented in Table S10 (Additional File 1), generally, there was no particularly significant difference from the overall estimates.

Age-standardized rates of drug use disorders-related burden in 2021 and the temporal trends from 1990 to 2021 by states in the US. A  ASIR in 2021; B EAPC in ASIR from 1990 to 2021; C ASPR in 2021; D EAPC in ASPR from 1990 to 2021; E ASMR in 2021; F EAPC in ASMR from 1990 to 2021; G  ASDR in 2021; and H EAPC in ASDR from 1990 to 2021. ASIR: age-standardized incidence rate; ASPR: age-standardized prevalence rate; ASMR: age-standardized mortality rate; ASDR: age-standardized DALYs rate; EAPC: estimated annual percentage change

Burden and temporal trends of DUDs in the US by age and sex

In 2021, the DUDs-related burden (both numbers and age-standardized rates) in males was higher than that in females in both the US and the world (Additional File 1: Tables S1-S8; Fig.  2 ; and Additional File 2: Figure S1). From 1990 to 2021, in the US, the ASIR, ASPR, ASMR, and ASDR increased in both sexes, especially in females (Additional File 1: Tables S1-S4; Additional File 2: Figure S1). However, at the global level, in both sexes, the ASIR and ASPR decreased, while the ASMR and ASDR remained stable, respectively (Additional File 1: Tables S5-S8).

Age-specific numbers and rates of drug use disorders-related burden by sex and subtype in 2021 in the US. A age-specific numbers and rates of incidence; B age-specific numbers and rates of prevalence; C age-specific numbers and rates of deaths; and D age-specific numbers and rates of DALYs. The bar plots represented the numbers; the line plots and their shade represented the rates and their 95%UIs. DALYs: disability-adjusted life years; UI: uncertainty interval

In 2021, similar to the world, more than half of the burden (numbers and age-specific rates) of DUDs was generally concentrated in the population 15–45 years old in the US in both sexes (Additional File 1: Tables S1-S8; Fig.  2 ; and Additional File 2: Figures S2-S3). Notably, the burden of deaths was still heavy in the population 45–65 years old in both sexes at the US and global levels (Additional File 1: Tables S3 and S7; Fig.  2 ; and Additional File 2: Figures S2-S3). From 1990 to 2021, in the US, the age-specific rates of burden increased in both sexes in all age-specific groups, except for the < 15 age-specific group (EAPC for ASIR = -0.27, 95%CI: -0.35, -0.18; EAPC for ASPR = -0.27, 95%CI: -0.36, -0.18; and EAPC for ASDR = -0.28, 95%CI: -0.37, -0.19, respectively) (Additional File 1: Tables S1-S4; Fig.  3 ; and Additional File 2: Figure S3). However, at the global level, in both sexes, the age-specific rates of incidence increased in the > 85 age-specific groups, while the upward trends of age-specific rates of prevalence, deaths, and DALYs were generally observed in the 45–60 and > 90 age-specific groups (Additional File 1: Tables S5-S8; Fig.  3 ; and Additional File 2: Figure S3).

The age-specific changing trends in drug use disorders-related burden by sex from 1990 to 2021 in the US and the world. A age-specific EAPCs of incidence rates; B age-specific EAPCs of prevalence rates; C age-specific EAPCs of death rates; and D age-specific EAPCs of DALYs rates. The error bar represented the EAPCs and their 95%CIs. CI: confidential interval; DALYs: disability-adjusted life years; EAPC: estimated annual percentage change

Burden and temporal trends of DUDs in the US by drug categories

For the subtypes of DUDs, in 2021, opioid use disorders generally occupied the highest burden in both sexes in the US (except for the incidence burden); the numbers of incident cases, prevalent cases, deaths, and DALYs were 435.11 (95%UI: 362.57, 528.38), 6607.64 (95%UI: 5815.22, 7532.22), 55.45 (95%UI: 48.82, 62.98), and 5317.91 (95%UI: 4382.17, 6157.94) thousand, respectively; the corresponding ASIR, ASPR, ASMR, and ASDR were 151.84 (95%UI: 125.79, 184.96), 2014.62 (95%UI: 1761.65, 2308.32), 15.37 (95%UI: 13.62, 17.33), and 1594.63 (95%UI: 1308.06, 1849.82) per 100,000, respectively (Additional File 1: Tables S1-S4; Fig.  2 ; and Additional File 2: Figure S1). Similar results could be found at the global level, except for the incidence and prevalence burden (Additional File 1: Tables S5-S8). Moreover, the burden of opioid use disorders accounted for a higher proportion among young people (< 30 years old) (Fig.  2 ).

From 1990 to 2021, the ASIR remained stable in subtypes of amphetamine (EPAC = -0.02, 95%CI: -0.75, 0.73) and cocaine (EPAC = -0.08, 95%CI: -0.31, 0.14) use disorders, increased in opioid (EPAC = 6.05, 95%CI: 5.44, 6.67) and other drug (EPAC = 0.89, 95%CI: 0.81, 0.96) use disorders subgroups, and slightly decreased in the cannabis (EPAC = -0.04, 95%CI: -0.08, 0.00) use disorders subtype (Additional File 1: Table S1; Additional File 2: Figure S1). The ASPR remained stable in subtypes of amphetamine (EPAC = -0.05, 95%CI: -1.02, 0.93), and decreased in the cannabis (EPAC = -0.05, 95%CI: -0.08, -0.02) use disorders subtype; while increased in cocaine (EPAC = 0.44, 95%CI: 0.26, 0.61), opioid (EPAC = 6.73, 95%CI: 6.21, 7.25), and other DUDs (EPAC = 2.70, 95%CI: 2.55, 2.85) subtypes (Additional File 1: Table S2; Additional File 2: Figure S1). The ASMR increased in all subtypes of DUDs, with the highest EAPC of 11.32 (95%CI: 10.50, 12.16) in the amphetamine use disorders subtype (Additional File 1: Table S3; Additional File 2: Figure S1). Except for the cannabis use disorders subtype (EAPC = -0.07, 95%CI: -0.10, -0.04), upward trends of ASDR were observed in the other subtypes (Additional File 1: Table S4; Additional File 2: Figure S1). Similar trends could be found at the global level in some subtypes, and the downward trends could be seen more widely (Additional File 1: Tables S1-S8).

Factors influencing the EAPC in DUDs in the US

At the state level, a significant inverse association was identified between EAPC and DUDs burden in 1990 ( r  = -0.3715, P  = 0.0073 for ASIR; ρ  = -0.3698, P  = 0.0076 for ASPR; ρ  = -0.5436, P  = 5.0e-5 for ASMR; and ρ  = -0.2415, P  = 0.0878 for ASDR, respectively) (Fig.  4 A, 4C, 4E, and 4G). Meanwhile, inverse associations between age-standardized rates of EAPCs and SDI were seen in 2021 ( r  = -0.4247, P  = 0.0019 for ASIR; ρ  = -0.4547, P  = 0.0008 for ASPR; r  = -0.2826, P  = 0.0445 for ASMR; and r  = -0.3552, P  = 0.0105 for ASDR, respectively), with an approximate “U” shape (turning point around 0.88) (Fig.  4 B, 4D, 4F, and 4H).

The influence factors of the EAPCs of drug use disorders-related burden in the US. A ASIR in 1990 and EAPC in ASIR; B SDI in 2021 and EAPC in ASIR; C  ASPR in 1990 and EAPC in ASPR; D SDI in 2021 and EAPC in ASPR; E ASMR in 1990 and EAPC in ASMR; F SDI in 2021 and EAPC in ASMR; G ASDR in 1990 and EAPC in ASDR; H SDI in 2021 and EAPC in ASDR. The circle represented the state, and the size of the circle represented the number. The r or ρ indices and P values were evaluated by Pearson or Spearman rank analysis. The blue line and its shade were fitted by LOESS. ASIR: age-standardized incidence rate; ASPR: age-standardized prevalence rate; ASMR: age-standardized mortality rate; ASDR: age-standardized DALYs rate; EAPC: estimated annual percentage change; SDI: socio-demographic index

Prediction of DUDs-related burden in the US in the next 14 years

Using the DUDs, we further predicted the burden in the next 14 years. We found that by 2035, the numbers of DUDs-related prevalent cases, deaths, and DALYs would increase to 12,241.20 thousand, 120.56 thousand, and 8653.48 thousand, representing increases of 0.78%, 70.07%, and 33.44% compared to 2021, respectively; while the number of incident cases would slightly decrease by 1.09% (with the number of 1566.16 in 2035) (Additional File 1: Table S9). Meanwhile, from 2022 to 2035, the ASIR (EAPC = -0.60, 95%CI: -0.67, -0.52) would decrease; however, the ASPR (EAPC = 0.37, 95%CI: 0.27, 0.46), ASMR (EAPC = 3.87, 95%CI: 3.73, 4.00), and ASDR (EAPC = 2.37, 95%CI: 2.18, 2.57) would increase (Fig.  5 ).

Changing trend and prediction rate of drug use disorders-related burden from 2022 to 2035 in the US. A ASIR from 1990 to 2035; B ASPR from 1990 to 2035; C ASMR from 1990 to 2035; D ASDR from 1990 to 2035. ASIR: age-standardized incidence rate; ASPR: age-standardized prevalence rate; ASMR: age-standardized mortality rate; ASDR: age-standardized DALYs rate. Shading represented a 1% decrease and increase interval based on the rate of 2021

This study disclosed the magnitude and temporal trends of DUDs-related burden during the past three decades in the US based on the lasted GBD 2021 and also conducted the projection until 2035. It revealed that the absolute number of DUDs in the US accounted for a relatively high proportion of the global numbers in 2021, especially the number of deaths (accounting for 51.6%). As measured by trends, the burden of DUDs in the US increased significantly from 1990 to 2021. However, during the same period, a slight increase was only observed in ASMR worldwide. DUDs have become a serious disease burden in the US, and more targeted health policies and projects should be timely taken to alleviate this burden.

From the perspective of drug categories, opioid use disorders had the heaviest burden in the US in 2021. Especially, ASPR, ASMR, and ASDR of opioid use disorders accounted for over 50% of all types of DUDs. Given that the number of deaths from opioid overdoses reached a historic high in 2016, the US Department of Health and Human Services (HHS) declared the opioid crisis a public health emergency in 2017 [ 22 , 23 ]. As of 2020, 37.309 million Americans aged 12 and above had used illegal drugs in the past 30 days, of which 24.7% had opioid use disorders [ 9 ]. Our study showed that in 2021, opioids accounted for more than 78% of the deaths attributed to DUDs in the US, exceeding half of the global death toll. In the same year, the ASMR of opioid use disorders in the US was 12.92 times higher than in the world. Opioids remain the most lethal drug, notably, strategies have been implemented to control the burden caused by opioid use disorders. Buprenorphine, methadone, and naltrexone have been approved by the FDA respectively for the treatment of opioid dependence, they are proven to be safe and effective when combined with counseling and behavioral therapies, known as medication-assisted treatment (MAT) [ 24 ]. The FDA subsequently approved the first over-the-counter (OTC) naloxone nasal spray and the first namefene hydrochloride nasal spray in March and May 2023, respectively [ 25 ]. These drugs belong to opioid receptor antagonists and can be used to treat acute opioid overdose, thereby reducing opioid overdose mortality. Our research findings also suggest that the implementation of these strategies has achieved certain effects, the overall ASIR will decrease in the next 14 years. Although the ASPR, ASMR, and ASDR would increase, with the implementation of strategies, they would also decrease.

DUDs in the US were more severe among males than females in most age-specific groups in 2021, possibly due to males being more likely to receive higher doses of psychotropic drugs [ 26 ]. There are also reports showing that during the previous year, males in the US were 2.33 and 2.25 times more likely than females to suffer from DUDs and drug dependence, respectively [ 27 , 28 ]. In addition, the number of death cases caused by DUDs among females has been consistently high from age groups of 25 to 59, and the peak age group appears later than males. This may be related to females who use psychotropic drugs later and are more prone to mental disorders compared to males, or there are more obstacles for females in accessing medication, leading to insufficient medication treatment [ 9 , 29 , 30 ]. The comprehensive women-centered treatment method includes treating the whole person and the mother–child dyad [ 31 ]. This may consist of a variety of intervention measures and services, such as childcare and parenting education; obstetric and gynecological care; general medical care; interventions and services for comorbid mental disorders; social support, including transportation, housing, and occupational rehabilitation; and legal aid [ 31 ]. However, females with DUDs have to face more pressure and barriers when receiving the treatment, they may endure more social stigmatization, fear legal sanctions, and possibly even lose custody of their children [ 9 , 32 ]. More practical and effective strategies for women should also be developed and implemented to alleviate or even relieve burdens.

Regardless of gender, the burden of DUDs is highest in the age-specific groups of 15–45 years and showed a decreasing trend with age, which was consistent with the world pattern. This indicated that in young adults DUDs were still very serious, especially in youthfulness. Studies have estimated that the past year and lifetime prevalence of DUDs among 18–29-year-olds in the US is 8.3% and 14.2%, respectively [ 33 ]. The earlier the use of psychoactive drugs, the greater the lifelong risk of DUDs [ 34 , 35 ]. Among users who try psychotropic drugs before the age of 13, 70% develop DUDs within the next 7 years, while for those after the age of 17, the proportion drops to 27% [ 36 ]. These adolescents and children can suffer physical, sexual, and emotional abuse, and be in a state of poverty, homelessness, famine, and gender discrimination [ 36 , 37 ]. Due to the neurotoxicity of psychoactive drugs on the developing brain, contact with the drugs should be immediately interrupted to reduce the damage [ 3 ]. Meanwhile, treatment services for DUDs should be provided promptly to accurately identify and meet the needs of adolescents and children [ 38 ]. In recent years, treatments including but not limited to cognitive behavioral therapies, vocational training, psychoeducation, and motivational enhancement therapies, have been applied across service settings in the US [ 3 , 39 , 40 , 41 ]. These approaches have achieved certain benefits in treating adolescent DUDs, as shown in this study, age-specific rates of incidence, prevalence, and DALYs have all decreased in the 10–14 age group.

Our results suggested that in 2021, the EAPCs for DUDs in various states in the US were negatively correlated with the overall SDI. Especially in West Virginia, it has lower SDI but in most cases higher EAPC, indicating a heavy drug abuse burden. According to reports, West Virginia has the highest per capita opioid overdose mortality rate and the highest case rate of neonatal opioid withdrawal (NOW) syndrome in the US [ 36 ]. Since the early 2010s, several states in the US have begun strengthening prescription drug monitoring programs (PDMP), with dramatic results, for example, Kentucky reduced its number of opioid prescriptions per capita by 85% in 2015 compared with 2010, Florida saw a 50% drop in oxycodone overdose deaths in 2012 compared with 2010, national opioid prescriptions fell 16% annually, and the rate of Americans receiving MAT increased 13% annually [ 36 ]. It should also be noted that the burden of DUDs usually increases with increasing SDI values [ 1 ]. People from higher SDI areas have relatively higher socio-economic status, they may have more propensity to initiate drugs [ 31 ]. However, populations in lower SDI areas may face more socio-economic disadvantages such as poverty, conflict, and lack of education and employment opportunities, making them highly susceptible to mental health issues and DUDs, as well as limited access to health promotion, prevention, and drug treatment services. Therefore, the latter pays a higher price and is highly likely to suffer a heavy burden [ 31 ].

Despite previous reports on the limitations of GBD [ 10 , 11 , 12 ], it is still necessary to clarify the limitations of this work. Firstly, in the GBD study (2021), the DUDs were defined based on the DSM-IV-TR or the ICD-10 diagnostic criteria, if the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was used, the estimation of DUDs may be changed. Secondly, the limited detailed information obtained from the GBD database regarding the US and its states in this study may limit the analysis of the burden of DUDs, although GBD study (2021) made improvements to the model to improve estimation accuracy. In addition, due to the lack of estimated deaths caused by cannabis use disorders in the GBD 2021 data, the total number of deaths from DUDs may be underestimated. Last but not least, this study evaluated the changing trends and predicted the burden of DUDs based on the GBD study 2021, but due to the information lag in this database (only data information from 1990 to 2021 could be obtained currently), the prediction results may not be accurate enough. However, our results still have significant public health implications for controlling the DUDs-related burden in the US.

In conclusion, in the past three decades, the burden of DUDs in the US was heavy, especially in males, 15–45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia. In the next 14 years, the projected DUDs burden remains exigent. Therefore, our study proposes that greater attention should be paid to the younger population, males and older females, opioid use disorders, and low-SDI states implemented by health policymakers to achieve goals such as reducing burden.

Availability of data and materials

Data can be obtained from the following website: http://ghdx.healthdata.org/gbd-results-tool .

Abbreviations

Age-standardized DALYs rate

Age-standardized incidence rate

Age-standardized mortality rate

Age-standardized prevalence rate

Confidence interval

Cause of Death Ensemble model

• Disability-adjusted life years

Estimated annual percentage change

The Global Burden of Diseases, Injuries, and Risk Factors Study

Linear mixed effects regression

Spatiotemporal Gaussian process regression

Uncertainty interval

World Health Organization

Years lived with disability

Years of life lost

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Acknowledgements

We appreciate all the academics who have contributed to the GBD study.

This study was supported by the National Natural Science Foundation of China (82204196, 82204129, and 82103912), the Shandong Provincial Natural Science Foundation (ZR2022QH162 and ZR2022QH015), the Taishan Scholars Program of Shandong Province (tstp202312328), and the Excellent Youth Innovation Team of Shandong Provincial Higher Education Institutions (2022KJ012). The funders were not involved in the collection, analysis, or interpretation of data or the writing or submitting of this report.

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Tongchao Zhang and Lin Sun contributed equally to this work.

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Clinical Epidemiology Unit, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

Tongchao Zhang, Xiaolin Yin, Hui Chen & Xiaorong Yang

Clinical Research Center of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China

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Tongchao Zhang and Xiaorong Yang conceived and designed the research; Tongchao Zhang, Lin Sun, Xiaolin Yin, Hui Chen, and Lejin Yang performed the research; Tongchao Zhang, Lin Sun, Hui Chen, and Lejin Yang provided discussions; Tongchao Zhang, Lin Sun, Xiaolin Yin, and Xiaorong Yang analyzed data; Tongchao Zhang and Lin Sun wrote the paper. All authors approved the final manuscript.

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Supplementary Information

12889_2024_19142_moesm1_esm.xlsx.

Additional File 1: Supplementary tables S1-S10. Table S1. Number of incident cases and incidence rate of drug use disorders in the US in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S2. Number of prevalent cases and prevalence rate of drug use disorders in the US in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S3. Number of death cases and mortality rate of drug use disorders in the US in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S4. Number of DALYs cases and DALYs rate of drug use disorders in the US in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S5. Number of incident cases and incidence rate of global drug use disorders in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S6. Number of prevalent cases and prevalence rate of global drug use disorders in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S7. Number of death cases and mortality rate of global drug use disorders in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S8. Number of DALYs cases and DALYs rate of global drug use disorders in 1990 and 2021, and the temporal trends from 1990 to 2021. Table S9. Prediction number of drug use disorders-related burden from 2022 to 2035 in the US. Table S10. Number and rate of drug use disorders burden by state, sex, and type in the US in 2021, and the temporal trends from 1990 to 2021.

12889_2024_19142_MOESM2_ESM.docx

Additional File 2: Supplementary figures S1-S3. Figure S1. Numbers and age-standardized rates of drug use disorders-related burden by sex and subtype from 1990 to 2021 in the US. (A) numbers and age-standardized rates of incidence; (B) numbers and age-standardized rates of prevalence; (C) numbers and age-standardized rates of deaths; and (D) numbers and age-standardized rates of DALYs. The bar plots represented the numbers; the line plots and their shade represented the age-standardized rates and their 95%UIs. DALYs: disability-adjusted life years; UI: uncertainty interval. Figure S2. Age-specific numbers of drug use disorders-related burden by sex from 1990 to 2021 in the US and the world. (A) age-specific numbers of incident cases; (B) age-specific numbers of prevalent cases; (C) age-specific numbers of deaths; and (D) age-specific numbers of DALYs. DALYs: disability-adjusted life years. Figure S3. Age-specific rates of drug use disorders-related burden by sex from 1990 to 2021 in the US and the world. (A) age-specific rates of incidence; (B) age-specific rates of prevalence; (C) age-specific rates of deaths; and (D) age-specific rates of DALYs. DALYs: disability-adjusted life years.

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Zhang, T., Sun, L., Yin, X. et al. Burden of drug use disorders in the United States from 1990 to 2021 and its projection until 2035: results from the GBD study. BMC Public Health 24 , 1639 (2024). https://doi.org/10.1186/s12889-024-19142-0

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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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Drug abuse persists as one of the most costly and contentious problems on the nation's agenda. Pathways of Addiction meets the need for a clear and thoughtful national research agenda that will yield the greatest benefit from today's limited resources.

The committee makes its recommendations within the public health framework and incorporates diverse fields of inquiry and a range of policy positions. It examines both the demand and supply aspects of drug abuse.

Pathways of Addiction offers a fact-filled, highly readable examination of drug abuse issues in the United States, describing findings and outlining research needs in the areas of behavioral and neurobiological foundations of drug abuse. The book covers the epidemiology and etiology of drug abuse and discusses several of its most troubling health and social consequences, including HIV, violence, and harm to children.

Pathways of Addiction looks at the efficacy of different prevention interventions and the many advances that have been made in treatment research in the past 20 years. The book also examines drug treatment in the criminal justice setting and the effectiveness of drug treatment under managed care.

The committee advocates systematic study of the laws by which the nation attempts to control drug use and identifies the research questions most germane to public policy. Pathways of Addiction provides a strategic outline for wise investment of the nation's research resources in drug abuse. This comprehensive and accessible volume will have widespread relevance—to policymakers, researchers, research administrators, foundation decisionmakers, healthcare professionals, faculty and students, and concerned individuals.

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• Published: 05 June 2024

The urgent need for designing greener drugs

• Tomas Brodin   ORCID: orcid.org/0000-0003-1086-7567 1   na1 ,
• Michael G. Bertram   ORCID: orcid.org/0000-0001-5320-8444 1 , 2 , 3   na1 ,
• Kathryn E. Arnold   ORCID: orcid.org/0000-0002-6485-6065 4 ,
• Alistair B. A. Boxall 4 ,
• Bryan W. Brooks   ORCID: orcid.org/0000-0002-6277-9852 5 ,
• Daniel Cerveny   ORCID: orcid.org/0000-0003-1491-309X 1 , 6 ,
• Manuela Jörg   ORCID: orcid.org/0000-0002-3116-373X 7 , 8 ,
• Karen A. Kidd   ORCID: orcid.org/0000-0002-5619-1358 9 ,
• Unax Lertxundi   ORCID: orcid.org/0000-0002-9575-1602 10 ,
• Jake M. Martin 1 , 2 ,
• Lauren T. May   ORCID: orcid.org/0000-0002-4412-1707 11 ,
• Erin S. McCallum 1 ,
• Marcus Michelangeli   ORCID: orcid.org/0000-0002-0053-6759 1 , 3 , 12 ,
• Charles R. Tyler 13 ,
• Bob B. M. Wong   ORCID: orcid.org/0000-0001-9352-6500 3 ,
• Klaus Kümmerer   ORCID: orcid.org/0000-0003-2027-6488 14 , 15   na2 &
• Gorka Orive 16 , 17 , 18   na2  

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The pervasive contamination of ecosystems with active pharmaceutical ingredients poses a serious threat to biodiversity, ecosystem services and public health. Urgent action is needed to design greener drugs that maintain efficacy but also minimize environmental impact.

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Acknowledgements

We acknowledge funding support from the Swedish Research Council Formas (2018-00828 to T.B., 2020-02293 to M.G.B., 2020-00981 to E.S.M., 2020-01052 to D.C., 2022-00503 to M.M. and 2022-02796/2023-01253 to J.M.M.), the Kempe Foundations (SMK-1954, SMK21-0069 and JCSMK23-0078 to M.G.B.), the Swedish Research Council VR (2022-03368 to E.S.M.), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (101061889 to M.M.), Research England (131911 to M.J.), the Spanish Ministry of Economy, Industry and Competitiveness (PID2022-139746OB-I00/AEI/10.13039/501100011033 to G.O.), the Australian Research Council (FT190100014 and DP220100245 to B.B.M.W.), the Jarislowsky Foundation (to K.A.K.), a Royal Society of New Zealand Catalyst Leaders Fellowship (ILF-CAW2201 to B.W.B.) and the National Institute of Environmental Health Sciences of the National Institutes of Health (1P01ES028942 to B.W.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

These authors contributed equally: Tomas Brodin, Michael G. Bertram.

These authors jointly supervised this work: Klaus Kümmerer, Gorka Orive.

Authors and Affiliations

Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden

Tomas Brodin, Michael G. Bertram, Daniel Cerveny, Jake M. Martin, Erin S. McCallum & Marcus Michelangeli

Department of Zoology, Stockholm University, Stockholm, Sweden

Michael G. Bertram & Jake M. Martin

School of Biological Sciences, Monash University, Melbourne, Victoria, Australia

Michael G. Bertram, Marcus Michelangeli & Bob B. M. Wong

Department of Environment and Geography, University of York, York, UK

Kathryn E. Arnold & Alistair B. A. Boxall

Department of Environmental Science, Baylor University, Waco, TX, USA

Bryan W. Brooks

Faculty of Fisheries and Protection of Waters, University of South Bohemia in České Budějovice, Vodňany, Czech Republic

Daniel Cerveny

Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

Manuela Jörg

Centre for Cancer, Chemistry – School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne, UK

Department of Biology, McMaster University, Hamilton, Ontario, Canada

Karen A. Kidd

Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba Mental Health Network, Araba Psychiatric Hospital, Pharmacy Service, Vitoria-Gasteiz, Spain

Unax Lertxundi

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

Lauren T. May

School of Environment and Science, Griffith University, Nathan, Queensland, Australia

Marcus Michelangeli

Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK

Charles R. Tyler

Institute of Sustainable Chemistry, Leuphana University Lüneburg, Lüneburg, Germany

Klaus Kümmerer

International Sustainable Chemistry Collaborative Centre (ISC3), Bonn, Germany

Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain

Gorka Orive

Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine, Vitoria-Gasteiz, Spain

Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain

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Brodin, T., Bertram, M.G., Arnold, K.E. et al. The urgent need for designing greener drugs. Nat Sustain (2024). https://doi.org/10.1038/s41893-024-01374-y

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Title: accelerating complex disease treatment through network medicine and genai: a case study on drug repurposing for breast cancer.

Abstract: The objective of this research is to introduce a network specialized in predicting drugs that can be repurposed by investigating real-world evidence sources, such as clinical trials and biomedical literature. Specifically, it aims to generate drug combination therapies for complex diseases (e.g., cancer, Alzheimer's). We present a multilayered network medicine approach, empowered by a highly configured ChatGPT prompt engineering system, which is constructed on the fly to extract drug mentions in clinical trials. Additionally, we introduce a novel algorithm that connects real-world evidence with disease-specific signaling pathways (e.g., KEGG database). This sheds light on the repurposability of drugs if they are found to bind with one or more protein constituents of a signaling pathway. To demonstrate, we instantiated the framework for breast cancer and found that, out of 46 breast cancer signaling pathways, the framework identified 38 pathways that were covered by at least two drugs. This evidence signals the potential for combining those drugs. Specifically, the most covered signaling pathway, ID hsa:2064, was covered by 108 drugs, some of which can be combined. Conversely, the signaling pathway ID hsa:1499 was covered by only two drugs, indicating a significant gap for further research. Our network medicine framework, empowered by GenAI, shows promise in identifying drug combinations with a high degree of specificity, knowing the exact signaling pathways and proteins that serve as targets. It is noteworthy that ChatGPT successfully accelerated the process of identifying drug mentions in clinical trials, though further investigations are required to determine the relationships among the drug mentions.

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Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs

• Emily Alger 1 ,
• Mary Van Zyl 2 ,
• Olalekan Lee Aiyegbusi 3 , 4 ,
• Dave Chuter 5 ,
• Lizzie Dean 5 ,
• Anna Minchom 2 &
• Christina Yap 1  

Research Involvement and Engagement volume  10 , Article number:  63 ( 2024 ) Cite this article

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In light of the FDA’s Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials.

It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials.

A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development.

Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose.

Conclusions

Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.

Plain English summary

The aim of dose-finding oncology trials is to make sure a treatment is safe, understand its side effects, and recommend the right dose (or doses) for future clinical trials. Traditionally, a patient’s tolerance to treatment is assessed by doctors who evaluate toxicities (side-effects) using established grading guidelines. Research has shown that doctors might not identify all the side effects that patients actually experience during a trial.

There is growing interest in the introduction of patient-reported outcomes (PROs) within dose-finding trials. PROs are reports of a patient’s health and well-being experiences which come directly from the patient themselves, usually assessed using a questionnaire.

In a dose-finding trial, we start with a low dose of a drug and increase it until too many patients have severe side effects. The highest safe dose is then investigated in a later phase trial.   We are suggesting a new way to do these trials. We want to look at both what doctors see as severe side effects and what patients say. This enables us to recommend a dose that balances both perspectives. We would also like to ask patients what level of risk they are comfortable with regarding severe side effects.

In this paper, we highlight the importance of involving patients in creating advanced dose-finding trial designs, particularly with PROs to help decide whether a dose is tolerable for patients. We also share findings of a patient and public involvement and engagement session and provide a guide for meaningful patient involvement in developing trial designs.

Peer Review reports

Patient and public involvement and engagement (PPIE) ensures that the voice of patients and their advocates inform the conception and development of clinical trial designs [ 1 ], contributing to the collection of an improved quality of data and increased patient adherence to the trial. Research has highlighted that, although uncommon, valuable opportunities for patient engagement exist and should be encouraged within the early phase dose-finding oncology trial setting.

Dose-finding oncology trials

Dose-finding oncology trials (DFOTs) are a crucial step in early clinical development. These trials assess the safety and tolerability of novel anti-cancer therapies across multiple doses. By employing multiple interim analyses, researchers can dynamically test different doses during the trial. Adaptive decision making is based on accumulating preliminary safety and clinical data. This adaptive strategy enhances efficiency and enriches our understanding of an investigational therapy based on emerging patient responses, guiding the selection of optimal doses for potential exploration in subsequent trials. In Phase I cancer trials, various new anticancer therapies, including drugs, radiotherapy, cell therapies and biologics, can be collectively referred to as investigational therapies or novel therapeutic approaches [ 2 ]. Henceforth, within this article we will use the term "investigational therapy" to emphasise the investigational nature of these novel therapies in early phase clinical research.

Patient-reported outcomes

Research has highlighted pitfalls of current practice to tolerability assessment within trials, including clinicians potentially underreporting adverse events compared to a patients’ own assessments of tolerability [ 3 ]. Recommendations from new Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce guidelines [ 4 ], encourage investigators to consider the toxicity burden of new oncology drugs on patients. There is growing interest in integrating Patient-Reported Outcomes (PROs) to enrich our understanding of an investigational therapy’s tolerability profile within early phase trials [ 4 , 5 , 6 ].

A PRO is defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else” [ 7 ]. PROs are readily incorporated within later phase trials, with research showing that the integration of PROs within later phase trials has been associated with improved survival [ 8 ]. Within dose-finding trials, the new standardised PRO measure (PROM) PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) has been developed by the National Cancer Institute so that patients can self-report symptomatic toxicities via a questionnaire [ 9 ]. However, a recent review has suggested that only 5.3% of DFOTs included PROs as an outcome in their trial [ 5 ]. Research has shown for those trials that included PROs, they are rarely incorporated to guide dose-escalation decisions in DFOTs (2.9%) [ 10 ].

PPIE for the development of advanced trial designs

The current landscape reveals a notable gap in understanding how to effectively embed PPIE within statistical methodology [ 11 ]. There has been a rise in the adoption of advanced model-based and model-assisted trial designs in DFOTs [ 12 ]. While these designs enhance efficiency, they come at the cost of increased complexity [ 13 ]. Integrating PROs into dose-finding trials requires the creation of smarter yet intricate designs [ 14 , 15 , 16 , 17 , 18 ]. Trial designs could incorporate PROs to dynamically inform dose decisions throughout the trial or influence the final recommended dose(s). Effectively communicating the statistical concepts and workings of these complex designs to a lay audience is crucial for facilitating meaningful PPIE. Exploring patient’s unique insights and lived experience of dose-finding trials is particularly crucial as we consider the patient-centred realm of PROs, where we look to encapsulate elements that are important to dose-finding oncology trial patients.

Particular focus has been placed on the importance of PPIE as we look to incorporate patient-reported outcomes (PROs) within dose-finding trials [ 19 ]. Their introduction within the early phase setting is contingent on the support of patients and their advocates. For example, the incorporation of PROs within early phase trials would require patients to record their symptoms, which may increase patient burden [ 20 ]. It also requires an alignment in patient and trialist objectives within the Phase I setting.

Within this article we present a case-study for a PPIE session held to discuss the exemplary integration of PROs within the PRO-CRM trial design and utility extension U-PRO-CRM [ 14 , 21 ]. At the PPIE session, we discussed how to define an intolerable patient toxicity, as identified through PROs, and how we could escalate doses using the rate of patient toxicity in conjunction with clinician assessed toxicities. We expected PPIE discussions to inform future research directions for the field of PRO-integrated trial designs [ 22 , 23 ], triggering the development of new advanced patient-empowered trial designs.

This paper describes how PPIE was successfully embedded within a statistical methodology project. It provides a template for the organisation of the event, consolidation of research outputs and determination of future directions to support statistical methodologists coordinating their own PPIE activities.

Previous published PPIE within early phase trials has focused on discussing preferences of PRO collection strategies and attitudes towards PRO integration [ 24 ]. However, to our knowledge, the session detailed in this paper is the first to discuss a statistical methodology project within the space of early-phase DFOTs.

Patient engagement to inform the development of a new novel trial design

A virtual PPIE session, that lasted an hour and a half, was held with nine participants on 18th October 2023. As well as reflecting on the insights provided by participants at the PPIE session, the aim of the session was to explore how PPIE could be embedded within a statistical methodology project and identify the lessons to be learnt from the session. We anticipated that discussions would inform future research directions in the field of PROs in early phase trials.

Potential participants for the PPIE event were contacted internally via the Institute of Cancer Research’s Drug Development Unit (which runs Phase I trials) and externally, via co-author connections and the National Cancer Research Institute (NCRI) Advocate Forum. Potential participants were eligible to contribute to this PPIE session if they had lived experience within a clinical trial or were experienced patient partners in the Phase I setting. Eleven prospective participants shared an interest in attending the PPIE session and were asked to share their availability via an online form, with the session scheduled for the most popular slot. Nine participants were able to make the scheduled time and two prospective participants were unable to attend due to scheduling conflicts. At first instance, patients enrolled in a Phase I trial at the Institute of Cancer Research’s Drug Development Unit were invited to participate in the session to ensure patients with lived experience in dose-finding trials were engaged with discussions. To ensure we engaged participants with a diverse range of expertise, we also encouraged the participation of other patient stakeholders, including patient advocates.

A PowerPoint presentation and Zoom polls were created for participants to answer pre-set questions. The presentation was developed and refined following a practice presentation with statisticians and clinicians. Questions were curated and reviewed by the team before the session. Strategies were developed to foster an engaging atmosphere, including allotted time for participant introduction, use of Zoom’s “hands up” feature, and appointing an experienced chair with PPIE activity, MVZ (an advanced nurse practitioner) to lead discussions separate to the presenter. Team members EA, MVZ, AM and CY hosted the PPIE session.

One week before the session, pre-reading materials on dose-finding trials and PROs were distributed to participants for a brief overview of the topic [ 25 , 26 ]. Following the session, minutes detailing the discussions were sent to participants for approval alongside a reimbursement form. A timeline of the organization for this PPIE event is presented in Fig.  1 .

Organisational timeline for PPIE event, from inception to completion

Participants were based in the UK and Canada. The majority of attendees (66.7%) were at least 65 years old and just over half (55.5%) were female. All participants were white. Six participants (66.7%) had participated in a clinical trial, and four (44.4%) had experience of a Phase I trial. Most (66.6%) were a novice or intermediate patient partner, with introductory or moderate experience as a patient partner in Phase I trials. Two discussants identified themselves as an experienced patient advocate. Characteristics for participants who attended the PPIE session are presented in Table  1 .

PPIE insights

At the start of the PPIE session, we defined PROs and current limitations to tolerability assessment. Seven participants (77.8%) agreed or strongly agreed that asking patients to self-identify their symptoms would add useful information to dose-finding clinical trials. Six participants (66.7%) also agreed that PROs should be used together with clinician assessed toxicities to inform dose-escalation decisions.

Assessing patient adverse events

Many participants agreed that it was “essential” to listen to a patient’s viewpoint on symptoms, however some had concerns regarding the frequency of PRO collection and the size of the questionnaire. Some participants suggested that PROs were a useful reminder to “help me remember side effects I may have forgotten during the period between doses” and that frequent PRO collection would prevent patients from forgetting the severity of side effects. Whilst some participants thought we “need to record all side effects”, other participants were concerned by the length of the PRO-CTCAE, suggesting that “there’d be an awful lot of things and boxes to tick – an overwhelming number”.

Patient tolerability levels

Under the conventional dose-efficacy paradigm, it is typically assumed that as dose increases, so too does its efficacy. Nevertheless, this might not necessarily hold true for modern immunotherapies or targeted agents [ 27 ]. For the PRO-CRM and U-PRO-CRM trial designs, PROs are utilised in conjunction with the toxicities assessed by a clinician. Dose-escalation decisions rely upon both the rate of clinician assessed toxicity and rate of patient assessed toxicity. Therefore, for such designs, the incorporation of PROs looks to inform the selection of an admissible set of more tolerable (and potentially lower) doses for investigation in later phase trials.

Participants were mindful about the potential subjectivity of PROs. Whilst some recognised that “[A smaller dose] can be as effective as a higher dose without the side effects”, after discussing the PRO-CRM and U-PRO-CRM design, some participants were concerned that “if individuals are going to report their side effects, and that’s going to influence dose going ahead, what about the fact that everyone reacts differently?”. It was also recognised that “past illnesses, comorbidities will affect how people report”.

Impact of PROs on dose decisions and efficacy

Participants discussed whether patients would be fully transparent about the severity of symptoms if the trial offered the last line of investigational therapy. This was a concern for some participants who reflected that “many patients would be reluctant to drop out of the treatment [investigational therapy], unless the clinicians thought that the side effect itself could be life threatening”. Another participant highlighted that “if you were to lower the dose. I feel that it would be a worry that it might not be as effective”. When discussing the possibility of discontinuing an investigational therapy following severe side effects, one discussant suggested that if they were “on a clinical trial and this is my last chance of treatment that might help me, I’m going to tolerate severe pain and probably downplay a little bit [side effects] to the clinicians”.

Toxicity vs. tolerability

There was also a suggestion to clarify what is meant by a patient toxicity. It was suggested that instead of using PROs to identify toxic doses, it should be used to identify intolerable doses. It was generally thought that “the clinicians should be the ones to define toxicity, but the patient should be the ones to define how tolerable”. Participants discussed at what point an unpleasant side effect would become “unbearable” – to the point where a patient would refuse further investigational therapy. Instead of defining a single unacceptable level of toxicity using the PRO-CTCAE criteria, one participant suggested that instead patients are asked if “this level [dose] of toxicity would stop them taking part in the trial”.

Reflections: Learned experiences of running PPIE sessions within the early phase setting

Coordinating this session with a cross-disciplinary team was incredibly beneficial. The allocation of a chair with a clinical background ensured that discussions were accessible and led by an expert with extensive experience of communicating with patients. The active involvement of additional clinicians, statisticians and PRO methodologists was instrumental in overseeing and guiding discussions and questions pertaining to current clinical practices and model-based dose-finding trial designs. It also ensured that the contents and concepts discussed during the session were presented in a manner that was accessible and easily comprehensible to a broad audience. This was evident in the successful engagement of patient partners, marked by numerous discussions throughout the session.

PPIE: Participants’ perspectives

Figure  2 presents perspective pieces written by two participants who attended the PPIE session.

Participant perspective pieces discussing PROs in early phase trials and the importance of PPIE involvement within the development of novel dose-finding trial designs

PPIE session findings

Participants highlighted concerns that recording their self-assessed side effects accurately may lead to discontinuation of the investigational therapy, potentially reducing their chances of benefiting from the therapy. To promote PRO completion, patients should be informed that individual dosing decisions in Phase I trials are based on protocol-defined adverse events, essential for preventing severe toxicity. Techniques such as intra-patient escalation methods are increasingly advocated to provide additional flexibility to dose escalation trials when implementation is deemed safe [ 4 ]. Such escalation routines may enhance the personalisation of dosing for individual patients and treat more patients at the recommended dosage(s). Implementing trial designs which personalise and identify the optimal tolerable dose for each patient by considering the variability in individual tolerability thresholds [ 28 , 29 ], may encourage patients to diligently complete PROMs. This, in turn, contributes to a more comprehensive understanding of the investigational therapy’s tolerability profile.

Participants also shared their hesitancy about PROs potentially lowering the recommended dose for later phase trials, affecting efficacy. The PPIE session discussion highlights the necessity for PRO-integrated dose-finding trial designs, combining an efficacy endpoint alongside tolerability through both PROs and conventional clinician assessed toxicities. This includes creating seamless Phase I/II designs that dynamically test different doses throughout the trial, based on accumulating tolerability and activity data.

Future research directions

Following the input of participants at the PPIE session, team members consolidated future study directions to advance the field of trial designs which incorporate PROs.

These include the exploration of PRO-integrated dose-finding trial designs which,

Incorporate both efficacy and toxicity assessment.

Define intolerable patient toxicities for each patient, allowing for dose-escalation rules to potentially vary among patients.

Employ PROs within the dose-optimisation stage of the trial design.

Utilise PROs within either interim or final analysis dose recommendations.

Discussions at the meeting indicated that some participants were concerned that PROs could potentially reduce the size of dose recommended for later phase trials. Future research could look to assess how a patient’s tolerability to PRO-determined MTDs would compare to traditional early phase DFOTs designs which rely solely on clinician assessed adverse events.

Future research should continue to explore effective strategies for incorporating patient input into complex statistical methodology projects. This involves the development of novel presentation approaches to ensure information is presented accessibly, including the creation of patient information sheets, slides and scripts for the session [ 19 ].

Strengths and limitations of the session

The virtual nature of this PPIE session encouraged international engagement but did prevent face-to-face discussions, potentially missing out on additional insights that such interactions might have provided.

Providing pre-reading material before the PPIE session helped participants, particularly those with novice or intermediate experience, familiarise themselves with new and advanced concepts on PROs in DFOTs. This pre-reading reflected the richness and depth of the material discussed in the session which included an overview of current practice, PROs and the newly proposed trial design. Participants engaged in some topics more than others, and discussions were often extensive. We would have therefore benefitted from a longer session to cover all areas comprehensively. In hindsight, we recognise it may have been beneficial to conduct this engagement across two separate sessions – first introducing current practice in the early phase setting before expanding on this topic to cover PROs at a later session. Though the time commitment required from participants may be prohibitive.

Our participants encompassed a diverse range of age groups and expertise levels, including individuals with lived experience of Phase I trials. However, whilst we looked to encourage a diverse range of participants to take part in this PPIE session, it is noteworthy that all individuals who expressed interest were white. We hope that future PPIE research which looks to shape trial design will make additional attempts to include a more diverse group of participants. Whilst the FDA provides guidance to help increase engagement of participants from underrepresented groups within later phase trials [ 30 ], barriers still remain to engage underserved groups within early phase trials [ 31 ].

The majority of participants within this PPIE session were patients within a clinical trial (6/9). Active engagement of patients with lived trial experience is vital to ensure that the perspectives provided are informed by current trial practice and patient viewpoint.

PPIE sessions have a vital role in ensuring that PROs are not just implemented within early phase trials, but to ensure that the implementation is feasible and in line with patient’s own objectives within the trial. These PPIE discussions support contemporary publications which have previously encouraged the tailoring of the PRO-CTCAE into a subset of core symptoms for patient ease [ 32 ].

PPIE in statistical methodology

The incorporation of meaningful PPI can be unclear due to a lack of resources, including successful case studies demonstrating effective implementation [ 11 ]. As the strategy for the successful incorporation of PPIE within research continues to be developed [ 33 ], case studies such as these can provide recommendations for other researchers looking to introduce PPIE within their research. This project demonstrates the feasibility of PPIE for statistical methodology and the potential of PPIE to originate new research directions within the field of early phase DFOT designs. This research reiterates recommendations of other PPIE in the space of statistical methodology – that engagement is achievable and fruitful if projects are thoroughly considered and organised [ 34 ]. Whilst the use of PPIE within statistical projects remains limited, recommendations have been provided by researchers exploring PPIE in the numerical components of trials [ 35 ]. Goulao et al. suggest the cultivation of a safe environment, ensuring that participants are listened to and adopting a flexible schedule to allow for additional questions and discussions throughout the session. Involving an experienced PPIE chair within our own session cultivated a safe environment for participants to share their thoughts and confidently raise questions.

Even before the development of the trial design, engaging patients has the potential to catalyse the direction of future trial designs toward patient-centric considerations – with the potential to inform outcomes, the integration of information in dose decision making, and the frequency of data collection to be considered within the prospective trial design. Continuing to engage patients during the development of trial designs can support methodologists to simplify their complex design and develop lay summaries. Following the adoption of the trial design in practice, such engagement supports the dissemination of the design among potential patients to be enrolled in the study.

Engaging patients in statistical methodology research for PPIE poses unique challenges, especially when compared to applied clinical research. Participants may be eligible for reimbursement for expenses and time. As such any PPIE activity requires financial considerations and budgeting. What’s more, unravelling the advanced statistical concepts of novel dose-finding trials for a lay audience may require the statistical methodologist to exhibit patience, understanding, and strong communication skills. Scheduling the PPIE meeting may be challenging dependent on the size of participants a session looks to engage, however the opportunity to hold sessions virtually does provide additional flexibility. Recruiting participants from ethnically diverse backgrounds remains a challenge in PPIE and clinical trials within the early phase field [ 31 ]. Engaging participants, particularly from underserved groups, requires on-going effort to build trust and rapport between prospective participants and the research team.

This article details our experience of optimizing PPIE input. Simplifying complex theories enables us to gather insights from patients on how they envision the utilization of PROs in DFOTs. Influential PPIE is essential as we look to incorporate patient voice into the development of new trial designs. Successful integration not only drives innovation, but also ensures that trials align more closely with what matters to patients, culminating in more patient-centred and impactful research.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

Patient-reported Outcome

Patient and Public Involvement and Engagement

Dose-Finding Oncology Trial

Patient-reported Outcome Measure

Patient-reported Outcome-Common Terminology Criteria for Adverse Events

Methodology for the Development of Innovative Cancer Therapies

National Cancer Research Institute

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Acknowledgements

The authors would like to acknowledge and thank all participants who attended the PPIE session.

EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership.

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OLA receives funding from the NIHR Birmingham Biomedical Research Centre (BRC), NIHR Applied Research Collaboration (ARC), West Midlands, NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation, Innovate UK (part of UK Research and Innovation), Gilead Sciences Ltd, Merck, GSK, Anthony Nolan, and Sarcoma UK. He declares personal fees from Gilead Sciences, Merck, and GlaxoSmithKline outside the submitted work.

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Alger, E., Van Zyl, M., Aiyegbusi, O.L. et al. Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs. Res Involv Engagem 10 , 63 (2024). https://doi.org/10.1186/s40900-024-00599-7

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A smarter way to streamline drug discovery

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The use of AI to streamline drug discovery is exploding. Researchers are deploying machine-learning models to help them identify molecules, among billions of options, that might have the properties they are seeking to develop new medicines.

But there are so many variables to consider — from the price of materials to the risk of something going wrong — that even when scientists use AI, weighing the costs of synthesizing the best candidates is no easy task.

The myriad challenges involved in identifying the best and most cost-efficient molecules to test is one reason new medicines take so long to develop, as well as a key driver of high prescription drug prices.

To help scientists make cost-aware choices, MIT researchers developed an algorithmic framework to automatically identify optimal molecular candidates, which minimizes synthetic cost while maximizing the likelihood candidates have desired properties. The algorithm also identifies the materials and experimental steps needed to synthesize these molecules.

Their quantitative framework, known as Synthesis Planning and Rewards-based Route Optimization Workflow (SPARROW), considers the costs of synthesizing a batch of molecules at once, since multiple candidates can often be derived from some of the same chemical compounds.

Moreover, this unified approach captures key information on molecular design, property prediction, and synthesis planning from online repositories and widely used AI tools.

Beyond helping pharmaceutical companies discover new drugs more efficiently, SPARROW could be used in applications like the invention of new agrichemicals or the discovery of specialized materials for organic electronics.

“The selection of compounds is very much an art at the moment — and at times it is a very successful art. But because we have all these other models and predictive tools that give us information on how molecules might perform and how they might be synthesized, we can and should be using that information to guide the decisions we make,” says Connor Coley, the Class of 1957 Career Development Assistant Professor in the MIT departments of Chemical Engineering and Electrical Engineering and Computer Science, and senior author of a paper on SPARROW.

Coley is joined on the paper by lead author Jenna Fromer SM ’24. The research appears today in Nature Computational Science .

Complex cost considerations

In a sense, whether a scientist should synthesize and test a certain molecule boils down to a question of the synthetic cost versus the value of the experiment. However, determining cost or value are tough problems on their own.

For instance, an experiment might require expensive materials or it could have a high risk of failure. On the value side, one might consider how useful it would be to know the properties of this molecule or whether those predictions carry a high level of uncertainty.

At the same time, pharmaceutical companies increasingly use batch synthesis to improve efficiency. Instead of testing molecules one at a time, they use combinations of chemical building blocks to test multiple candidates at once. However, this means the chemical reactions must all require the same experimental conditions. This makes estimating cost and value even more challenging.

SPARROW tackles this challenge by considering the shared intermediary compounds involved in synthesizing molecules and incorporating that information into its cost-versus-value function.

“When you think about this optimization game of designing a batch of molecules, the cost of adding on a new structure depends on the molecules you have already chosen,” Coley says.

The framework also considers things like the costs of starting materials, the number of reactions that are involved in each synthetic route, and the likelihood those reactions will be successful on the first try.

To utilize SPARROW, a scientist provides a set of molecular compounds they are thinking of testing and a definition of the properties they are hoping to find.

From there, SPARROW collects information on the molecules and their synthetic pathways and then weighs the value of each one against the cost of synthesizing a batch of candidates. It automatically selects the best subset of candidates that meet the user’s criteria and finds the most cost-effective synthetic routes for those compounds.

“It does all this optimization in one step, so it can really capture all of these competing objectives simultaneously,” Fromer says.

A versatile framework

SPARROW is unique because it can incorporate molecular structures that have been hand-designed by humans, those that exist in virtual catalogs, or never-before-seen molecules that have been invented by generative AI models.

“We have all these different sources of ideas. Part of the appeal of SPARROW is that you can take all these ideas and put them on a level playing field,” Coley adds.

The researchers evaluated SPARROW by applying it in three case studies. The case studies, based on real-world problems faced by chemists, were designed to test SPARROW’s ability to find cost-efficient synthesis plans while working with a wide range of input molecules.

They found that SPARROW effectively captured the marginal costs of batch synthesis and identified common experimental steps and intermediate chemicals. In addition, it could scale up to handle hundreds of potential molecular candidates.

“In the machine-learning-for-chemistry community, there are so many models that work well for retrosynthesis or molecular property prediction, for example, but how do we actually use them? Our framework aims to bring out the value of this prior work. By creating SPARROW, hopefully we can guide other researchers to think about compound downselection using their own cost and utility functions,” Fromer says.

In the future, the researchers want to incorporate additional complexity into SPARROW. For instance, they’d like to enable the algorithm to consider that the value of testing one compound may not always be constant. They also want to include more elements of parallel chemistry in its cost-versus-value function.

“The work by Fromer and Coley better aligns algorithmic decision making to the practical realities of chemical synthesis. When existing computational design algorithms are used, the work of determining how to best synthesize the set of designs is left to the medicinal chemist, resulting in less optimal choices and extra work for the medicinal chemist,” says Patrick Riley, senior vice president of artificial intelligence at Relay Therapeutics, who was not involved with this research. “This paper shows a principled path to include consideration of joint synthesis, which I expect to result in higher quality and more accepted algorithmic designs.”

“Identifying which compounds to synthesize in a way that carefully balances time, cost, and the potential for making progress toward goals while providing useful new information is one of the most challenging tasks for drug discovery teams. The SPARROW approach from Fromer and Coley does this in an effective and automated way, providing a useful tool for human medicinal chemistry teams and taking important steps toward fully autonomous approaches to drug discovery,” adds John Chodera, a computational chemist at Memorial Sloan Kettering Cancer Center, who was not involved with this work.

This research was supported, in part, by the DARPA Accelerated Molecular Discovery Program, the Office of Naval Research, and the National Science Foundation.

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A Review Study of Substance Abuse Status in High School Students, Isfahan, Iran

Mah monir nahvizadeh.

Provincial Health Center, Isfahan University of Medical Sciences, Isfahan, Iran

Shohreh Akhavan

1 Vice-chancellery for Research, Isfahan University of Medical Sciences, Isfahan, Iran

Leila Qaraat

Nahid geramian, ziba farajzadegan.

2 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Kamal Heidari

3 Social Determinants of Health Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Background:

As the first experience of substance abuse often starts in adolescence, and studies have shown that drug use is mainly related to cigarette and alcohol consumption, an initial exploration of substance abuse prevalence, including cigarette and alcohol, seems to be the first step in preventing and controlling drug consumption. This study aimed to explore studies on drug use among high school students by investigating articles published in the past decade in Iran.

In this study, the databases inside the country were used to access articles related to substance abuse by students during 2001–2011, among which 7 articles on 14–19 years old high school students were studied.

The seven studied articles showed that the highest drug use prevalence pertained to cigarette and hookah, followed by alcohol, opium, ecstasy, hashish and heroin. Opium and heroin use in Kerman city were, respectively, about 4 and 5 times of their use in other studied cities.

Conclusions:

Drug use is relatively high in the adolescent and effective group of the society, which requires particular attention and prompt and immediate intervention.

INTRODUCTION

Substance abuse is a common phenomenon in the world and has invaded the human society as the most important social damage.[ 1 , 2 ] Substance abuse is a nonadaptive model of drug use, which results in adverse problems and consequences, and includes a set of cognitive, behavioral, and psychological symptoms.[ 3 ]

Iran also, due to its specific human and geographic features, has a relatively high degree of contamination.[ 4 ] The World Health Organization's report in 2005 shows that there are about 200 million opiate addicts in the world, reporting the highest prevalence in Iran and the most frequency in the 25–35 year-age group.[ 5 ] The onset of drug use is often rooted in adolescence, and studies show that substance abuse is often related to cigarette and alcohol consumption in adolescence.[ 6 ] Results of studies indicate that age, being male, high-risk behavirs, and the existence of a cigarette smoker in the family or among friends, the experience of substance abuse, inclination and positive thoughts about smoking have relationship with adolescent cigarette smoking.[ 7 ] Studies also confirm that the chance of becoming a cigarette smoker among males and females is almost equal (11.2%); however, the prevalence of regular alcohol consumption in males (22.4%) is slightly higher than in females (19.3%).[ 8 ]

Few studies have been conducted in Iran on adolescents’ patterns of substance abuse, producing various data on the prevalence and the type of consumed drugs, but there is currently no known specific pattern of substance abuse in this age group; therefore, this review study has studied drug consumption prevalence in the student population of the country by collecting various data.

This article is a narrative review focusing on studies conducted in Iran. In this research, all articles related to substance abuse and its patterns among high school students, which were conducted in Iran and published in domestic and international journals, were investigated. The articles were acquired from academic medical journals, research periodicals and the Scholar Google, Magiran, Irandoc, and Medlib. The search keywords included prevalence, substance abuse, Iranian student, and addiction.

This study explored articles in the past 10 years (2001–2011) about Iranian high school students. The full texts of the articles were often accessible in the scientific information database and magiran websites, but the full text of the article about Gilan Province was obtained after contacting the journal's office. Correspondence was made with the author of the article about Mahriz city to obtain the article as it was not published in the Toloee Behdasht journal.

These articles provide information about the consumed drug type, its prevalence in terms of the sex and age, and the experience of at-least-once consumption in the adolescent's life. Some articles had only pointed to drug consumption, which was also included in this research. Some had attended to substance abuse in general terms without distinguishing different kinds of drugs, and in some articles only psychoactive drug use, was mentioned.

The cases, in which the sample volume was not sufficient, or were not in the studied age groups, were excluded from the study. Due to different categorizations in these articles regarding the long-term prevalence of substance abuse or the experience of at-least-once consumption, in this study the shared aspect of these articles, that is, the experience of at-least-once use was adopted. Some articles had addressed the students’ predisposing factors for drug abuse, in addition to drug use prevalence, which were not included in this study for being scattered.

An initial search into the data bases yielded 11 articles, two of which were related to years before the study time frame (1997 and 1998). Furthermore, two articles were ignored, one because of its different age group (a lower age) and the other because it had addressed a particular district in Tehran with a small sample size. These results are based on 7 articles. All studies were about the 14–19 years old group, and only three studies had distinguished between the sexes. All 7 studies considered in this article were cross-sectional.

The prevalence of drug consumption in the studied cities

A study was conducted in 2003 on 500 students, from 142 high schools and vocational schools in Zahedan City, using a multi-stage cluster sampling method. In total, from the total of 259 females and 216 males who completed the questionnaire, the following results were obtained. 0.4% of the females and 2.3% of the males would usually smoke cigarette. The first experience of smoking was most often seen at the age of 14 (26.2%). The prevalence of other drugs was not studied in this research.[ 9 ] A study was conducted in 2009 on 610 students of Kerman's Male Pre-university Centers, in which the prevalence of each drug was reported, but the total consumption prevalence was not mentioned.[ 10 ]

A study in Gilan Province in 2004–2009 on 1927 high school students, including 46% females and 54% males, showed that the percentage of at-least-once use, including and excluding cigarette, was 23.7 and 12.8, respectively.[ 11 ]

A study in Karaj city in 2009–2010 on 447 high school students, including 239 females and 208 males, showed that 57% had at-least-once experience of drug use, including cigarette, of this number 56.1% were male and 43.9% were female.[ 12 ]

A study in Nazarabad city in 2007 on 400 3 rd year high school students, including 204 females and 196 males with the mean age of 17.3, showed that drug use prevalence, including and excluding cigarette, was 24.5% and 11.1%, respectively.[ 13 ] A study was performed in Lahijan city in 2004 on 2328 high school students, including 42.2% females and 57.8% males.[ 14 ] A descriptive study was conducted in 2008 on a 285-member sample of male high school students.[ 15 ]

The consumption prevalence for each drug type in different cities

A research on Kerman's Male Pre-university students yielded the following results. The consumption prevalence of hookah was 15.5%, sedatives (without medical prescription) 40.7%, alcohol 37.7%, cigarette 34.6%, strong analgesics 10.2%, nas 9.7%, opium 8.7%, hashish 6.7%, ecstasy 6.6%, and heroin 4.9%.

Consumption prevalence for each drug type in Gilan: The prevalence was 20% for cigarette, 10.5% for alcohol, 2.4% for opium, 1.2% for ecstasy, 2% for hashish, and 0.3% for heroin. In Karaj city, the consumption prevalence was 53% for hookah, 24.8% for cigarette, 13.6% for alcohol, 2% for ecstasy, 2% for opium, 1.1% for hashish, 0.4% for crystal, and 0.2% for heroin.

In Nazarabad City, the consumption prevalence was found to be 23.1% for cigarette, 2% for opium, 1% for amphetamines and ecstasy, 0.5% for heroin, 0.3% for hashish and cocaine. The male and female drug consumption was 69.7% and 36.2%, respectively, representing a significant statistical difference ( P < 0.05).

A study in Lahijan City showed that the consumption prevalence was 14.9% for cigarette, 2.4% for ecstasy, 4.1% for other drug types (with the highest rate of consumption for opium and hashish). In the Mahriz city of Yazd, the consumption prevalence among the male 3 rd year high school students in 2008 was reported 6.8% for alcohol and 3% for psychoactive substances [ Table 1 ].

The comparison of the prevalence of at-least-once drug use for each drug type in each studied region[ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]

Drug consumption prevalence for each sex

A study in Zahedan also reported that at-least-once drug use prevalence was 1.6% and 8%, respectively, among females and males; and at-least-once cigarette smoking prevalence was 7.8% and 25.2%, respectively, for females with the mean age of 15.8 and males with the mean age of 16.

In Gilan, drug use, excluding cigarette, was reported 19.1% and 5.3%, respectively, for males and females, representing a significant statistical difference ( P < 0.05). Furthermore, cigarette and drug use prevalence was 31.3% and 14.8% in males and females, respectively, showing that this rate was significantly higher in males ( P < 0.05). Cigarette use prevalence was 25.9% and 3%, respectively, for male and female students. Alcohol consumption was 16.6% and 3.4% for males and females, respectively. Opium consumption was 3.3% and 1.5% among males and females, respectively, which was a significant statistical difference (…). Drug consumption, excluding cigarette, was 19.1% and 5.3%, respectively, for males and females, pointing to a statistically significant difference ( P < 0.05). Ecstasy use prevalence was reported 3% and 1.1%, respectively, for males and females, pointing to a statistically significant difference ( P < 0.00081); 0.5% of males and 0.1% of females were heroin consumers, lacking any significant statistical difference ( P > 0.05). In Karaj city, drug consumption prevalence was studied for each sex and drug type [ Table 2 ].

The comparison of the prevalence of at-least-once drug consumption for each sex in each studied region

Drug consumption prevalence based on the age distribution in the studied populations

As the study conducted on students with the mean age of 16 in Zahedan showed that the highest incidence of the first experience of cigarette smoking belonged to the age of 14. A study in Kerman on students with the mean age of 17.9 about the age at the first experience yielded the following results for each drug type: 14 for cigarette, 14.6 for alcohol, 13.9 for hookah, 13.1 for sedatives, 15.3 for analgesics, 17 for ecstasy, 16.7 for hashish, 16.7 for heroin, 16.7 for opium, and 15.3 for naswar.

A study in Gilan indicated that drug and cigarette consumption had significantly increased in males aged 19 and above (88.9% of males aged 19 and above) ( P < 0.05). According to a study in Nazarabad, the highest drug use onset was at the age of 15–16. The students’ mean age in the Karaj study was 16.9.

Exploring the MFT performed in the USA on the 10 th graders showed that drug use had increased from 11% to 34% during 1992–1996. In 1998, 12.10% of the 8 th year and 12.5% of the 10 th graders and 25.611 th % had experienced illegal drug use in the previous month.[ 16 ] It was shown that hashish, followed by opium and alcohol, is the most commonly used illicit drug.[ 17 ] The immediate necessity of planning for reducing the consumption of these drugs among students, and consequently among university students, has become increasingly important.

Investigating addictive drugs prevalence among university students showed the prevalence in the following order: Hookah (74.5%), cigarette (67.5%), opium (6.1%), alcohol (13.5%), psychoactive pills (5.26%), hashish and heroin. Entertainment constitutes the tendency for drug consumption in most cases (47.4%).[ 18 ] Results of a meta-analysis showed that 7% of Iranian adolescents regularly smoke, and 27% had experienced smoking. The increased cigarette use prevalence among Iranian adolescents is a major public health concern.[ 19 ] Paying attention to healthy recreations for adolescents and the youth has become increasingly important and needs planning for discouraging drug use. The cross-sectional prevalence of drug use in 1997 among American 12–17 years old adolescents was reported 11.4%, which was close to drug use prevalence, excluding cigarette.[ 16 ]

Another study showed that 56% of male and 42% of female university students were drug users, which accords with the present research with regard to the higher number of the males.[ 20 ] Since, the addiction problem is an old problem in other countries, it might be better to use the solutions practiced by them to speed up our reaction in cases which adhere to our culture and customs.

At-least-once alcohol use prevalence among the 8 th year American students in 2005 and 2006 was 27% and 20%, respectively, increasing to 88% among the 12 th year students.[ 20 ] The history of hashish consumption among the 8 th , the 10 th , and the 12 th year students was 10%, 23%, and 36%, respectively, representing a remarkable difference with our country's students.[ 20 ] About 0.5% of the 8 th year and 10% of the 12 th year students consumed cocaine, and the consumption of amphetamines by the 12 th year students was 1.5%,[ 20 ] being almost close to the consumption rate of Iranian students. The open consumption of hashish is common in France by almost one-third of the population (nearly 30%), compared with the average rate of 19% in European countries; also the consumption of ecstasy and cocaine has increased over 2000–2005, although it is 4% but yet remarkable.[ 21 ]

A study on students’ knowledge of narcotics in Rafsanjan and Yazd cities showed that 5.6% of Yazdian and 10% of Rafsanjanian students had at least one addicted person in their families. Also, 2.23% of the Yazdian and 7% of the Rafsanjanian students held that narcotics could also be useful.[ 22 ] The important issue here is the existence of an addicted relative and his or her leadership role in this regard; therefore, this point suggests the further importance of the sensitivity of this age group with regard to their dependence on narcotics.

It is noteworthy that Kerman City, compared to other studied cities, has received higher rates of drug use, such that opium and heroin consumption in this city has been, respectively, almost 4 and 5 times that of other cities. These statistics also hold true clearly with regard to ecstasy and alcohol consumption, each being almost 3 times that of Karaj and Gilan. Hashish consumption in the pre-university stage in this city is also higher than in other cities, which might be related to easier drug access in Kerman.

In the cities, in which sex-distinct studies were conducted, drug consumption by males had been, with no exception, far higher than by the females, which is, almost 4 times except for hookah and then cigarette. Of course, it is not possible to judge firmly about drug use general prevalence as a result of the few studies in this field; however, the important point is the relatively high drug use among the adolescent and effective group of the society, which deserves particular attention for education and intervention in this group. It has been observed that adolescent and young crystal users, compared to nonusers, show clinical symptoms, have less control and affection in their families, with excitable, aggressive and anxious personalities, and low accountability;[ 23 ] on the other hand, behavioral problems and friend influence are among the strongest risk factors of drug consumption among adolescent consumers.

Nevertheless, it is not clear to what extent the adolescent can manage the effect of behavioral problems and peer group interaction for refusing invitations for drug consumption.[ 24 ] It has been stated that using software programs would assist in the prevention and increasing the youth's skills for reducing drug use.[ 25 ] It has been shown that adolescent inclination to and consumption of drugs decrease significantly in the 1 st year of educational intervention.[ 26 ] On the other hand, studies indicate that there is a relationship between the borderline personality disorder and the extent of drug abuse.[ 27 ]

Therefore, prevention programs for harm reduction, treatment and consultation as the main objective of the intervention structure should apply to consumers.[ 28 ] Also, emphasis should be laid upon the relationship between schools and parental care as important protective factors for adolescents’ health.[ 29 ] Adolescence is a growth period which is associated with a relatively high rate of drug use and its related disorders. Accordingly, recent progress in evaluating drug abuse among adolescents would continue for information sharing in the field of clinical and research services.[ 30 ] Therefore, attention to this group through coherent planning for damage prevention would still remain in priority.

CONCLUSIONS

Source of Support: Nil

Conflict of Interest: None declared.