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Psychiatry Online

  • February 01, 2024 | VOL. 181, NO. 2 CURRENT ISSUE pp.83-170
  • January 01, 2024 | VOL. 181, NO. 1 pp.1-82

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

  • Ned H. Kalin , M.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

Conclusions

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

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

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

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

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

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

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

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

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

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

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

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

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

  • Cited by None

research papers on drugs

  • Substance-Related and Addictive Disorders
  • Addiction Psychiatry
  • Transgender (LGBT) Issues
  • Open access
  • Published: 13 November 2021

Risk and protective factors of drug abuse among adolescents: a systematic review

  • Azmawati Mohammed Nawi 1 ,
  • Rozmi Ismail 2 ,
  • Fauziah Ibrahim 2 ,
  • Mohd Rohaizat Hassan 1 ,
  • Mohd Rizal Abdul Manaf 1 ,
  • Noh Amit 3 ,
  • Norhayati Ibrahim 3 &
  • Nurul Shafini Shafurdin 2  

BMC Public Health volume  21 , Article number:  2088 ( 2021 ) Cite this article

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Drug abuse is detrimental, and excessive drug usage is a worldwide problem. Drug usage typically begins during adolescence. Factors for drug abuse include a variety of protective and risk factors. Hence, this systematic review aimed to determine the risk and protective factors of drug abuse among adolescents worldwide.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was adopted for the review which utilized three main journal databases, namely PubMed, EBSCOhost, and Web of Science. Tobacco addiction and alcohol abuse were excluded in this review. Retrieved citations were screened, and the data were extracted based on strict inclusion and exclusion criteria. Inclusion criteria include the article being full text, published from the year 2016 until 2020 and provided via open access resource or subscribed to by the institution. Quality assessment was done using Mixed Methods Appraisal Tools (MMAT) version 2018 to assess the methodological quality of the included studies. Given the heterogeneity of the included studies, a descriptive synthesis of the included studies was undertaken.

Out of 425 articles identified, 22 quantitative articles and one qualitative article were included in the final review. Both the risk and protective factors obtained were categorized into three main domains: individual, family, and community factors. The individual risk factors identified were traits of high impulsivity; rebelliousness; emotional regulation impairment, low religious, pain catastrophic, homework completeness, total screen time and alexithymia; the experience of maltreatment or a negative upbringing; having psychiatric disorders such as conduct problems and major depressive disorder; previous e-cigarette exposure; behavioral addiction; low-perceived risk; high-perceived drug accessibility; and high-attitude to use synthetic drugs. The familial risk factors were prenatal maternal smoking; poor maternal psychological control; low parental education; negligence; poor supervision; uncontrolled pocket money; and the presence of substance-using family members. One community risk factor reported was having peers who abuse drugs. The protective factors determined were individual traits of optimism; a high level of mindfulness; having social phobia; having strong beliefs against substance abuse; the desire to maintain one’s health; high paternal awareness of drug abuse; school connectedness; structured activity and having strong religious beliefs.

The outcomes of this review suggest a complex interaction between a multitude of factors influencing adolescent drug abuse. Therefore, successful adolescent drug abuse prevention programs will require extensive work at all levels of domains.

Peer Review reports

Introduction

Drug abuse is a global problem; 5.6% of the global population aged 15–64 years used drugs at least once during 2016 [ 1 ]. The usage of drugs among younger people has been shown to be higher than that among older people for most drugs. Drug abuse is also on the rise in many ASEAN (Association of Southeast Asian Nations) countries, especially among young males between 15 and 30 years of age. The increased burden due to drug abuse among adolescents and young adults was shown by the Global Burden of Disease (GBD) study in 2013 [ 2 ]. About 14% of the total health burden in young men is caused by alcohol and drug abuse. Younger people are also more likely to die from substance use disorders [ 3 ], and cannabis is the drug of choice among such users [ 4 ].

Adolescents are the group of people most prone to addiction [ 5 ]. The critical age of initiation of drug use begins during the adolescent period, and the maximum usage of drugs occurs among young people aged 18–25 years old [ 1 ]. During this period, adolescents have a strong inclination toward experimentation, curiosity, susceptibility to peer pressure, rebellion against authority, and poor self-worth, which makes such individuals vulnerable to drug abuse [ 2 ]. During adolescence, the basic development process generally involves changing relations between the individual and the multiple levels of the context within which the young person is accustomed. Variation in the substance and timing of these relations promotes diversity in adolescence and represents sources of risk or protective factors across this life period [ 6 ]. All these factors are crucial to helping young people develop their full potential and attain the best health in the transition to adulthood. Abusing drugs impairs the successful transition to adulthood by impairing the development of critical thinking and the learning of crucial cognitive skills [ 7 ]. Adolescents who abuse drugs are also reported to have higher rates of physical and mental illness and reduced overall health and well-being [ 8 ].

The absence of protective factors and the presence of risk factors predispose adolescents to drug abuse. Some of the risk factors are the presence of early mental and behavioral health problems, peer pressure, poorly equipped schools, poverty, poor parental supervision and relationships, a poor family structure, a lack of opportunities, isolation, gender, and accessibility to drugs [ 9 ]. The protective factors include high self-esteem, religiosity, grit, peer factors, self-control, parental monitoring, academic competence, anti-drug use policies, and strong neighborhood attachment [ 10 , 11 , 12 , 13 , 14 , 15 ].

The majority of previous systematic reviews done worldwide on drug usage focused on the mental, psychological, or social consequences of substance abuse [ 16 , 17 , 18 ], while some focused only on risk and protective factors for the non-medical use of prescription drugs among youths [ 19 ]. A few studies focused only on the risk factors of single drug usage among adolescents [ 20 ]. Therefore, the development of the current systematic review is based on the main research question: What is the current risk and protective factors among adolescent on the involvement with drug abuse? To the best of our knowledge, there is limited evidence from systematic reviews that explores the risk and protective factors among the adolescent population involved in drug abuse. Especially among developing countries, such as those in South East Asia, such research on the risk and protective factors for drug abuse is scarce. Furthermore, this review will shed light on the recent trends of risk and protective factors and provide insight into the main focus factors for prevention and control activities program. Additionally, this review will provide information on how these risk and protective factors change throughout various developmental stages. Therefore, the objective of this systematic review was to determine the risk and protective factors of drug abuse among adolescents worldwide. This paper thus fills in the gaps of previous studies and adds to the existing body of knowledge. In addition, this review may benefit certain parties in developing countries like Malaysia, where the national response to drugs is developing in terms of harm reduction, prison sentences, drug treatments, law enforcement responses, and civil society participation.

This systematic review was conducted using three databases, PubMed, EBSCOhost, and Web of Science, considering the easy access and wide coverage of reliable journals, focusing on the risk and protective factors of drug abuse among adolescents from 2016 until December 2020. The search was limited to the last 5 years to focus only on the most recent findings related to risk and protective factors. The search strategy employed was performed in accordance with the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) checklist.

A preliminary search was conducted to identify appropriate keywords and determine whether this review was feasible. Subsequently, the related keywords were searched using online thesauruses, online dictionaries, and online encyclopedias. These keywords were verified and validated by an academic professor at the National University of Malaysia. The keywords used as shown in Table  1 .

Selection criteria

The systematic review process for searching the articles was carried out via the steps shown in Fig.  1 . Firstly, screening was done to remove duplicate articles from the selected search engines. A total of 240 articles were removed in this stage. Titles and abstracts were screened based on the relevancy of the titles to the inclusion and exclusion criteria and the objectives. The inclusion criteria were full text original articles, open access articles or articles subscribed to by the institution, observation and intervention study design and English language articles. The exclusion criteria in this search were (a) case study articles, (b) systematic and narrative review paper articles, (c) non-adolescent-based analyses, (d) non-English articles, and (e) articles focusing on smoking (nicotine) and alcohol-related issues only. A total of 130 articles were excluded after title and abstract screening, leaving 55 articles to be assessed for eligibility. The full text of each article was obtained, and each full article was checked thoroughly to determine if it would fulfil the inclusion criteria and objectives of this study. Each of the authors compared their list of potentially relevant articles and discussed their selections until a final agreement was obtained. A total of 22 articles were accepted to be included in this review. Most of the excluded articles were excluded because the population was not of the target age range—i.e., featuring subjects with an age > 18 years, a cohort born in 1965–1975, or undergraduate college students; the subject matter was not related to the study objective—i.e., assessing the effects on premature mortality, violent behavior, psychiatric illness, individual traits, and personality; type of article such as narrative review and neuropsychiatry review; and because of our inability to obtain the full article—e.g., forthcoming work in 2021. One qualitative article was added to explain the domain related to risk and the protective factors among the adolescents.

figure 1

PRISMA flow diagram showing the selection of studies on risk and protective factors for drug abuse among adolescents.2.2. Operational Definition

Drug-related substances in this context refer to narcotics, opioids, psychoactive substances, amphetamines, cannabis, ecstasy, heroin, cocaine, hallucinogens, depressants, and stimulants. Drugs of abuse can be either off-label drugs or drugs that are medically prescribed. The two most commonly abused substances not included in this review are nicotine (tobacco) and alcohol. Accordingly, e-cigarettes and nicotine vape were also not included. Further, “adolescence” in this study refers to members of the population aged between 10 to 18 years [ 21 ].

Data extraction tool

All researchers independently extracted information for each article into an Excel spreadsheet. The data were then customized based on their (a) number; (b) year; (c) author and country; (d) titles; (e) study design; (f) type of substance abuse; (g) results—risks and protective factors; and (h) conclusions. A second reviewer crossed-checked the articles assigned to them and provided comments in the table.

Quality assessment tool

By using the Mixed Method Assessment Tool (MMAT version 2018), all articles were critically appraised for their quality by two independent reviewers. This tool has been shown to be useful in systematic reviews encompassing different study designs [ 22 ]. Articles were only selected if both reviewers agreed upon the articles’ quality. Any disagreement between the assigned reviewers was managed by employing a third independent reviewer. All included studies received a rating of “yes” for the questions in the respective domains of the MMAT checklists. Therefore, none of the articles were removed from this review due to poor quality. The Cohen’s kappa (agreement) between the two reviewers was 0.77, indicating moderate agreement [ 23 ].

The initial search found 425 studies for review, but after removing duplicates and applying the criteria listed above, we narrowed the pool to 22 articles, all of which are quantitative in their study design. The studies include three prospective cohort studies [ 24 , 25 , 26 ], one community trial [ 27 ], one case-control study [ 28 ], and nine cross-sectional studies [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. After careful discussion, all reviewer panels agreed to add one qualitative study [ 46 ] to help provide reasoning for the quantitative results. The selected qualitative paper was chosen because it discussed almost all domains on the risk and protective factors found in this review.

A summary of all 23 articles is listed in Table  2 . A majority of the studies (13 articles) were from the United States of America (USA) [ 25 , 26 , 27 , 29 , 30 , 31 , 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ], three studies were from the Asia region [ 32 , 33 , 38 ], four studies were from Europe [ 24 , 28 , 40 , 44 ], and one study was from Latin America [ 35 ], Africa [ 43 ] and Mediterranean [ 45 ]. The number of sample participants varied widely between the studies, ranging from 70 samples (minimum) to 700,178 samples (maximum), while the qualitative paper utilized a total of 100 interviewees. There were a wide range of drugs assessed in the quantitative articles, with marijuana being mentioned in 11 studies, cannabis in five studies, and opioid (six studies). There was also large heterogeneity in terms of the study design, type of drug abused, measurements of outcomes, and analysis techniques used. Therefore, the data were presented descriptively.

After thorough discussion and evaluation, all the findings (both risk and protective factors) from the review were categorized into three main domains: individual factors, family factors, and community factors. The conceptual framework is summarized in Fig.  2 .

figure 2

Conceptual framework of risk and protective factors related to adolescent drug abuse

DOMAIN: individual factor

Risk factors.

Almost all the articles highlighted significant findings of individual risk factors for adolescent drug abuse. Therefore, our findings for this domain were further broken down into five more sub-domains consisting of personal/individual traits, significant negative growth exposure, personal psychiatric diagnosis, previous substance history, comorbidity and an individual’s attitude and perception.

Personal/individual traits

Chuang et al. [ 29 ] found that adolescents with high impulsivity traits had a significant positive association with drug addiction. This study also showed that the impulsivity trait alone was an independent risk factor that increased the odds between two to four times for using any drug compared to the non-impulsive group. Another longitudinal study by Guttmannova et al. showed that rebellious traits are positively associated with marijuana drug abuse [ 27 ]. The authors argued that measures of rebelliousness are a good proxy for a youth’s propensity to engage in risky behavior. Nevertheless, Wilson et al. [ 37 ], in a study involving 112 youths undergoing detoxification treatment for opioid abuse, found that a majority of the affected respondents had difficulty in regulating their emotions. The authors found that those with emotional regulation impairment traits became opioid dependent at an earlier age. Apart from that, a case-control study among outpatient youths found that adolescents involved in cannabis abuse had significant alexithymia traits compared to the control population [ 28 ]. Those adolescents scored high in the dimension of Difficulty in Identifying Emotion (DIF), which is one of the key definitions of diagnosing alexithymia. Overall, the adjusted Odds Ratio for DIF in cannabis abuse was 1.11 (95% CI, 1.03–1.20).

Significant negative growth exposure

A history of maltreatment in the past was also shown to have a positive association with adolescent drug abuse. A study found that a history of physical abuse in the past is associated with adolescent drug abuse through a Path Analysis, despite evidence being limited to the female gender [ 25 ]. However, evidence from another study focusing at foster care concluded that any type of maltreatment might result in a prevalence as high as 85.7% for the lifetime use of cannabis and as high as 31.7% for the prevalence of cannabis use within the last 3-months [ 30 ]. The study also found significant latent variables that accounted for drug abuse outcomes, which were chronic physical maltreatment (factor loading of 0.858) and chronic psychological maltreatment (factor loading of 0.825), with an r 2 of 73.6 and 68.1%, respectively. Another study shed light on those living in child welfare service (CWS) [ 35 ]. It was observed through longitudinal measurements that proportions of marijuana usage increased from 9 to 18% after 36 months in CWS. Hence, there is evidence of the possibility of a negative upbringing at such shelters.

Personal psychiatric diagnosis

The robust studies conducted in the USA have deduced that adolescents diagnosed with a conduct problem (CP) have a positive association with marijuana abuse (OR = 1.75 [1.56, 1.96], p  < 0.0001). Furthermore, those with a diagnosis of Major Depressive Disorder (MDD) showed a significant positive association with marijuana abuse.

Previous substance and addiction history

Another study found that exposure to e-cigarettes within the past 30 days is related to an increase in the prevalence of marijuana use and prescription drug use by at least four times in the 8th and 10th grades and by at least three times in the 12th grade [ 34 ]. An association between other behavioral addictions and the development of drug abuse was also studied [ 29 ]. Using a 12-item index to assess potential addictive behaviors [ 39 ], significant associations between drug abuse and the groups with two behavioral addictions (OR = 3.19, 95% CI 1.25,9.77) and three behavioral addictions (OR = 3.46, 95% CI 1.25,9.58) were reported.

Comorbidity

The paper by Dash et al. (2020) highlight adolescent with a disease who needs routine medical pain treatment have higher risk of opioid misuse [ 38 ]. The adolescents who have disorder symptoms may have a risk for opioid misuse despite for the pain intensity.

Individual’s attitudes and perceptions

In a study conducted in three Latin America countries (Argentina, Chile, and Uruguay), it was shown that adolescents with low or no perceived risk of taking marijuana had a higher risk of abuse (OR = 8.22 times, 95% CI 7.56, 10.30) [ 35 ]. This finding is in line with another study that investigated 2002 adolescents and concluded that perceiving the drug as harmless was an independent risk factor that could prospectively predict future marijuana abuse [ 27 ]. Moreover, some youth interviewed perceived that they gained benefits from substance use [ 38 ]. The focus group discussion summarized that the youth felt positive personal motivation and could escape from a negative state by taking drugs. Apart from that, adolescents who had high-perceived availability of drugs in their neighborhoods were more likely to increase their usage of marijuana over time (OR = 11.00, 95% CI 9.11, 13.27) [ 35 ]. A cheap price of the substance and the availability of drug dealers around schools were factors for youth accessibility [ 38 ]. Perceived drug accessibility has also been linked with the authorities’ enforcement programs. The youth perception of a lax community enforcement of laws regarding drug use at all-time points predicted an increase in marijuana use in the subsequent assessment period [ 27 ]. Besides perception, a study examining the attitudes towards synthetic drugs based on 8076 probabilistic samples of Macau students found that the odds of the lifetime use of marijuana was almost three times higher among those with a strong attitude towards the use of synthetic drugs [ 32 ]. In addition, total screen time among the adolescent increase the likelihood of frequent cannabis use. Those who reported daily cannabis use have a mean of 12.56 h of total screen time, compared to a mean of 6.93 h among those who reported no cannabis use. Adolescent with more time on internet use, messaging, playing video games and watching TV/movies were significantly associated with more frequent cannabis use [ 44 ].

Protective factors

Individual traits.

Some individual traits have been determined to protect adolescents from developing drug abuse habits. A study by Marin et al. found that youth with an optimistic trait were less likely to become drug dependent [ 33 ]. In this study involving 1104 Iranian students, it was concluded that a higher optimism score (measured using the Children Attributional Style Questionnaire, CASQ) was a protective factor against illicit drug use (OR = 0.90, 95% CI: 0.85–0.95). Another study found that high levels of mindfulness, measured using the 25-item Child Acceptance and Mindfulness Measure, CAMM, lead to a slower progression toward injectable drug abuse among youth with opioid addiction (1.67 years, p  = .041) [ 37 ]. In addition, the social phobia trait was found to have a negative association with marijuana use (OR = 0.87, 95% CI 0.77–0.97), as suggested [ 31 ].

According to El Kazdouh et al., individuals with a strong belief against substance use and those with a strong desire to maintain their health were more likely to be protected from involvement in drug abuse [ 46 ].

DOMAIN: family factors

The biological factors underlying drug abuse in adolescents have been reported in several studies. Epigenetic studies are considered important, as they can provide a good outline of the potential pre-natal factors that can be targeted at an earlier stage. Expecting mothers who smoke tobacco and alcohol have an indirect link with adolescent substance abuse in later life [ 24 , 39 ]. Moreover, the dynamic relationship between parents and their children may have some profound effects on the child’s growth. Luk et al. examined the mediator effects between parenting style and substance abuse and found the maternal psychological control dimension to be a significant variable [ 26 ]. The mother’s psychological control was two times higher in influencing her children to be involved in substance abuse compared to the other dimension. Conversely, an indirect risk factor towards youth drug abuse was elaborated in a study in which low parental educational level predicted a greater risk of future drug abuse by reducing the youth’s perception of harm [ 27 , 43 ]. Negligence from a parental perspective could also contribute to this problem. According to El Kazdouh et al. [ 46 ], a lack of parental supervision, uncontrolled pocket money spending among children, and the presence of substance-using family members were the most common negligence factors.

While the maternal factors above were shown to be risk factors, the opposite effect was seen when the paternal figure equipped himself with sufficient knowledge. A study found that fathers with good information and awareness were more likely to protect their adolescent children from drug abuse [ 26 ]. El Kazdouh et al. noted that support and advice could be some of the protective factors in this area [ 46 ].

DOMAIN: community factors

  • Risk factor

A study in 2017 showed a positive association between adolescent drug abuse and peers who abuse drugs [ 32 , 39 ]. It was estimated that the odds of becoming a lifetime marijuana user was significantly increased by a factor of 2.5 ( p  < 0.001) among peer groups who were taking synthetic drugs. This factor served as peer pressure for youth, who subconsciously had desire to be like the others [ 38 ]. The impact of availability and engagement in structured and unstructured activities also play a role in marijuana use. The findings from Spillane (2000) found that the availability of unstructured activities was associated with increased likelihood of marijuana use [ 42 ].

  • Protective factor

Strong religious beliefs integrated into society serve as a crucial protective factor that can prevent adolescents from engaging in drug abuse [ 38 , 45 ]. In addition, the school connectedness and adult support also play a major contribution in the drug use [ 40 ].

The goal of this review was to identify and classify the risks and protective factors that lead adolescents to drug abuse across the three important domains of the individual, family, and community. No findings conflicted with each other, as each of them had their own arguments and justifications. The findings from our review showed that individual factors were the most commonly highlighted. These factors include individual traits, significant negative growth exposure, personal psychiatric diagnosis, previous substance and addiction history, and an individual’s attitude and perception as risk factors.

Within the individual factor domain, nine articles were found to contribute to the subdomain of personal/ individual traits [ 27 , 28 , 29 , 37 , 38 , 39 , 40 , 43 , 44 ]. Despite the heterogeneity of the study designs and the substances under investigation, all of the papers found statistically significant results for the possible risk factors of adolescent drug abuse. The traits of high impulsivity, rebelliousness, difficulty in regulating emotions, and alexithymia can be considered negative characteristic traits. These adolescents suffer from the inability to self-regulate their emotions, so they tend to externalize their behaviors as a way to avoid or suppress the negative feelings that they are experiencing [ 41 , 47 , 48 ]. On the other hand, engaging in such behaviors could plausibly provide a greater sense of positive emotions and make them feel good [ 49 ]. Apart from that, evidence from a neurophysiological point of view also suggests that the compulsive drive toward drug use is complemented by deficits in impulse control and decision making (impulsive trait) [ 50 ]. A person’s ability in self-control will seriously impaired with continuous drug use and will lead to the hallmark of addiction [ 51 ].

On the other hand, there are articles that reported some individual traits to be protective for adolescents from engaging in drug abuse. Youth with the optimistic trait, a high level of mindfulness, and social phobia were less likely to become drug dependent [ 31 , 33 , 37 ]. All of these articles used different psychometric instruments to classify each individual trait and were mutually exclusive. Therefore, each trait measured the chance of engaging in drug abuse on its own and did not reflect the chance at the end of the spectrum. These findings show that individual traits can be either protective or risk factors for the drugs used among adolescents. Therefore, any adolescent with negative personality traits should be monitored closely by providing health education, motivation, counselling, and emotional support since it can be concluded that negative personality traits are correlated with high risk behaviours such as drug abuse [ 52 ].

Our study also found that a history of maltreatment has a positive association with adolescent drug abuse. Those adolescents with episodes of maltreatment were considered to have negative growth exposure, as their childhoods were negatively affected by traumatic events. Some significant associations were found between maltreatment and adolescent drug abuse, although the former factor was limited to the female gender [ 25 , 30 , 36 ]. One possible reason for the contrasting results between genders is the different sample populations, which only covered child welfare centers [ 36 ] and foster care [ 30 ]. Regardless of the place, maltreatment can happen anywhere depending on the presence of the perpetrators. To date, evidence that concretely links maltreatment and substance abuse remains limited. However, a plausible explanation for this link could be the indirect effects of posttraumatic stress (i.e., a history of maltreatment) leading to substance use [ 53 , 54 ]. These findings highlight the importance of continuous monitoring and follow-ups with adolescents who have a history of maltreatment and who have ever attended a welfare center.

Addiction sometimes leads to another addiction, as described by the findings of several studies [ 29 , 34 ]. An initial study focused on the effects of e-cigarettes in the development of other substance abuse disorders, particularly those related to marijuana, alcohol, and commonly prescribed medications [ 34 ]. The authors found that the use of e-cigarettes can lead to more severe substance addiction [ 55 ], possibly through normalization of the behavior. On the other hand, Chuang et al.’s extensive study in 2017 analyzed the combined effects of either multiple addictions alone or a combination of multiple addictions together with the impulsivity trait [ 29 ]. The outcomes reported were intriguing and provide the opportunity for targeted intervention. The synergistic effects of impulsiveness and three other substance addictions (marijuana, tobacco, and alcohol) substantially increased the likelihood for drug abuse from 3.46 (95%CI 1.25, 9.58) to 10.13 (95% CI 3.95, 25.95). Therefore, proper rehabilitation is an important strategy to ensure that one addiction will not lead to another addiction.

The likelihood for drug abuse increases as the population perceives little or no harmful risks associated with the drugs. On the opposite side of the coin, a greater perceived risk remains a protective factor for marijuana abuse [ 56 ]. However, another study noted that a stronger determinant for adolescent drug abuse was the perceived availability of the drug [ 35 , 57 ]. Looking at the bigger picture, both perceptions corroborate each other and may inform drug use. Another study, on the other hand, reported that there was a decreasing trend of perceived drug risk in conjunction with the increasing usage of drugs [ 58 ]. As more people do drugs, youth may inevitably perceive those drugs as an acceptable norm without any harmful consequences [ 59 ].

In addition, the total spent for screen time also contribute to drug abuse among adolescent [ 43 ]. This scenario has been proven by many researchers on the effect of screen time on the mental health [ 60 ] that leads to the substance use among the adolescent due to the ubiquity of pro-substance use content on the internet. Adolescent with comorbidity who needs medical pain management by opioids also tend to misuse in future. A qualitative exploration on the perspectives among general practitioners concerning the risk of opioid misuse in people with pain, showed pain management by opioids is a default treatment and misuse is not a main problem for the them [ 61 ]. A careful decision on the use of opioids as a pain management should be consider among the adolescents and their understanding is needed.

Within the family factor domain, family structures were found to have both positive and negative associations with drug abuse among adolescents. As described in one study, paternal knowledge was consistently found to be a protective factor against substance abuse [ 26 ]. With sufficient knowledge, the father can serve as the guardian of his family to monitor and protect his children from negative influences [ 62 ]. The work by Luk et al. also reported a positive association of maternal psychological association towards drug abuse (IRR 2.41, p  < 0.05) [ 26 ]. The authors also observed the same effect of paternal psychological control, although it was statistically insignificant. This construct relates to parenting style, and the authors argued that parenting style might have a profound effect on the outcomes under study. While an earlier literature review [ 63 ] also reported such a relationship, a recent study showed a lesser impact [ 64 ] with regards to neglectful parenting styles leading to poorer substance abuse outcomes. Nevertheless, it was highlighted in another study that the adolescents’ perception of a neglectful parenting style increased their odds (OR 2.14, p  = 0.012) of developing alcohol abuse, not the parenting style itself [ 65 ]. Altogether, families play vital roles in adolescents’ risk for engaging in substance abuse [ 66 ]. Therefore, any intervention to impede the initiation of substance use or curb existing substance use among adolescents needs to include parents—especially improving parent–child communication and ensuring that parents monitor their children’s activities.

Finally, the community also contributes to drug abuse among adolescents. As shown by Li et al. [ 32 ] and El Kazdouh et al. [ 46 ], peers exert a certain influence on other teenagers by making them subconsciously want to fit into the group. Peer selection and peer socialization processes might explain why peer pressure serves as a risk factor for drug-abuse among adolescents [ 67 ]. Another study reported that strong religious beliefs integrated into society play a crucial role in preventing adolescents from engaging in drug abuse [ 46 ]. Most religions devalue any actions that can cause harmful health effects, such as substance abuse [ 68 ]. Hence, spiritual beliefs may help protect adolescents. This theme has been well established in many studies [ 60 , 69 , 70 , 71 , 72 ] and, therefore, could be implemented by religious societies as part of interventions to curb the issue of adolescent drug abuse. The connection with school and structured activity did reduce the risk as a study in USA found exposure to media anti-drug messages had an indirect negative effect on substances abuse through school-related activity and social activity [ 73 ]. The school activity should highlight on the importance of developmental perspective when designing and offering school-based prevention programs [75].

Limitations

We adopted a review approach that synthesized existing evidence on the risk and protective factors of adolescents engaging in drug abuse. Although this systematic review builds on the conclusion of a rigorous review of studies in different settings, there are some potential limitations to this work. We may have missed some other important factors, as we only included English articles, and article extraction was only done from the three search engines mentioned. Nonetheless, this review focused on worldwide drug abuse studies, rather than the broader context of substance abuse including alcohol and cigarettes, thereby making this paper more focused.

Conclusions

This review has addressed some recent knowledge related to the individual, familial, and community risk and preventive factors for adolescent drug use. We suggest that more attention should be given to individual factors since most findings were discussed in relation to such factors. With the increasing trend of drug abuse, it will be critical to focus research specifically on this area. Localized studies, especially those related to demographic factors, may be more effective in generating results that are specific to particular areas and thus may be more useful in generating and assessing local control and prevention efforts. Interventions using different theory-based psychotherapies and a recognition of the unique developmental milestones specific to adolescents are among examples that can be used. Relevant holistic approaches should be strengthened not only by relevant government agencies but also by the private sector and non-governmental organizations by promoting protective factors while reducing risk factors in programs involving adolescents from primary school up to adulthood to prevent and control drug abuse. Finally, legal legislation and enforcement against drug abuse should be engaged with regularly as part of our commitment to combat this public health burden.

Data availability and materials

All data generated or analysed during this study are included in this published article.

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The authors acknowledge The Ministry of Higher Education Malaysia and The Universiti Kebangsaan Malaysia, (UKM) for funding this study under the Long-Term Research Grant Scheme-(LGRS/1/2019/UKM-UKM/2/1). We also thank the team for their commitment and tireless efforts in ensuring that manuscript was well executed.

Financial support for this study was obtained from the Ministry of Higher Education, Malaysia through the Long-Term Research Grant Scheme-(LGRS/1/2019/UKM-UKM/2/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Nawi, A.M., Ismail, R., Ibrahim, F. et al. Risk and protective factors of drug abuse among adolescents: a systematic review. BMC Public Health 21 , 2088 (2021). https://doi.org/10.1186/s12889-021-11906-2

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  • Drug abuse, substance, adolescent

BMC Public Health

ISSN: 1471-2458

research papers on drugs

Characteristics of Alcohol, Marijuana, and Other Drug Use Among Persons Aged 13–18 Years Being Assessed for Substance Use Disorder Treatment — United States, 2014–2022

Weekly / February 8, 2024 / 73(5);93–98

Sarah Connolly, PhD 1 ,2 ; Taryn Dailey Govoni, MPH 3 ; Xinyi Jiang, PhD 2 ; Andrew Terranella, MD 2 ; Gery P. Guy Jr., PhD 2 ; Jody L. Green, PhD 3 ; Christina Mikosz, MD 2 ( View author affiliations )

What is already known about this topic?

Substance use, including drugs and alcohol, often begins during adolescence.

What is added by this report?

Among adolescents being assessed for substance use disorder treatment, the most commonly reported reasons for substance use included seeking to feel mellow or calm, experimentation, and other stress-related motivations. Most reported using substances with friends; however, approximately one half of respondents who reported past–30-day prescription drug misuse reported using alone.

What are the implications for public health practice?

Reducing stress and promoting mental health among adolescents might lessen motivations for substance use. Educating adolescents on harm reduction practices, including the risks of using drugs alone and ensuring they are able to recognize and respond to overdose (e.g., administering naloxone), could prevent fatal overdoses.

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The figure is a graphic with text about how clinicians can help address teen substance use with illustrations of teens doing healthy activities.

Substance use often begins during adolescence, placing youths at risk for fatal overdose and substance use disorders (SUD) in adulthood. Understanding the motivations reported by adolescents for using alcohol, marijuana, and other drugs and the persons with whom they use these substances could guide strategies to prevent or reduce substance use and its related consequences among adolescents. A cross-sectional study was conducted among adolescents being assessed for SUD treatment in the United States during 2014–2022, to examine self-reported motivations for using substances and the persons with whom substances were used. The most commonly reported motivation for substance use was “to feel mellow, calm, or relaxed” (73%), with other stress-related motivations among the top reasons, including “to stop worrying about a problem or to forget bad memories” (44%) and “to help with depression or anxiety” (40%); one half (50%) reported using substances “to have fun or experiment.” The majority of adolescents reported using substances with friends (81%) or using alone (50%). These findings suggest that interventions related to reducing stress and addressing mental health concerns might reduce these leading motivations for substance use among adolescents. Education for adolescents about harm reduction strategies, including the danger of using drugs while alone and how to recognize and respond to an overdose, can reduce the risk for fatal overdose.

Introduction

Initiation of substance use often occurs during adolescence ( 1 ), and adolescents commonly report using substances to feel good or get high and to relieve pain or aid with sleep problems ( 2 , 3 ). Adverse consequences of adolescent substance use include overdose, risk for development of substance use disorder (SUD), negative impact on brain development, and death. Prescription opioid misuse during adolescence is associated with SUD in adulthood ( 4 ). In the event of an overdose, immediate medical attention is necessary; bystanders can respond by calling emergency medical personnel and administering naloxone, which reverses overdoses caused by opioids. To guide the development and implementation of prevention strategies and help reduce substance use and fatal overdoses among youths, the motivations for substance use and the persons with whom adolescents report using substances were studied.

Data Source

Data were obtained from the National Addictions Vigilance Intervention and Prevention Program’s Comprehensive Health Assessment for Teens (CHAT) ( 5 ). CHAT is a self-reported, online assessment for persons aged 13–18 years who are being evaluated for SUD treatment. Assessments conducted during January 1, 2014–September 28, 2022, were analyzed. Because the assessment may be completed more than once, assessments completed by the same person within 60 days of a previous assessment were removed. The data set was restricted to assessments reporting past–30-day use of alcohol, marijuana, or other drugs* and with at least one option selected for motivation or persons with whom substances were used.

Respondents were asked to report specific substances used within six categories: 1) alcohol, 2) marijuana, hashish, or tetrahydrocannabinol (THC), 3) drugs other than alcohol or marijuana, † and misuse § of 4) prescription pain medications, ¶ 5) prescription stimulants,** or 6) prescription sedatives or tranquilizers. †† Motivation for use was asked for each of the six categories; each motivation question had 15 response options §§ and respondents were asked to select all options that applied. Respondents were also asked to select the persons with whom they used substances from four categories of substances: 1) alcohol, 2) marijuana, hashish, or THC, 3) drugs other than alcohol or marijuana, and 4) prescription drugs (which included prescription pain medications, prescription stimulants, and prescription sedatives or tranquilizers). Ten options describing the persons with whom substances were used were presented, ¶¶ and respondents were asked to select all that applied.

Data Analysis

The percentages of each motivation and the persons with whom substances were used were calculated.*** Responses were not mutually exclusive: a respondent could report more than one motivation or person with whom substances were used; therefore, the percentages sum to >100. R software (version 4.2.2; R Foundation) was used to conduct all analyses. This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy. †††

Substance Use

Among 15,963 CHAT assessments conducted during the study period, 9,557 (60%) indicated past–30-day use of alcohol, marijuana, or other drugs. Of those, 9,543 reported at least one motivation or person with whom substances were used and were included in further analyses. Marijuana was most commonly reported (84% of assessments), followed by alcohol (49%) ( Figure ) ( Table ). Nonprescription drug use was indicated on 2,032 (21%) assessments; those most commonly reported were methamphetamine (8%), cough syrup (7%), and hallucinogens (6%). Prescription drug misuse was indicated on 1,812 (19%) assessments, with prescription pain medication reported most commonly (13%), followed by prescription sedatives or tranquilizers (11%), and prescription stimulants (9%).

Reasons Reported for Using Substances

Overall, the most common reasons adolescents reported for using substances were to feel mellow, calm, or relaxed (73%), to have fun or experiment (50%), to sleep better or to fall asleep (44%), to stop worrying about a problem or to forget bad memories (44%), to make something less boring (41%), and to help with depression or anxiety (40%). By category, the most frequently reported motivation for alcohol use and nonprescription drug misuse was to have fun or experiment (51% and 55%, respectively), whereas use to feel mellow, calm, or relaxed was the most reported motivation for use of marijuana (76%), and misuse of prescription pain medications (61%) and prescription sedatives or tranquilizers (55%). The most common motivation for prescription stimulant misuse was to stay awake (31%).

Persons with Whom Substances Were Used

Adolescents most commonly used substances with friends (81%), a boyfriend or girlfriend (24%), anyone who has drugs (23%), and someone else (17%); however, one half (50%) reported using alone. Although using with friends and using alone were reported most often for all substances, the prevalence varied by substance type. Approximately 80% of adolescents who reported using alcohol, marijuana, or nonprescription drugs reported using these substances with friends; however, 64% of those who reported misusing prescription drugs used them with friends. Among adolescents reporting prescription drug misuse, more than one half (51%) reported using these drugs alone, whereas using alone was reported by 44% of those who used marijuana, 39% of those who used nonprescription drugs, and 26% of those who used alcohol.

This analysis summarizing self-reported motivations for use of various substances among adolescents being assessed for SUD treatment who used alcohol, marijuana, or other drugs during the previous 30 days, and the persons with whom adolescents used these substances, found that many adolescents use substances to have fun or experiment or to seek relief mentally, emotionally, or physically. These findings are consistent with those reported in a 2020 study that examined motivations for the nonmedical use of prescription drugs in a sample of young adults, which identified recreational and self-treatment motivations among young adults over time and across drug classes ( 2 ). Anxiety and experiencing traumatic life events have been associated with substance use in adolescents ( 6 ). Specific reporting of motivations, including “to stop worrying about a problem or to forget bad memories” and “to help with depression or anxiety,” underscores the potential direct impact that improving mental health could have on substance use.

One half of adolescents reported using substances while alone. Of particular concern, more than one half of respondents who reported past–30-day prescription drug misuse reported using the drugs alone. Prescription drug misuse while alone presents a significant risk for fatal overdose, especially given the proliferation of counterfeit pills resembling prescription drugs and containing illegal drugs (e.g., illegally manufactured fentanyl) ( 7 ). Education about harm reduction behaviors, such as using in the presence of others and expanding access to naloxone to all persons who use drugs, could reduce this risk.

Adolescents most commonly reported using substances with friends, which presents the opportunity for bystander intervention in the event of an overdose. Nearly 70% of fatal adolescent overdoses occurred with a potential bystander present, yet in most cases no bystander response was documented ( 8 ). Overdose deaths can be prevented through education tailored to adolescents to improve recognition of signs of overdose and teach bystanders how to respond, including the administration of naloxone ( 9 ) and increasing awareness of local Good Samaritan laws, which protect persons against liability when they provide emergency care to others ( 10 ). In addition, ensuring access to effective, evidence-based treatment for SUD and mental health conditions might decrease overdose risk.

Limitations

The findings in this report are subject to at least three limitations. First, the population represents a convenience sample of adolescents being assessed for SUD treatment and is not generalizable to all adolescents in the United States. Second, the assessment is self-reported and subject to potential reporting and recall biases as well as social desirability bias. Finally, several questions on motivations and persons with whom respondents use substances refer to categories of substances; thus, it was not possible to ascertain to which specific drug a person might be referring in their response if use of more than one substance within a drug category was reported.

Implications for Public Health Practice

Harm reduction education specifically tailored to adolescents has the potential to discourage using substances while alone and teach how to recognize and respond to an overdose in others, which could thereby prevent overdoses that occur when adolescents use drugs with friends from becoming fatal. Public health action ensuring that youths have access to treatment and support for mental health concerns and stress could reduce some of the reported motivations for substance use. These interventions could be implemented on a broad or local scale to improve adolescent well-being and reduce harms related to substance use.

Acknowledgment

Akadia Kacha-Ochana, CDC.

Corresponding author: Sarah Connolly, [email protected] .

1 Epidemic Intelligence Service, CDC; 2 Division of Overdose Prevention, National Center for Injury Prevention and Control, CDC; 3 Inflexxion, Irvine, California.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

* Two assessments that reported using only methadone were excluded.

† The category “drugs, other than alcohol or marijuana” included the following nonprescription drugs: inhalants, cocaine, methamphetamines, hallucinogens, phenylcyclidine or ketamine, heroin, ecstasy or 3,4-methylenedioxy-methamphetamine, gamma hydroxybutyrate or rohypnol, cough syrup, illegally made fentanyl (added to assessment in 2017), and xylazine (added to assessment in 2022), methadone, “other drug,” and “any drug.”

§ Misuse is described as prescription medication use “not as prescribed,” “without a prescription from a doctor,” “to get high,” or “to change how you feel.”

¶ A description of prescription pain medications provided in the assessment states, “Examples of painkillers include Oxycontin, Vicodin, and Percocet. Pain medications help people feel less pain after surgery, and help manage intense chronic pain.”

** A description of prescription stimulants provided in the assessment states, “Examples of stimulants include Ritalin, Adderall, and Dexedrine. Stimulants help people concentrate or focus better.”

†† A description of prescription sedatives or tranquilizers provided in the assessment states, “Examples of sedatives include Valium, Xanax, and Klonopin. Sedatives or tranquilizers help people sleep or feel less anxious.”

§§ 1) To feel mellow, calm, or relaxed, 2) to sleep better or fall asleep, 3) to stay awake, 4) to feel less shy or more social, 5) to stop worrying about a problem or forget bad memories, 6) to have fun or experiment, 7) to be sexier or make sex more fun, 8) to lose weight, 9) to make something less boring, 10) to improve or get rid of the effects of other drugs, 11) to concentrate better, 12) to deal with chronic pain, 13) to help with depression or anxiety, 14) to fit in, or 15) other reasons.

¶¶ 1) Friend or friends, 2) brother or sister, 3) parent or parents, 4) adult relative or other adult, 5) relative near adolescent’s own age, 6) boyfriend or girlfriend, 7) coworker, 8) someone else, 9) anyone who has drugs, or 10) used alone.

*** The number of assessments for which an option was selected was divided by the total number of assessments in that substance type category.

††† 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.

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FIGURE . Percentage of persons aged 13–18 years being assessed for substance use disorder treatment reporting specific substances used during the previous 30 days* — National Addictions Vigilance Intervention and Prevention Program Comprehensive Health Assessment for Teens, United States, 2014–2022

Abbreviations: GHB = gamma hydroxybutyrate; MDMA = 3,4-methylenedioxy-methamphetamine; PCP = phenylcyclidine.

* Among those reporting previous 30-day use of any alcohol, marijuana, or other drugs, and at least one motivation or person with whom substances were used.

Abbreviation: THC = tetrahydrocannabinol. * Includes motivations or persons with whom adolescents used substances reported for any of the following: alcohol, marijuana, nonprescription drugs, prescription drug misuse, methadone, “other drug,” and “any drug.” † The alcohol motivation question is phrased, “People use alcohol for many reasons. Why have you used alcohol? Select all that apply.” The question asking with whom alcohol is used is phrased, “When you drink, who do you drink with? Select all that apply.” § The marijuana motivation question is phrased, “People use marijuana, hashish, or THC for many reasons. Why have you used marijuana, hashish, or THC? Select all that apply.” The question asking with whom marijuana is used is phrased, “When you use marijuana, hashish, or THC, who do you use it with? Select all that apply.” ¶ Inhalants, cocaine, methamphetamines, hallucinogens, phenylcyclidine or ketamine, heroin, ecstasy or 3,4-methylenedioxy-methamphetamine, gamma hydroxybutyrate or rohypnol, cough syrup, illegally made fentanyl (added to assessment in 2017), and xylazine (added to assessment in 2022). The motivation question is phrased, “People use drugs for many reasons. Why have you used drugs, other than alcohol or marijuana? Select all that apply.” The question asking with whom these substances are used is phrased, “When you use drugs, other than alcohol or marijuana, who do you use them with? Select all that apply.” This assessment section also included methadone, “other drug,” and “any drug,” which are captured by the same motivation question and the question asking with whom persons use. If a person reported methadone, “other drug,” or “any drug” in addition to one or more nonprescription drugs, the motivations and with whom they use (for methadone, “other drug,” or “any drug”) cannot be differentiated and are counted in this table. ** Includes persons who responded affirmatively to assessment questions asking about prescription pain medication use “not as prescribed,” “without a prescription from a doctor,” “to get high,” or “to change how you feel.” The motivation question is phrased, “People use drugs for many reasons. Why have you used prescription pain medications on your own? Select all that apply.” †† Includes persons who responded affirmatively to assessment questions asking about prescription stimulant use “not as prescribed,” “without a prescription from a doctor,” “to get high,” or “to change how you feel.” The motivation question is phrased, “People use drugs for many reasons. Why have you used prescription stimulants on your own? Select all that apply.” §§ Includes persons who responded affirmatively to assessment questions asking about prescription sedative and tranquilizer use “not as prescribed,” “without a prescription from a doctor,” “to get high,” or “to change how you feel.” The motivation question is phrased, “People use drugs for many reasons. Why have you used prescription sedatives or tranquilizers on your own? Select all that apply.” ¶¶ The question asking with whom substances are used is asked once for all prescription drugs and is phrased, “When you use prescription drugs, who do you use them with? Select all that apply.” The denominator for the number of assessments indicating past–30-day misuse of at least one prescription drug is 1,812. *** Motivation and persons with whom substances are used questions are in a “select all that apply” format; therefore, percentages sum to >100. Median and IQR summarize the number of motivations and the number of persons with whom they use substances that respondents selected for each question.

Suggested citation for this article: Connolly S, Govoni TD, Jiang X, et al. Characteristics of Alcohol, Marijuana, and Other Drug Use Among Persons Aged 13–18 Years Being Assessed for Substance Use Disorder Treatment — United States, 2014–2022. MMWR Morb Mortal Wkly Rep 2024;73:93–98. DOI: http://dx.doi.org/10.15585/mmwr.mm7305a1 .

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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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Drug repurposing: a systematic review on root causes, barriers and facilitators

  • Nithya Krishnamurthy 1 ,
  • Alyssa A. Grimshaw 2 ,
  • Sydney A. Axson 1 ,
  • Sung Hee Choe 3 &
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BMC Health Services Research volume  22 , Article number:  970 ( 2022 ) Cite this article

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Repurposing is a drug development strategy receiving heightened attention after the Food and Drug Administration granted emergency use authorization of several repurposed drugs to treat Covid-19. There remain knowledge gaps on the root causes, facilitators and barriers for repurposing.

This systematic review used controlled vocabulary and free text terms to search ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases for the characteristics, reasons and example of companies deprioritizing development of promising drugs and barriers, facilitators and examples of successful re-purposing.

We identified 11,814 articles, screened 5,976 for relevance, found 437 eligible for full text review, 115 of which were included in full analysis. Most articles (66%, 76/115) discussed why promising drugs are abandoned, with lack of efficacy or superiority to other therapies ( n  = 59), strategic business reasons ( n  = 35), safety problems ( n  = 28), research design decisions ( n  = 12), the complex nature of a studied disease or drug ( n  = 7) and regulatory bodies requiring more information ( n  = 2) among top reasons. Key barriers to repurposing include inadequate resources ( n  = 42), trial data access and transparency around abandoned compounds ( n  = 20) and expertise ( n  = 11). Additional barriers include uncertainty about the value of repurposing ( n  = 13), liability risks ( n  = 5) and intellectual property (IP) challenges ( n  = 26). Facilitators include the ability to form multi-partner collaborations ( n  = 38), access to compound databases and database screening tools ( n  = 32), regulatory modifications ( n  = 5) and tax incentives ( n  = 2).

Promising drugs are commonly shelved due to insufficient efficacy or superiority to alternate therapies, poor market prospects, and industry consolidation. Inadequate resources and data access and challenges negotiating IP are key barriers to repurposing reaching its full potential as a core approach in drug development. Multi-partner collaborations and the availability and use of compound databases and tax incentives are key facilitators for repurposing. More research is needed on the current value of repurposing in drug development and how to better facilitate resources to support it, where valuable, especially financial, staffing for out-licensing shelved products, and legal expertise to negotiate IP agreements in multi-partner collaborations.

Trial registration

The protocol was registered on Open Science Framework ( https://osf.io/f634k/ ) as it was not eligible for registration on PROSPERO as the review did not focus on a health-related outcome.

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Introduction

Drug repurposing, defined as researching new indications for already approved drugs or advancing previously studied but unapproved drugs, is a core approach in drug development. Some reports state that about 30–40% of new drugs and biologics approved by the US Food and Drug Administration (FDA) between 2007 and 2009 can be considered repurposed or repositioned products [ 1 ]. Similarly, a study found that 35% of transformative drugs approved by the FDA between 1984 and 2009, defined as drugs that were both innovative and had groundbreaking effects on patient care, were repurposed products [ 2 ].

Many experts claim re-purposing drugs can be faster, cheaper, less risky and carry higher success rates than traditional drug development approaches, primarily because researchers can bypass earlier stages of development that establish drug safety, as they have already been completed [ 3 ]. However, exactly how much time, risk and money are saved can be unclear, with some conflicting evidence.

Some reviews state about 30% of repurposing efforts are successful and result in a product approved for marketing, in comparison to about 10% for new drug applications more generally [ 4 ]. However, others conclude contradictorily that repurposed agents do not necessarily succeed more often than new agents, with efficacy typically being the limiting factor rather than safety [ 5 ]. Reports indicate de novo drug discovery and development can be a 10-to-17-year process. In contrast, repurposed drugs are generally approved sooner, within 3–12 years, and at about half the cost [ 6 , 7 ].

Repurposing is receiving renewed attention during the Covid-19 pandemic, after the FDA granted emergency use authorization (EUA) for several repurposed drugs to treat Covid-19 [ 7 ]. Within six months of the start of the pandemic, for instance, it granted an EUA for remdesivir to treat Covid-19, sold under the name Veklury. Originally developed as an antiviral for the treatment of RNA-based viruses, and evaluated for use against the Ebola virus, remdesivir had not yet received FDA approval for an indication prior to its authorization as a Covid-19 treatment.

Despite the enthusiasm around drug repurposing, there has been no systematic literature review on why pharmaceutical companies de-prioritize or abandon promising drug candidates in the first place, coupled with an identification of the facilitators and barriers for repurposing promising compounds. Accordingly, this study aims to systematically review the literature to identify the root causes associated with companies shelving development of seemingly promising drug candidates unapproved by the FDA for any indication, as well as obstacles and facilitators for moving them off the shelf and back into development, a process often referred to as drug repurposing.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement for reporting was used for this study (Supplementary Table 1 ). The protocol was registered on Open Science Framework ( https://osf.io/f634k/ ) as it was not eligible for registration on PROSPERO, as this review does not have a health related outcome, as required by PROSPERO for registration.

Search strategy

A systematic search of the literature was conducted by a medical librarian (AAG) in ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases to find relevant articles published from inception of each database to April 16, 2020. Databases were searched using a combination of controlled vocabulary and free text terms related to the de-prioritization, shelving, abandonment, and repurposing of promising experimental drugs unapproved by the FDA for any indication. The search was peer-reviewed by a second medical librarian using PRESS (Peer Review of Electronic Search Strategies). Details of the full search strategy are listed in Supplementary Table 2 .

Study selection

Citations from all databases were imported in an Endnote × 9 library (Clarivate Analytics, Philadelphia, PA), where duplicates were removed. The de-duplicated results were imported into Covidence v2627 (Covidence, Melbourne, Victoria, Australia) for screening and data extraction. Two independent trained screeners performed a title and abstract review; disagreements were resolved through discussion (SA, NK, JM). The full text of the resulting papers was then reviewed for inclusion by two independent screeners with disagreements also resolved through discussion. The main outcomes of interest were the characteristics of and reasons for the phenomenon of companies deprioritizing or abandoning development of promising drugs, facilitators and successful examples of advancing development of promising abandoned or deprioritized drugs (often referred to as drug repositioning or re-purposing), and barriers to advancing development of promising abandoned or de-prioritized drugs. Study inclusion was not limited by publication date or type. Commentaries, editorials, expert opinions, and perspective pieces were included. Book chapters, conference abstracts, animal studies, dissertations, and papers not available in English were excluded.

Data extraction and analysis

Two reviewers (SA, NK) independently extracted data using Qualtrics software (Qualtrics, Provo, UT). JM performed data extraction on 20% of the final sample, selected at random to verify data reliability. Descriptive analysis was performed by NK, SA and JM. Data extracted included article type, article title, journal title, first author, publication date, extraction and analysis of terminology used to describe abandoned investigational drugs and moving them back into research and development, reason(s) and methods for drug de-prioritization or abandonment, conditions treated, examples of deprioritized or repurposed drugs, as well as barriers and facilitators to drug repurposing. Risk of bias was not performed due to the varying study designs included in this study. Instead, Oxford Centre for Evidence-Based Medicine: Levels of Evidence was used to grade the level of evidence included in this study.

Sample characteristics

We identified 11,814 articles through our literature review, 5,838 of which were duplicates. After de-duplicating the sample, we screened 5,976 articles for relevance, finding 437 eligible for full text review, 115 of which were included in our full analysis (See Fig.  1 and Supplement Table 3 ). Of these 115 publications, 18 were expert opinions/editorials, 25 were reviews, 32 were articles, 31 news articles, and 9 were other formats such as commentaries, technical reports, viewpoints and correspondence (Supplement Table 4 ).

figure 1

Prisma 2009 Flow Diagram

Sixty-six percent of these articles (76) presented reasons why promising drugs are abandoned (i.e., because a drug is projected not to be a blockbuster or to be less commercially viable than another portfolio drug) and 43% (49) discussed barriers and 63% (72) facilitators for repurposing. The number of articles published on drug repurposing and abandonment has grown over time, from 6 published before 2004, 12 in the period 2005 to 2009, 41 in 2010 to 2014, 51 in 2015–2019, and 5 in 2020, through April 16, 2020 (See Fig.  2 ).

figure 2

No. papers published per year on the abandonment and repurposing of promising drugs through 2020 * . * Five papers were also published from Jan 1, 2020 to April 16, 2020

Concept definition

Drug candidates pursued by developers not reaching a commercial market are commonly referred to as failed ( n  = 26), abandoned ( n  = 23), discontinued ( n  = 7), shelved ( n  = 8) or deprioritized ( n  = 5), hereafter referred to simply as abandoned. Re-starting investigation of an abandoned drug is commonly referred to as drug repurposing ( n  = 47), repositioning ( n  = 41), reprofiling ( n  = 12), rescue ( n  = 12) and re-tasking ( n  = 5) in the literature. Several articles ( n  = 7) describe how these terms are often used interchangeably in the literature and policy efforts, without consistent definitions, a finding confirmed by our analysis. However, some articles ( n  = 14) distinguish drug repurposing from repositioning, generally referring to repurposing as researching new indications for approved drugs already on the market (i.e., investigating applications for entirely new therapeutic areas), in contrast to repositioning which develops previously studied but unapproved active pharmacological ingredients. Of the articles using repurposing as the primary term and providing an operational definition, 13 stated repurposing applied to both approved and unapproved compounds.

Reasons drugs are abandoned

Most articles (76/115, 66%) discussed the reasons why a drug candidate’s development may be abandoned, with lack of efficacy for the studied indication ( n  = 59), strategic business reasons by the sponsor ( n  = 35), drug safety problems ( n  = 28), and research design decisions ( n  = 12) being the most commonly discussed reasons. Other cited reasons included the complex nature of the studied disease or drug ( n  = 7) and regulatory bodies requiring more information ( n  = 2) (See Fig.  3 ). Below we go into more detail about some of these reasons.

figure 3

Reasons why a drug’s research and development may be abandoned or shelved

Efficacy and superiority challenges

The most frequently cited reason for why drug candidates are abandoned was inadequate efficacy for the studied indication or target population ( n  = 59) or a lack of superiority to alternative therapies ( n  = 11). Thymitaq™, an experimental cancer drug, for example, was discussed as shelved by Agouron Pharmaceuticals after studies showed it was "clearly active," but "not sufficiently superior to alternative therapies to justify the required investment [ 8 ]." Similarly, imagabalin was discussed as discontinued by Pfizer because it appeared unlikely to “provide meaningful benefit to patients beyond the (then) current standard of care [ 9 ].” Capravirine was also discontinued after two Phase IIb studies sponsored by Pfizer failed to show a statistically significant difference between standard triple-drug HIV therapies and the same therapy combined with Capravirine [ 10 ].

Strategic business reasons

After efficacy challenges, strategic business reasons were the second most commonly discussed reason for why a promising drug candidate might be abandoned ( n  = 35). Specifically, poor market prospects ( n  = 14), incompatibility with company disease priorities ( n  = 7), industry consolidation ( n  = 5), and type II decision-making errors that can cause a manger(s) to underestimate a drug’s value ( n  = 6) were discussed as leading reasons for a company abandoning development of a promising drug candidate.

Poor market prospects

Poor market prospects were discussed as a top factor in decisions around whether to shelve an asset ( n  = 14). For example, vaccines were discussed as often abandoned due to their smaller markets and lower projected revenues, as generally the federal government is their largest purchaser, and due to their lower frequency use and higher manufacturing costs than drugs [ 11 ]. Drugs may be used every day, while a vaccine may only be used a few times throughout a person’s lifespan [ 12 ]. One article discussed how the highest revenue generating vaccine, Prevnar 13®, a pneumococcal vaccine for children, grossed $1 billion in annual U.S. sales, in comparison to individual drugs which were grossing around $7 billion in annual US sales, such as those for high cholesterol, hair loss, heart disease, obesity, and neurology [ 12 ]. To further put this in perspective, the revenues for Lipitor®, a cholesterol drug, were described as “greater than revenues for the entire worldwide vaccine industry,” according to an article published in 2005 [ 12 ]. Articles did not generally elaborate on the amount of profits or returns on investments (ROI) needed to sustain investment in an asset and avoid shelving risks [ 11 , 13 , 14 ]. Instead, companies were described as needing to make prioritization decisions about which compounds to advance at every stage of development, given limited resources and in light of current and future projects [ 15 ]. If a late-stage compound does not meet set endpoints it is often shelved for the next lead candidate. Re-evaluating a drug’s activity for use in multiple indications is not generally considered economical [ 16 ].

Disease priorities

Companies often focus on developing products for specific categories of diseases and conditions and can abandon drugs targeting conditions outside their research priorities. For example, AstraZeneca sold the rights to its shelved schizophrenia drug candidate to Millendo therapeutics. While the drug was ineffective in schizophrenia, hormonal side effects seen in testing suggested a potential use in polycystic ovary syndrome (POS), which was not a priority therapeutic area for AstraZeneca at the time [ 17 ]. Pagoclone (PGC), is another drug that was discussed as abandoned after multiple unsuccessful repurposing efforts by different companies. Studied in 1994 for anxiety by Rhone-Poulenc Rorer, now Sanofi, the drug was later licensed and abandoned by Pfizer due to a lack of robust efficacy data. The drug was then pursued by Endo Pharmaceuticals for stuttering and discontinued for reportedly not fitting into the company’s defined R&D priorities and for having low projected commercial potential [ 9 ].

Consolidation

Industry consolidation, through for example mergers and acquisitions, can also lead to culling of promising development programs, merging of portfolios, and rivaling factions of scientists [ 13 , 15 , 18 ]. Pfizer, for instance, cut nearly 20% of its development pipeline after acquiring Wyeth in 2009, to help ensure its key disease priority areas were dominant in the new portfolio and to consolidate resources post-merger. This included abandoning imagabalin, under development by Pfizer, reportedly because Pfizer and Wyeth both already had other successful and popular drugs with anxiolytic activity, including Pfizer’s pregabalin and Wyeth’s venlafaxine [ 9 ].

After the merger, Pfizer also withdrew its supplemental marketing application for Lyrica, a drug already approved to treat seizures, fibromyalgia, and nerve pain, among other projects, to treat anxiety because these did not fit within their disease and condition priority groups of oncology, pain, inflammation, Alzheimer's, psychoses, and diabetes. Most abandoned drugs were in phase 1 of development, though three drugs in Phase 2 were also culled. Similarly, Merck cut multiple programs across its pipeline after acquiring Schering-Plough [ 13 ].

Managerial judgment errors

The literature also noted that managers allocating resources inevitably make errors in their assessment of which projects to continue and which to terminate, especially “type 2 errors,” defined as false negative decisions that underestimate a drug’s value; had the organization found the right target and business model, it may have had therapeutic value. These types of judgment errors, where managers underestimate therapeutics’ potential, were discussed as resulting in fewer drugs for patients than would arise in an ideal world [ 13 ]. Type 2 errors, that is false negatives, were described as harder to mitigate in comparison to type 1 errors, false positives, which may be caught and or addressed through a rigorous regulatory review. Examples of such errors include the “class effect” (that is negative results for one drug affecting value judgments for others in the same class) and a “felt inferiority” for a compound or “assumption that the compound could be too late to enter the market [ 19 ]”. Dalcetrapib, for instance, was abandoned by Roche after an independent group stated the drug lacked clinically meaningful efficacy in a late-stage trial. The drug targeted cardiovascular risks, and its failure was discussed as potentially having repercussions for other companies studying similar drugs, like Eli Lilly [ 20 ].

Research design decisions.

Selection of the wrong indication, endpoints, populations to enroll, or patient stratification methodologies in a trial, as well as suboptimal dosing or insensitive biomarkers were discussed as potential drivers of drug abandonment, which we have classified as “research design decisions” ( n  = 12) [ 21 , 22 ]. One paper, for instance, suggested Nelivaptan, a treatment for major depressive disorder and generalized anxiety disorder, may have appeared ineffective because it was studied in the wrong population and for the wrong indication. Study authors noted Nelivaptan, an AVPR1b antagonist, would be best utilized in acute stress conditions, as V1b receptors are particularly activated, with limited efficacy for the chronic stress states in which it was tested [ 21 ].

In terms of dosing decisions, after initially declaring Aducanumab ineffective for treating Alzheimer’s disease after phase III trials, Biogen found statistically significant improvements in cognitive decline in a subset of the sample who had received the highest doses and thus revived the nearly abandoned therapy with new dosage selections [ 23 , 24 , 25 ].There have been over 200 failed Alzheimer’s drugs and candidates, reflecting poorly understood etiology and deficiencies in development and methodology, including issues with dosing, biases, and protocol violations [ 26 ]. Papers by Becker described how researchers found several trial related factors in Phenserine’s development, also an Alzheimer’s-related drug, that suggested they did not provide fair and unbiased conditions for the drug to demonstrate efficacy, including variance on assessment scores, improvement in the placebo groups, and unaddressed errors [ 26 , 27 ].

In general, placebo-based trials were discussed as possibly having higher risks for drug abandonment. Comparing a new compound with a placebo was discussed as having a higher risk of a false negative trial, particularly in diseases like irritable bowel syndrome and mild depression, where the placebo responder rate can be as high as 40–50%. Inability to pick a correct dose can also lead to a false-negative effect with placebos, as often the highest acceptable dose, not the most optimal dose, is chosen in order to emphasize the difference versus a placebo [ 19 ].

Complex diseases

An inadequate understanding of therapeutic pathways in complex diseases ( n  = 8)- such as Alzheimer’s disease, cardiovascular disease, psychiatric conditions, and stroke- was discussed as a contributor to trial design challenges [ 22 ]. In psychiatric disease, for example, inferences from animal research remain limited in scope [ 28 ]. In addition, indication selection is relevant as repurposing aims to find new uses for shelved drugs. Importantly, a lack of efficacy for the original indication does not mean a lack of efficacy in other indications. An illustrative example is Nelivaptan, which was found to be ineffective as a treatment for major depressive disorder (MDD) and generalized anxiety disorder (GAD). However, nelivaptan is an AVPR1b antagonist and V1b receptors are particularly activated during acute stress, not chronic stress in which it was tested. Thus, Nelivaptan is an attractive option for anxiety and disorders of sociality; despite this promising evidence, a company contact suggested that Nelivaptan is not available [ 21 ]. Lack of efficacy is multifactorial, and interrogating causes of drug abandonment is crucial to demonstrate the potential of repurposing.

Companies were described in the literature as recently drifting away from CNS drug development, as it is now perceived to carry a high risk of failure, despite a high potential reward with a market valued at over $40 billion [ 29 ]. High attrition rates in this area reflect issues in translation due to a lack of knowledge of disease etiology and pathology and thus a lack of predictivity of animal models. For example, understanding of the neurophysiology associated with schizophrenia is limited and thus there have been high-profile drug development failures such as the Roche GLYT1 glycine uptake inhibitors. Additionally, despite costly clinical trials of more than 15 neuroprotectant drugs for ischemic stroke, the results were negative [ 29 ].

Regulatory challenges

Regulatory hurdles ( n  = 2), such as regulators requesting additional studies and a sponsor unwilling to comply, were also discussed as potential drivers for the abandonment of promising drugs [ 30 ].

Barriers to repurposing

Barriers to repurposing commonly cited in the literature include a lack of finances and resources ( n  = 42), including a lack of expertise ( n  = 11), intellectual property (IP) challenges ( n  = 26), poor data access ( n  = 20), bias ( n  = 13) and liability risks ( n  = 5) (See Fig.  4 ). These barriers were discussed as resulting in an unknown number of abandoned compounds stored in company vaults, with some suggesting they may number in the thousands [ 21 , 31 ].

figure 4

Barriers to repurposing, discussed in the literature

Financial and resource barriers

Organizations require financial resources and personnel with relevant expertise on the compound and studied indications to advance a shelved drug candidate. Because pharmaceutical research and development is often organized around specific therapeutic areas within an organization, it can be hard to internally realize the repurposing potential of compounds outside this focus [ 14 , 16 ]. As such, multi-partner collaborations in repurposing are often needed [ 32 ]. Academic researchers may have the expertise to study compounds, but not have access to a pool of deprioritized pharmaceutical compounds [ 33 ]. Likewise, small biotechnology companies and academic institutions may need to find commercial partners to address a lack of resources [ 34 ]. Additionally, companies often lack sufficient staff dedicated to out-licensing discontinued compounds, and thus most are abandoned [ 35 ].

Despite the promise of repurposing being a cheaper and faster alternative to de novo development, bringing a repurposed compound to market was described as still costing hundreds of millions to billions of dollars, despite early cost savings from not having to conduct preclinical research [ 21 , 32 , 36 ]. Although many of the compounds have existing data and are well understood, repurposing only reduces, not eliminates drug development risks. Ultimately, repurposing can still require substantive testing, and repurposed compounds must still undergo the same approval process and meet quality, efficacy and safety standards.

Repurposing can result in millions of dollars’ worth of savings, given its potential to save 6–7 years of time spent on preclinical and early-stage research [ 36 , 37 ]. However, in the later stages of clinical research, repurposed compounds can still have the same failure rate as any other compound, if not higher, after failing in a primary indication [ 14 , 34 ]. Repurposed drugs can still require phase 2 and 3 clinical trials, which eliminate 68% and 40% of compounds, respectively, which make it that far, for their new indications [ 38 ].

Even when out-licensing a compound, there can be burdensome “in-kind” costs from remanufacturing the active product and placebo, completing study reports and regulatory documentation, pharmacovigilance, monitoring and reporting on patient safety, and coordination [ 39 , 40 ]. It is challenging to persuade management to allocate resources to compounds that were initially unsuccessful, especially if the new indication is not a strategic focus [ 14 ].

Intellectual property barriers

The second most common barrier to drug repurposing discussed in the literature was IP related. Pharmaceutical companies were described as patenting many compounds, even if they are later abandoned, and thus prevent others from developing these compounds without a license [ 13 ]. There can also be limited patent time left for compounds that failed in later stages, limiting return on investments (ROI) in drug repurposing. The threshold companies use to determine if an ROI is worth their investment varies by company size. Larger companies may require a greater ROI than smaller ones. What may not be a sufficient ROI for a large company may be enough for a small company and result in a new medication for patients [ 35 ].

Further discussed is a lack of traditional IP protections for repurposed compounds, though products can still be economically successful without this type of protection. Composition of matter (COM) claims are among the most powerful IP protections for newly synthesized compounds. But COM claims can be difficult to gain for repurposed compounds, as the patentee must somehow differentiate their patent claims over what is in the public domain and present data that the drug is a credible candidate for the new indication [ 41 , 42 ].

Entanglement with core IP is another issue. The literature states it can be common for developers to patent a number of compounds in development, which protects not only the final candidate, but the semi-finalists as well [ 13 ]. Thus, shelved compounds from the same family cannot be developed by another party without a license of access to the relevant patents that protect the compounds.

As IP protects pharmaceutical investment and disallows competitors from building upon original research and repurposing compounds, it poses a difficult barrier to address [ 11 , 43 ]. Material transfer agreements (MTAs) pose a particularly challenging and time-consuming barrier. Negotiations on MTAs are most heated around issues of limiting compound use to non-commercial research, limiting company liability, delaying academic publications to protect confidential information, and IP provisions. IP terms were described as difficult and time-consuming to negotiate as companies often want to protect their freedom to operate using their own compounds, while universities want to maintain ownership of inventions, receive consideration, and make compounds available to the public [ 44 ].

Data access barriers

Barriers to accessing shelved compounds and their trial data were the second most commonly discussed challenge to drug repurposing. Compounds were described as “disappearing” once their development is abandoned, with trial data and results left unpublished [ 19 , 38 ]. Several factors were described as influencing trial publication practices around shelved drugs, including the difficulty of publishing negative trial results, that many trials end up terminated abruptly after a company merger or acquisition [ 9 ], and the lack of commercial benefit in dedicating time and resources to publishing results on a discontinued project, and no legal requirement to do so [ 30 ]. Moreover, data are sometimes sequestered if considered a “trade secret” or of potential commercial value.

Gaining knowledge about and access to shelved industry compounds was often described as difficult and, in many cases, requiring an internal company champion for success [ 40 ]. Companies were cited as expressing reluctance to share shelved compounds with other companies in case they turn out to be blockbusters. Nonprofits and government-funded bodies, on the other hand, have a lower risk of commercial embarrassment [ 13 ].

Furthermore, a lack of repositories to transparently register abandoned compounds and a reluctance from companies to release compounds to a shared resource were cited as reasons shelved drugs can “disappear [ 44 ]”. Within companies, paper records need to be digitized and often the company’s experts on the compound move on and teams responsible for the regulatory and safety data are disbanded [ 31 ]. Additionally, mining large datasets poses a logistical hurdle and integration of different types of data in a user-friendly manner is challenging [ 42 , 45 ].

Value questions and biases about repurposing

Developers make assumptions on the value of reinvestigating shelved compounds. Some critics have expressed concern that focusing on repurposing detracts from innovation and the pursuit of novel drugs and therefore poses a disservice to the possibility of finding new cures [ 46 ]. Some experts also disagree with the notion that shelved drugs represent a significant opportunity for development and report believing there has been “an awful lot of hype” regarding repurposing programs [ 44 , 47 ]. Addressing value biases was discussed as requiring a great deal of information and is a process that is described as time-consuming and expensive for all involved parties.

The “not sold here” and “not invented here” syndromes were discussed. The “not sold here” syndrome refers to the unwillingness of companies to out-license compounds that may be promising for other indications [ 13 ]. Business units argue that if they do not sell a product, no one else should, leading to a waste of human talent in research and development as compound attrition rates are quite high. The “not invented here” syndrome refers to the bias that external research and technology are inferior to a company’s own R&D capabilities and standards and therefore not worth pursuing. External parties may also assume a seller is keeping the best compounds for themselves and offering lesser value compounds for out-licensing [ 13 ].

Pharmaceutical companies were generally described as employing few, if any, staff to aid in out-licensing shelved compounds, thus limiting outside companies’ evaluation of shelved drugs.

Liability risks

Drug companies may also face liability risks ( n  = 5) when out-licensing abandoned compounds, which include risks of adverse patient events, a need to continuously supply the compound to the licensee, and litigation [ 13 ]. Testing compounds for new indications and populations may reveal new adverse events or unforeseen toxicities [ 48 ]. For externally sponsored studies, the investigator must report back safety data to the parent company.

The high cost of liability insurance was discussed as a reason pharmaceutical companies discontinue development of lower-revenue products like vaccines. To meet the demand for increased liability insurance, the cost of the pertussis vaccine rose from 17 cents to 11 dollars per dose, and the number of companies making the vaccine reportedly decreased [ 12 ].

Facilitators of repurposing

The most common facilitators of drug repurposing discussed were collaborative initiatives ( n  = 38), compound libraries and databases ( n  = 24), computational-based strategies and tools ( n  = 32), regulatory modifications ( n  = 5), and tax incentives ( n  = 2) (See Fig.  5 ).

figure 5

Facilitators of drug repurposing, discussed in the literature

Collaborative initiatives

Multi-partner collaborations between pharmaceutical companies and academic institutions, non-profit organizations and biotechnology companies was the most commonly discussed facilitator for drug repurposing cited in the literature ( n  = 38). Pharmaceutical companies have the resources as well as a pool of shelved compounds and data while biotechnology companies and academia have knowledge and expertise on emerging areas to study compounds and contribute to innovation [ 49 ]. A staff dedicated to out-licensing discontinued compounds was described as a facilitator for collaborative partnerships [ 13 ].

Several examples of collaborative initiatives focused on drug repurposing were discussed in the literature, including the NIH National Center for Advancing Translational Sciences (NCATS) program: Discovering New Therapeutic Uses for Existing Molecules ( n  = 23), the Medical Research Council (MRC) and AstraZeneca (AZ) Mechanisms of Human Disease Initiative, ( n  = 16), the AZ Open Innovation program ( n  = 6), European College of Neuropsychopharmacology (ECNP) Medicines Chest Program ( n  = 5), The Clinical and Translational Science Award (CTSA) Pharmaceutical Assets Portal ( n  = 2), Pfizer’s SpringWorks Program ( n  = 2), the AstraZeneca/National Research Program for Biopharmaceuticals(NRPB) partnership in Taiwan ( n  = 2), the Clinical Development Partnerships Initiative ( n  = 1), the Roche/Broad Institute Collaboration ( n  = 1), and the Drugs for Neglected Diseases Initiative (DNDI) ( n  = 1).

The NIH NCATS’ Discovering New Therapeutic Uses for Existing Molecules program was initiated in 2012 to help scientists explore new treatments for patients by matching NIH-funded researchers with a selection of 58 compounds previously discontinued from development due to lack of efficacy, selectivity, or strategy [ 36 , 39 , 50 ]. Co-launched with AstraZeneca (AZ), Eli Lilly, and Pfizer, the initiative required that compounds had prior evidence and manageable tolerability in humans and that companies publicly posted online template confidentiality disclosure agreements (CDAs) and collaborative research agreements (CRAs) to enable rapid implementation [ 39 , 51 ]. In the program, the NIH acts as a trusted intermediary, facilitates deals between researchers and companies that are often characterized by prolonged negotiation, and moves promising compounds into the private sector [ 36 , 42 , 52 , 53 ]. Organizations maintain IP on the original compound, but the repurposed use belongs to the researchers. However, companies can license the IP from researchers, and researchers can request licenses for additional studies [ 52 ]. In short, the NIH NCATS initiative facilitates the availability of compounds, data, human, and financial resources, and addresses issues of intellectual property and data sharing in drug repurposing [ 31 ].

Another partnership between the MRC and AZ, the Mechanisms of Human Disease Initiative, launched in 2011 and provided researchers with what was described as “unprecedented access” to clinical and pre-clinical AstraZeneca compounds. It accepted proposals for novel research projects with a focus on understanding human disease [ 38 ]. The MRC posted data on 22 compounds on its website, and over 100 proposals were submitted from across the UK. Full proposals were developed by UK researchers and AZ scientists, and selected proposals were funded by the MRC [ 39 ]. AstraZeneca also launched another program with the National Research Program for Biopharmaceuticals (NRPB) in Taiwan to facilitate translational research locally, which included live compounds [ 42 ]. As a result of the success of pilot programs, AstraZeneca launched an Open Innovation program that seeks to make a range of unwanted molecules readily available to university researchers who can propose novel repositioning ideas [ 39 ]. In doing so, AstraZeneca gains a competitive advantage when the same scientists are looking for companies to share breakthroughs with [ 17 ].

The European College of Neuropsychopharmacology (ECNP) Medicines Chest Program was set up to provide academic and small company researchers access to promising compounds for experimental medicine studies. Similar to the NIH NCATS program, the compounds are placed on the ECNP website, and researchers are invited to submit a 2–3-page proposal outlining a clinical study. After the ECNP vets the study, a contract, of which a sample is publicly available, is drawn up between the company and academic institutions and access to confidential information is provided for grant applications to fund the study [ 40 ].

The Clinical and Translational Science Award (CTSA) Pharmaceutical Assets Portal facilitates industry-academic collaborations for discovery of new indications for shelved compounds by providing a foci-of-expertise tool that identifies investigators with complementary interests, access to resource-management tools, facilities to house, maintain and distribute the discontinued compounds, management of IP and material transfer agreements, and selection of projects for funding [ 44 , 52 ].

Likewise, The Clinical Development Partnerships Initiative presents a cost-effective, rapid means by which pharmaceutical companies can boost their product lines. Companies retain IP rights to their original molecule and the first option to view trial data if they loan their compounds to Cancer Research UK, which will conduct early phase I and II clinical trials. The company retains the option to develop and market the drug, and the charity receives a share of any revenue [ 15 ].

The Roche/Broad Institute Collaboration made 300 compounds that failed to meet critical phase II milestones or were shelved for strategic reasons available to researchers who could suggest experiments. If collaborators uncovered any shared findings, Roche and the partner would agree on next steps, including publishing results, further experimentation, or a development plan [ 52 ].

Lastly, the Drugs for Neglected Diseases Initiative (DNDI) is an open-source collaborative endeavor that partners the expertise and assets of pharmaceutical companies with networks of public and private scientists to support repurposing and investigation of novel treatments for neglected tropical diseases. Merck entered a collaboration with DNDI in which it would provide small molecule assets and respective intellectual property through socially responsible licensing agreements to develop, manufacture and distribute cost-effective treatments for NTDs to resource-poor countries. The pharma company would share joint IP rights on candidates in early development, with an opportunity to continue late clinical development and registration of successful candidates. In doing so, collaboration is incentivized and resident expertise and contributions in later stages of development help maximize the drug’s potential [ 54 ].

Databases and registries

Compound access is another important facilitator for repurposing. Many initiatives serve to create databases that provide target and drug profiles, including protein and active site structures and associations with related diseases and biological functions, to interested researchers. Databases discussed in the literature include PubChem (7), DrugBank (6), Promiscuous (5), ChEMBL(5), the NIH clinical collection (2), the Open PHACTS Initiative (2), DisGeNet (1), the Drug Repurposing Hub (1), DrugSig (1), and the US FDA’s Orange Book of discontinued drug products list (1).

Compound-specific databases include: PubChem, which is administered by the NIH and holds data from several hundred biochemical and phenotypic screens, with more deposited each month [ 55 ], ChEMBL, an open target platform that enables investigation of evidence-associated targets and diseases in an accessible manner by presenting molecules with drug-like properties [ 56 ] and the US FDA’s Orange Book of discontinued drug products.

DrugBank is the most comprehensive publicly available database of approved, experimental and withdrawn drugs which are annotated by indication and intended targets [ 57 ]. The Promiscuous database provides an exhaustive set of drugs (25,000), including withdrawn or experimental drugs with drug-protein and protein–protein relationships annotated, allowing researchers to identify prospective new uses by examining predictive interaction points [ 52 ]. The NIH clinical collection presents a library of drugs that passed safety tests but for various reasons did not reach the market [ 38 ]. The Open Phacts initiative allows for multiple sources of publicly available pharmacological and physicochemical data to be intuitively queried, with 28 partners from public and private sectors [ 52 ]. DisGeNet offers associations between genes and diseases, as well as disease-variant associations.

The Drug Repurposing Hub is a database of approved, clinical-trial tested, and pre-clinical compounds that are annotated with literature-reported targets, and DrugSig is a public resource for signature-based drug repositioning that builds off the Connectivity Map from the Broad Institute [ 57 ]. Open-source databases allow for efficient sharing of resources and drug profiles to cost-effectively advance shelved compounds, and provide a public relations benefit for pharmaceutical contributors who are not locked into long-term commitments.

Systematic methods for repurposing

Many novel methods have been developed and applied to help identify and validate repurposing targets, greatly advancing repurposing endeavors ( n  = 32). Computational approaches coupled with open-access databases were described as central in identifying potential repurposing opportunities by predicting drug-disease responses and validating targets and pathways [ 21 ].

Of these newer methods, signature-based approaches ( n  = 5) were commonly employed for drug repurposing. These include investigating published GWAS data from institutes like the US National Human Genome institute to systematically and rapidly identify alternative indications for existing drugs and exploring how many genes are amenable to pharmacological intervention using biopharmaceuticals or small molecules [ 58 ]. However, key limiting factors are the expertise and time required to develop such assays and integrating databases that identify known drugs among confirmed activities [ 55 ].

In-silico screening of compound libraries ( n  = 4) is useful in both significantly reducing wet-laboratory work and lowering the cost of experimental determination of drug-target interactions [ 59 ]. Additionally, public access to high throughput screens (HTS) of small molecules ( n  = 3), particularly mining of phenotypic screens, was described as an effective and economical strategy for repurposing drugs [ 55 ].

Computer-aided approximations include bioinformatics-based approaches ( n  = 3) which employ domain similarity prediction tools and sequence alignment to discover novel protein–protein similarities, identifying closely related targets and new repurposing opportunities, and chemoinformatics-based approaches ( n  = 2) which involve molecular representations of candidate compounds which are submitted to computational algorithms which rank and prioritize compounds for experimental testing.

When 3D structures are available, molecular docking ( n  = 1) can be used to screen a large number of compounds against a target protein. When they are not, ligand and network-based approaches can be utilized [ 59 ].

Network modeling ( n  = 1) and systems-biology approaches ( n  = 1) were also discussed as helpful. Network modeling reconstructs a biological network and simulates its interactions to reveal potential drug targets [ 60 , 61 ]. A systems-biology approach was described as the use of omics data, signaling pathways, metabolic pathways and protein interactions to come up with a new pathway for a proposed disease [ 43 ].

While most network-based approaches are limited in their predictions of how drugs and targets interact, machine learning approaches ( n  = 3) can go further in accurately predicting drug-target interactions and inferring modes of action and novel drug-target relationships [ 59 ].

Finally, Artificial Intelligence (AI)-driven technology ( n  = 1) can integrate diverse types of data and look for connections. For example, Biovista has developed an AI solution called Project Prodigy which does not limit itself to machine learning but rather is capable of building entirely new clinical scenarios and has led to internal repurposing successes in multiple sclerosis and epilepsy. Their AI system has been used in collaboration with major pharmaceutical companies, patient advocacy groups, and the FDA [ 62 ].

Tax incentives and regulatory modifications

Tax incentives and certain regulatory modifications may further facilitate drug repurposing. Tax incentives such as allowing for the deduction of residual product value upon donation of a compound or for sharing trial data to a third party could help advance development of shelved compounds. Regulatory modifications to the FDA’s 505(b)(2) pathway could allow for use of previously compiled safety data. Use of the FDA’s safety findings could expand the number of drugs available without adversely impacting risk benefit [ 21 ].

Examples of successfully repurposed or re-positioned drugs

The most frequently discussed repurposing opportunities were for rare and neglected diseases ( n  = 12), Alzheimer’s disease ( n  = 10), AIDS ( n  = 2), and central nervous system disorders ( n  = 2). Examples of successfully repositioned drugs ( n  = 50) discussed in the literature included thalidomide ( n  = 8), Viagra ® /slidenafil ( n  = 7), Saracatinib (6), AZT ( n  = 5), Aducanumab ( n  = 4), Sunitinib ( n  = 3), Ebselen ( n  = 2), tamoxifen ( n  = 2), raloxifene ( n  = 2) and daptomycin ( n  = 1).

Drug promiscuity, the notion that one drug can affect more than a single pathway and lead to new indications for drug candidates was frequently discussed, with thalidomide the most commonly cited example [ 61 ]. Thalidomide ( n  = 8), originally manufactured by the German company Chemie Grunenthal in the mid 1950’s, was discussed as an example of a drug that failed after its market launch in several countries, though it was not approved by the US FDA at the time, and later successfully repurposed [ 13 ]. Originally indicated for sedation and morning sickness, it was withdrawn for its teratogenic effects. However, further studies revealed that the drug inhibited tumor necrosis factor-alpha signaling, and it was subsequently approved for the treatment of erythema nodosum leprosum, a life-threatening complication of leprosy, and then multiple myeloma. In the US, the FDA approved the drug for acute erythema nodosum leprosum (ENL), in 1998, however, “use was limited by very strict guidelines,” according to the literature [ 13 ].

Viagra ® was also presented in the literature as a well-known example of a drug that showed a lack of efficacy in clinical trials for its originally studied indication, but interestingly, analysis of its unusual side effects and its poor pharmacokinetic properties for angina led to its eventual use for erectile dysfunction [ 13 , 61 ].

Daptomycin, an antibiotic, was successfully repurposed by Cubist after Eli Lilly abandoned it when downsizing its infectious disease division. Eli Lilly out-licensed the drug to Cubist after four years on the shelf. Cubist’s Chief scientific officer advocated for use of daptomycin as an antibiotic. IP negotiations proved challenging, but eventually Cubist purchased worldwide development and commercialization rights to Daptomycin along with a license to the underlying IP related to the compound. Eli Lilly has received over $333 million in royalties on the product sales to date [ 13 ]. Cubist redesigned the clinical trials and filed a patent on the basis of a once-daily treatment regimen to minimize adverse effects from the drug. Daptomycin is now an important public health tool, serving as a useful last resort medication in diseases like MRSA that have become increasingly resistant to front-line antibiotics.

Saracatinib was originally developed for multiple oncology indications, but phase II studies showed limited benefit and the drug was deprioritized. The concept for repositioning of this agent came from discoveries of memory impairments in mouse models of AD and data that showed the phosphorylation of the Fyn tyrosine kinase was related to Aβ- and tau-associated synaptic dysfunction. The drug is currently being investigated for other indications like bone pain and lymphangioleiomyomatosis through MRC, NIH, and NCATS programs [ 39 , 63 , 64 ].

Azidothymidine (AZT) likewise reflects how a detailed understanding of disease and drug mechanisms of action can lead to repurposing discoveries in entirely new indications. AZT was originally investigated as a chemotherapy drug in the 1960’s but was abandoned due to lack of efficacy. However, in the early days of the HIV epidemic, AZT’s anti-retroviral effect was noted, and the NIH partnered with industry experts to repurpose the drug, which became the first treatment for patients with HIV [ 32 , 38 , 65 , 66 ].

Aducanumab was abandoned after a futility analysis from an independent monitoring committee indicated the drug was not going to be effective for treating Alzheimer’s disease. However, a re-analysis of data from two failed clinical trials showed promising results, as a subset of patients treated with the highest dose appeared to show a statistically significant slowing of decline of cognitive ability and basic activities of daily living. Biogen concluded the initial analysis had been incorrect and got support from the FDA to move forward with a regulatory filing, reviving the nearly abandoned drug [ 23 , 24 , 25 ].

Sunitinib presents an example of on-target repurposing. It failed in clinical trials for colorectal, breast, prostate, and non-small cell lung cancer, but was successfully repositioned for treatment of gastrointestinal stromal tumor and renal cancers. After a repurposing effort, it was approved for treatment of pancreatic neuroendocrine tumors in 2010 [ 61 ]. Analysis of the lack of efficacy of Sunitinib in some cancers demonstrates the importance of a targeted approach [ 67 ].

A drug repurposing approach screening of the National Health Institute Clinical Collection identified Ebselen as a potential lithium mimetic [ 68 ]. Ebselen was originally indicated for stroke, but showed a lack of efficacy. Never marketed, Ebselen could have repurposing potential for treatment of bipolar disorder, and in a paper published in 2016 was described as currently under investigation [ 38 ].

Tamoxifen was a failed contraceptive and orphan drug, though in translational laboratory work it showed efficacy in induction of ovulation in sub-fertile women and in the treatment of metastatic breast cancer in postmenopausal women. A nonsteroidal antiestrogen, tamoxifen was repurposed and approved for treatment of metastatic breast cancer and later for breast cancer risk reduction, and is currently the standard of care for long-term adjuvant therapy for estrogen receptor-positive breast cancer [ 69 ]. A cluster of translational studies around the 1970’s and 80’s focused on the uterus, breast and bone created a database for further studies and trials that also resulted in the reinvention of keoxifene, a failed breast cancer drug, to raloxifene, the first clinically available selective estrogen receptor modulator for breast cancer and osteoporosis prevention [ 69 ].

In this systematic literature review, we examined why pharmaceutical companies de-prioritize, shelve or abandon the development of promising drug candidates as well as facilitators and barriers for their successful repurposing.

The chief reason promising drugs are abandoned is their lack of efficacy or superiority over alternate therapies for a studied indication or population. Other key reasons for drug abandonment were strategic business reasons by the sponsor, often related to judgments about a drug’s market prospects, industry consolidation, and flawed research design decisions. Inadequate understanding of therapeutic pathways in complex diseases, such as for Alzheimer’s disease, cardiovascular disease, psychiatric conditions, and stroke was presented as compounding trial design challenges. In psychiatric disease, for example, inferences from animal research were discussed as remaining limited in scope. Regulators requesting the completion of additional studies and a sponsor unwilling to comply, were also discussed as potential drivers for drug abandonment. These findings support a previous study evaluating why clinical stage compounds that have cleared regulatory review in Phase 1 safety trials are subsequently abandoned before reaching the market, which found 38% were due to inadequate efficacy for the studied disease, 34% due to poor perceived economics, 20% for safety reasons, and 9% for other reasons.

The top barrier to drug repurposing was inadequate resources, especially financial, subject matter expertise, and dedicated staff focused on out-licensing. IP challenges and inadequate data access were among other leading barriers as well as value questions and assumptions on the role of repurposing as an effective tool in drug development. While some papers describe drug repurposing as faster, cheaper, and more likely to succeed than traditional drug development approaches, others note that in later stages, repurposed compounds may still have the same failure rate as any other compound, if not higher, after failing in a primary indication. Liability risks were also presented as barriers to re-purposing. Altogether, these barriers were presented as resulting in an unknown number of abandoned compounds stored in company vaults, with some suggesting they may number in the thousands [ 21 , 31 ].

The most common facilitators for repurposing, we found, were collaborative partnerships between bio-pharmaceutical companies, academia, and non-profit organizations that help bring together needed resources and expertise. Of note, the role of patients and patient organizations as collaborators in drug repurposing was largely unaddressed in the reviewed literature, despite their growing role in more traditional forms of drug research and development [ 70 ]. Access to compound libraries and databases, the development and application of new computational methods to screen databases, regulatory modifications, and tax incentives were also identified as facilitators. Many of these facilitators generally correlate, as opposites, to the barriers we found to re-purposing.

However, a major barrier also includes successful negotiation of material transfer agreements between potential collaborators, an issue without a clear solution in the literature, suggesting a need for further study on ways to better support IP negotiations to more fully realize repurposing benefits. There are some models in the literature, such as the NIH NCATS repurposing program, which may offer helpful generalizable best practices for supporting IP negotiations. The program was described as allowing the NIH to act as a trusted intermediary with procedures for facilitating deals, including on IP, between researchers and companies.

Further, the literature emphasizes biases around the value of repurposing in drug development, as a barrier to repurposing. We found these value questions reflected in our findings, as some papers described repurposing as faster, cheaper, and more likely to succeed than traditional drug development approaches, while others argued that in later stages, repurposed compounds may still have the same failure rate as any other compound, if not higher, after failing in a primary indication. More systematic study may be needed on the current value of repurposing as a tool in drug development.

There are limitations to this study. Notably, included publications were often descriptive papers and perspective pieces, not rigorous scientific studies, which limits the conclusions that can be drawn. Importantly, 25 of our analyzed papers were classified as reviews, under type of publication, by their publishing journals. These were generally not systematic reviews and did not always include methods or details on how the review was undertaken. We could not easily devise a method for assessing duplication of information in these review papers. For instance, we could not easily merge data around mention of specific drugs. Some papers discussed multiple drugs, while others didn’t reference specific drugs at all. A similar challenge arose for news articles. Notwithstanding, this paper is in alignment with methods for a bibliometric analysis of information, which can be published with a systematic review and allows for different types of study designs within one synthesis [ 71 ]. This review excluded one paper that was not available in English and did not search any non-English database. Conference abstracts were excluded due to insufficient extractable data. Additionally, information on the characteristics we were abstracting about drug abandonment and repurposing may not have been published in the medical or pharmaceutical peer-review literature and may have been missed.

In this systematic literature review assessing why development of promising drug candidates are abandoned, we found insufficient efficacy, or superiority to other therapies, for studied indications or populations, judgments about a product’s market prospects and industry consolidation among leading factors. Inadequate resources and challenges negotiating IP and data access are key barriers needing reform for repurposing to reach its full potential as a core approach in drug development. Multi-partner collaborations, along with the creation, accessibility, and use of compound databases, regulatory modifications and tax incentives are key facilitators for repurposing promising shelved drugs. More research is needed on the current value of repurposing as a core method in drug development and how to better facilitate resources to support it, where valuable, especially financial, staffing focused on out-licensing shelved products, and legal expertise to negotiate IP agreements in multi-partner collaborations.

Availability of data and materials

The datasets generated and/or analysed during the current study will be made available in dryad.

Abbreviations

AstraZeneca

Confidentiality disclosure agreement

Composition of matter

Collaborative research agreements

Clinical and Translational Science Award

Drugs for Neglected Diseases Initiative

European College of Neuropsychopharmacology

Generalized anxiety disorder

High throughput screens

Intellectual property

Major depressive disorder

Material transfer agreements

National Research Program for Biopharmaceuticals

Preferred Reporting Items for Systematic Reviews and Meta-analyses

Return on investments

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Additional file 1: supplementary table 1..

PRISMA 2020 Main Checklist. Supplementary Table 2. Search Strategy. Supplementary Table 3. Table of Excluded Studies with Reasons for Exclusion. Supplementary Table 4. Table of Included Studies [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ].

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Krishnamurthy, N., Grimshaw, A.A., Axson, S.A. et al. Drug repurposing: a systematic review on root causes, barriers and facilitators. BMC Health Serv Res 22 , 970 (2022). https://doi.org/10.1186/s12913-022-08272-z

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Supported by

More Young People Are on Multiple Psychiatric Drugs, Study Finds

A teenager holds two prescription bottles in her hand in a bathroom.

By Matt Richtel

Growing numbers of children and adolescents are being prescribed multiple psychiatric drugs to take simultaneously, according to a new study by researchers at the University of Maryland. The phenomenon is increasing despite warnings that psychotropic drug combinations in young people have not been tested for safety or studied for their impact on the developing brain.

The study, published Friday in JAMA Open Network, looked at the prescribing patterns among patients 17 or younger enrolled in Medicaid from 2015 to 2020 in a single U.S. state that the researchers declined to name. In this group, there was a 9.5 percent increase in the prevalence of “polypharmacy,” which the study defined as taking three or more different classes of psychiatric medications, including antidepressants, mood-stabilizing anticonvulsants, sedatives and drugs for A.D.H.D. and anxiety drugs.

The Big Picture

The study looked at only one state, but state data have been used in the past to explore this issue, in part because of the relative ease of gathering data from Medicaid, the health insurance program administered by states.

At the same time, some research using nationally weighted samples have revealed the increasing prevalence of polypharmacy among young people. One recent paper drew data from the National Ambulatory Medical Care Survey and found that in 2015, 40.7 percent of people aged 2 to 24 in the United States who took a medication for A.D.H.D. also took a second psychiatric drug. That figure had risen from 26 percent in 2006.

The latest data from the University of Maryland researchers show that, at least in one state, the practice continues to grow and “was significantly more likely among youths who were disabled or in foster care,” the new study noted.

Mental health experts said that psychotropic medications can prove very helpful and that doctors have discretion to prescribe what they see fit. A concern among some experts is that many drugs used in frequently prescribed cocktails have not been approved for use in young people. And it is unclear how the simultaneous use of multiple psychotropic medications affects brain development long-term.

The Numbers

The latest study looked at data from 126,972 people over the study period. It found that in 2015, 4.2 percent of Medicaid enrollees under the age of 17 in Maryland had overlapping prescriptions of three or more different classes of psychiatric medications. That figure rose to 4.6 percent in 2020.

The numbers were higher for those in foster care, where the prevalence of polypharmacy rose to 11.3 percent from 10.8 percent.

“The findings emphasize the importance of monitoring the use of psychotropic combinations, particularly among vulnerable populations, such as youths enrolled in Medicaid who have a disability or are in foster care,” the study concluded.

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

Understanding A.D.H.D.

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Drugs Research Paper

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Introduction

Bingham dai, alfred lindesmith, howard s. becker, edwin schur, implications of early sociological insights, social control, self-control, social learning, patterns in drug use, policy and legal issues, epidemiology and etiology, drugs and crime, drugs and the community, the effectiveness of treatment programs, the methodology of surveying drug use, the dynamics of drug markets, other topics, conclusion: the future of the sociology of drug use.

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  • Psychoactive Drugs Research Paper

Pharmacologists refer to substances that have an impact on thinking, feeling, mood, and perception as psychoactive. Humans have always ingested psychoactive substances. Higher organisms are neurologically hardwired to derive pleasure from the action of certain chemical substances. Psychoactive drugs, some powerfully so, activate pleasure centers of the brain, thereby potentiating continuing drug-taking behavior. People take drugs to experience the effects that come with their mind-active properties.

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The neurological/pharmacological factor addresses how and why drug-taking behavior got started, but it does not address the most sociologically relevant issues: differences in drug-taking behavior between and among societies, social categories, and individuals in the population, as well as among drug types. In addition, the predisposition to use is a necessary but not sufficient explanation of use. Use also presupposes the availability or supply of, or opportunity to take, a given drug. Without a predisposition to use, drug use will not take place; without availability, it cannot take place.

Moreover, substances are defined as “drugs” in a variety of ways. Indeed, most substances referred to as drugs do not influence the mind at all—that is, they are not psychoactive. Many have medicinal or therapeutic value: Antibiotics, antacids, and antitussives offer ready examples. Why people take such drugs can be answered by addressing medical motives. Other drugs influence perception, mood, cognitive processes, and emotion. Alcohol clearly qualifies in this respect, as do methamphetamine and PCP. Hence, the recreational motive—getting high—factors into the explanatory equation. Still other substances, such as LSD, marijuana, and heroin, are illegal or illicit—their possession and sale are controlled by law. Hence, their legal status is implicated in why—or, more accurately, why not—some people use them. The medical, psychoactive, and illegal categories overlap: LSD is both psychoactive and a controlled substance, and morphine is both psychoactive and used as medicine, as well as illegal for nonmedical or recreational purposes.

Medical sociologists are interested in the use of drugs in therapy. Criminologists study drugs as illegal substances. Economists look at drugs as an exchange commodity, bought, sold, and distributed according to patterns both similar to and different from those of legal products. Anthropologists conduct research on the consumption of psychoactive plant products by tribal and agrarian peoples; here, cultural factors in drug use predominate. Policy analysts examine the feasibility of specific drug policies. Pharmacologists consider the effects of drug substances on the physical organism; psychologists and psychopharmacologists study their effects on the brain—that is, the mind. In this research paper, I will focus on the use of drugs that are both psychoactive and illicit. In fact, drugs that strongly influence the mind tend to become criminalized. In the United States, aside from tobacco, which generates a “low-key” high, and alcohol, the only psychoactive substances that are not illegal for recreational purposes are those that are not widely used and have not yet become publicized as recreational drugs.

The task of sociologists has always been and remains establishing a distinctive voice in the din of competing perspectives and disciplines investigating drug use. Their focus is on what makes drug use a specifically social activity, how socialization, culture, social interaction, social inequality, deviance, and group membership play a central role in the use of psychoactive substances; what people do under the influence; and what societies do about the control of—or why they tolerate or accept—drug use and distribution.

Early Sociological Research on Drug Use

People have been writing about psychoactive drug use and drug effects for at least 6,000 years, but it was not until little more than a century ago that the pathological or harmful side of substance abuse proved to be the major theme in texts on drug use. Surveys on rates of and dependence on medical opium and morphine were conducted in the United States as early as 1877 (Courtwright 1982:10). During a brief period following 1884, the medical profession dubbed cocaine “a miracle of modern science” (Spillane 2000:7–24), but within a decade, physicians began recognizing danger lurking in the unregulated use of the drug, specifically for causing overdoses, or what was then referred to as “cocaine poisoning,” and dependence, or developing the “cocaine habit” (pp. 25–42). With respect to drugs, the second half of the nineteenth century witnessed a shift from a completely tolerant, laissez-faire or “hands off” legal policy to one that favored increasingly strict controls over their distribution and sale. By 1900, the unregulated medical consumption of drugs was drawing to a close, while users who sought recreation and intoxication loomed increasingly larger in the drug picture. By the 1920s, the intellectual context that surrounded drug use was saturated with the view that medical use is often, and recreational use is by its very nature, dangerous, harmful, and pathological.

Hence, most of the early sociological researchers found themselves challenging the dominant, conventional view. None of them questioned the idea that nonmedical drug use could be or was often harmful; the view they challenged was that such harm was intrinsic to the activity itself and was unmediated by social forces or factors. Moreover, these early sociologists suggested that the cure for the drug problem, namely, the drug laws and their enforcement, may be more harmful than drug use itself.

The first systematic sociological research on the subject of drug use grew out of the research on deviance, delinquency, and crime that was conducted in the 1920s by the faculty and graduate students of the Department of Sociology at the University of Chicago. These early Chicago sociologists located the cause of such untoward behavior in the social disorganization of certain neighborhoods, which they characterized by high residence density, poverty, transience, and dilapidation, conditions that generate moral cynicism among residents, increased opportunities for crime and deviance, and diminished social control.

During the 1920s, intellectuals, along with society’s more enlightened wealthier citizens, abandoned the idea of a laissez-faire program of letting problems take care of themselves and began to see their role as one of progressive stewardship—that is, they saw themselves as having “a moral obligation to further the betterment of society.” The early Chicago sociologists saw themselves as part of this emerging liberal, enlightened, reformist perspective, seeking solutions to “such social problems as crime, mental disorders, family breakdown, and alcoholism” (Pfohl 1994:184–85). It was out of this sociohistorical context that the sociology department’s focus on social disorganization and the problematic behaviors it spawned was born.

The first systematic, full-scale sociological study of drug addiction in the Chicago tradition was conducted in the 1930s by Bingham Dai (1937) and was published as Opium Addiction in Chicago. While a tradition of medical and legal writings existed when he began his research, Dai argued that the sociological approach represented a contribution because the addict is “a member of society and a carrier of culture” (p. v). Moreover, sociology attempts to trace out the etiological or causal factors related to addiction. Dai examined data on 2,500 addicts from a psychiatric hospital, more than 300 nonaddict drug dealers, and 118 female addicts, for the period from 1928 to 1934. In addition, he conducted interviews and summarized 25 of them as “case studies” in his book.

The lives of these addicts, nearly all above the age of 20, were marked by irregular employment, poverty, weak or nonexistent family ties, and high rates of property crime after they became addicted. Dai (1937) characterized the neighborhoods in which his sample lived by a low level of community spirit and weak or absent “primary group associations” among residents, a high percentage of unattached males, many transients, physical deterioration, and cheap rental units. His drug addicts, he said, lived in an environment of high levels of “family disorganization, crime, vice, alcoholism, insanity and suicide” (p. 189). Such neighborhoods tolerated, gave license to, or encouraged deviant and criminal behavior—and drug addiction fit comfortably within this constellation of social problems.

Dai (1937) did, however, stress that opiate addicts were psychologically normal, did not commit crime prior to their addiction, and tended to commit property crimes rather than crimes of violence and, most important, that opiates did not have a medically harmful or “deteriorating effect” on the body (p. 72). Moreover, Dai’s social disorganization approach emphasized an important truth that can be found in much sociological writing: Aside from their “unfortunate spatial location in the natural ecology of a changing society,” the perspective “asks us to imagine” that drug addicts, like deviants in general, “are people like ourselves” (Pfohl 1994:209). In short, in most respects, Dai challenged the pathology orientation of the writings on drug use that were current at that time.

Alfred Lindesmith also studied drug addiction, but unlike Dai, whose work fit squarely within the social disorganization tradition, made very little use of the Chicago School’s focus on communities and neighborhoods. Lindesmith’s dissertation devised and tested a microinteractionist theory of opiate addiction. In Opiate Addiction, Lindesmith (1947, 1968) argued that in the initial stage of narcotic use, pleasure dominates as a motivating force. Because of the body’s growing tolerance to narcotics, the user, to continue receiving pleasure, is forced to increase the dose of the drug—eventually to a point at which a physical dependence takes place. If use is discontinued because of arrest, disrupted supply, insufficient funds, or attempts at abstinence—or for any reason whatever—painful withdrawal symptoms wrack the addict’s body. When the addict administers a dose of a narcotic and recognizes that it alleviates the anguish of withdrawal, an intense craving is generated for the drug. Hence, the addict does not become addicted voluntarily “but is rather trapped ‘against his [or her] will’ by the hook of withdrawal” (Lindesmith 1968:9). Lindesmith saw addicts as basically normal people ensnared in a compulsive habit over which they have no control. The crimes they commit are strictly to maintain their habits. Moreover, he argued, addicts derive no pleasure from opiates. Interestingly, Lindesmith’s formulation begs the question of what it was that led the addict to experiment with opiates initially.

The political and policy implications of Lindesmith’s (1965) conclusions were profound, conclusions that he developed in considerable detail in The Addict and the Law. If addiction is a direct consequence of the conjunction of a biophysical mechanism (withdrawal distress) and a cognitive process (recognizing that a dose of an opiate relieves withdrawal), then the addict cannot be held responsible for his or her condition. Like Dai’s addicts, who were caught up in the tangle of community disruption, Lindesmith’s addicts were innocents caught up in the uncontrollable impulse to avoid a relentless pharmacological process. Consequently, he reasoned, addiction should not be a crime, and addicts should not be locked up for attempting to relieve what is in effect a medical condition. Moreover, Lindesmith emphasized, the effects of the opiates are not medically harmful, adding further fuel to the fire of his criticism of the drug laws. As a consequence of his findings, Lindesmith became a staunch critic of American drug policy. Indeed, from the 1930s until the early 1960s, Lindesmith was one of the few critical voices speaking out against the government’s war on drugs. Lindesmith’s impact on the sociology of drug use has been enormous.

Howard S. Becker earned his way through graduate school by playing the piano for jazz bands. His musical experience led to acquaintances with other musicians, most of whom used one or another illicit, controlled substance, mainly marijuana. Just as Lindesmith had raised the question of how someone becomes an opiate addict, Becker’s research posed the issue of how one becomes a marijuana smoker. The intersection of the physiology of marijuana’s effects and three social/cognitive processes—namely, learning how to use it, learning to perceive its effects, and learning to enjoy its effects—provides the mechanism that accounts for its use. Once one enjoys the effects of marijuana, to continue using it, one needs to nullify the forces of social control that conventional society exercises to prohibit this behavior—namely, maintain a supply of the drug, ensure a measure of secrecy about its use, and reorganize the sense of morality so that definitions of the deviance of use are neutralized. Becker’s (1953, 1955) two articles on marijuana use, published in the 1950s, were later incorporated as chapters into his treatise, Outsiders: Studies in the Sociology of Deviance (Becker 1963).

Becker’s analysis departed even more radically than did Dai’s and Lindesmith’s from the dominant “pathology” perspective: Dai’s addicts were a product of a negative condition (community disruption), and Lindesmith regarded addiction as a medical condition, much like an illness, in need of treatment. But Becker’s marijuana smokers— and his depiction of marijuana use—were normal in every imaginable way. Users had no pathological characteristics that impelled them to take the drug. There is no hint that the effects of marijuana are harmful. Even more striking, Becker’s intellectual problem is not how users stop their use of this drug, it is precisely the reverse: He asks how people manage to continue using marijuana. And like Dai and Lindesmith, Becker staked out the distinctively sociological factors that influence the lineaments of drug use.

Edwin Schur (1962) compared the British policy of narcotic control versus the American policy. Since 1914, when the Harrison Narcotic Act was passed, and especially during the 1920s, when it came to be enforced, the dominant stance toward drug use in the United States has been punitive. And in the United States, Schur explained, because of this punitive policy, narcotics are extremely expensive and can be purchased regularly only if the user resorts to a life of crime. Hence, the connection between drug use and crime is extremely intimate: Nearly all addicts engage in money-making crimes. A large and vigorous addict subculture flourishes that serves to continually entice fresh, young recruits into the world of addiction. And the population of addicts in the United States is enormous—in the late 1950s, as many as a million, according to the estimate of “some authorities” (Schur 1962:44). Clearly, the punitive drug policy that prevailed in the 1950s—and still prevails today—has failed to curb drug addiction.

In contrast, the British system in the 1950s regarded narcotic addiction as a disease in need of treatment. Drugs were not then—and are not now—“legalized” in the United Kingdom. The dispensation of narcotics for recreational purposes was a crime, punishable by a prison sentence. Physicians could use narcotics for “ministering to the strictly medical” needs of their patients. But what this includes was fairly broadly construed. It included administering narcotics in the following situations: in diminishing doses for the purpose of gradual withdrawal; where it is medically unsafe to withdraw the patient from narcotics because of the severity of withdrawal; and when the patient leads a normal life maintained on narcotics but is incapable of doing so when withdrawn. There was the recognition “that in some cases prolonged prescribing of drugs may be necessary” (Schur 1962:205). In short, during the 1950s, the policy that prevailed in the United Kingdom was medical rather than punitive. Law enforcement did not interfere with a medical judgment that maintaining an addict on narcotics may be necessary. Under the British program, Schur argues, doses of narcotics were very cheap, addicts engaged in little criminal behavior, there was no addict subculture, there was no recruitment of novices by addicts, there was almost no diversion of drugs into the black market, there were very few addict-sellers, and the number of narcotic addicts in the United Kingdom was extremely low (fewer than 500 registered addicts). In sum, concluded Schur (1962), this “medically oriented approach seems to work very well” (p. 205).

Schur was interested in the contrasts between the British medical approach and the American punitive approach to addiction for both policy and theoretical reasons. From a policy standpoint, he wanted to convince authorities in the United States that their war on drugs was a failure and that the British system was a “humane and workable” program that had much to teach them about how to deal with the problem of addiction. Of theoretical interest, Schur critiqued the view that drug effects alone, or the predisposition to engage in deviance alone, could account for engaging in deviant behavior. In Britain, he explained, addicts—a population customarily thought of as highly predisposed to engage in crime and deviance—were taking narcotics, a behavior associated elsewhere with engaging in crime and deviance, but engaging in very little deviance and crime. Clearly, addiction per se does not generate high rates of crime and deviance.

To explain the low rates of deviant behavior in the United Kingdom, Schur employed the work of the early deviance theorists Edwin Lemert (1951) and Cloward and Ohlin (1960). Addicts in Britain were not labeled as deviants, Schur explained, and hence, neither developed a deviant identity nor became “secondary” deviants—that is, their lives did not revolve around their addiction, as Lemert’s theory would predict, had they been stigmatized. And widespread illicit drug trafficking did not exist in the United Kingdom because no social structure of illicit drug distribution existed there, supporting Cloward and Ohlin’s insights on the importance of opportunity in criminal behavior.

However, beginning in the late 1960s, recreational drug use exploded in Britain, as it did elsewhere in the Western world. According to a BBC broadcast (March 24, 2002), there are 540 times as many registered narcotic addicts in the early twenty-first century in the United Kingdom as there were in the 1960s. There exists a huge black market there in heroin, as well as in all other illicit drugs, in addition to a vigorous, vibrant drug subculture. According to surveys conducted in Britain (Ramsay et al. 2001) and the European Union (European Monitoring Centre for Drugs and Drug Addiction 2004), the recreational use of illicit drugs, heroin included, in the United Kingdom is at the high end of use of other Western European countries and is only slightly below that of the United States. Moreover, in some ways, the drug policy in the United States is less punitive than it was in the late 1950s. For instance, there are 150,000 addicts in methadone maintenance programs here, and most first- or second-time nonviolent drug offenders end up in treatment programs, through the drug courts, rather than jail or prison. Hence, Schur’s analysis is no longer as applicable today as it was in the late 1950s. The implications of these developments are now being debated by researchers and other observers.

These early sociologists of drug use imparted their distinctively sociological vision to the behavior they studied. The perspective on drug addiction, abuse, and consumption that prevailed at the time they wrote were overwhelmingly pathology oriented: Either the drug created out of whole cloth a new and fearsome creature, impelling the user against his or her will to engage in behavior totally alien and uncharacteristic, or users were psychopaths, their consumption of psychoactive substances a manifestation of their abnormal personalities. Sociologists challenged both versions of this pathology perspective, arguing that the social structure in which users interacted mediated and shaped their drug-taking and the impact that drugs had on their behavior. Neighborhood, cognitive processes, culture and subculture, laws and politics, all played a role in shaping why drugs are used and what impact they have on the lives of users as well as the society at large. The early research on drug use carved out a specialty where none had previously existed and placed its distinctive mark on future research.

If a single theme could be isolated out of the work of the pioneers of drug use, it would be that illicit drug use, abuse, and addiction are normative violations—that is, a form of deviance. Dai recognized that his drug addicts lived in disorganized neighborhoods, in which crime, delinquency, mental disorder, and suicide prevailed—drug addiction was in fact yet another variety of the deviant behavior that so abundantly thrived in such communities. Lindesmith’s research was dedicated to the proposition that his addicts were not mentally ill, not inherently or intrinsically mentally aberrant or criminal, but that their criminality was a function of their legal status and their addiction, their association with the world of crime, the deviant and criminal label imposed on them and their inevitable, forced, subsequent subcultural associations. Becker’s marijuana smokers struggled to neutralize the exercise of social control. Indeed, his work on drugs fit so neatly into the deviance paradigm that it provided chapters and case studies in a treatise on the sociology of deviance (Becker 1963). And Schur compared the impact of defining drug addiction as a crime and a form of deviance (as it was in the United States) with defining it as an illness (as it was in the United Kingdom) and found that criminalizing and stigmatizing the user here exacerbated the social and medical problems associated with addiction, while not doing so there minimized them. In short, these early researchers positioned the field of illicit drug use squarely within the context of the emerging field of the sociology of deviance.

Theories of Drug Use

The field of drug use studies has devised a substantial number of theories to explain or account for drug use. Most address predisposition only; very few attempt to explain availability or supply. In this section, I summarize a few of the more sociologically relevant theories of drug use. None of these theories is sufficient in itself to account for all drug use; instead, each argues that the condition or factor it focuses on makes drug use more likely than would be the case without it. Moreover, the validity of one of these theories should not imply that any of the others is false; for the most part, each of these theories complements rather than invalidates the others.

As with the efforts of the pioneers, current sociological theories depict illicit drug use as a subtype of deviant, nonnormative, and criminal behavior—that is, current theories account for the consumption of psychoactive substances with the same theory used to explain the violation of society’s laws and norms. As the authors of the “general theory of crime” point out (Gottfredson and Hirschi 1990), nearly all theories of crime and deviance—and the same applies to theories of drug use—are theories of motivation or predisposition. But a predisposition to behave a certain way is not a complete explanation. When it comes to drug use, predisposition alone is incomplete. Opportunity has not been fully incorporated into theories of drug use. The availability of a disposable income for the age cohort most likely to use drugs, a development that did not begin until well into the twentieth century, and the globalization of drug distribution, which did not begin in earnest until the 1970s, must be counted among those structural factors that expanded opportunities for persons so disposed to use drugs. A full exposition of the role of opportunity in illicit drug use awaits later research.

Social control theory assumes that violations of society’s norms are natural, understandable, and not in need of an explanation. What needs to be explained, its proponents argue, is why people conform to society’s norms. If left to our own devices, we would all break the law and indulge in any manner of criminal behavior and normative violations. And what explains law-abiding behavior and conformity to society’s norms, they say, is attachment (or “bonds”) to conventional people, beliefs, institutions, and activities (Hirschi 1969). To the extent that we are bonded to our parents, to an education, to marriage and children, to a legal job and career, and to mainstream religion, we do not want to threaten or undermine our “investment” in them by engaging in deviant or criminal behavior—and that includes recreational, especially illicit, drug use. Hence, we see the patterning in drug use discussed in the following; that is, adolescents with college plans or persons who are religious, married, and/or have children are less likely to use drugs, while those with no college plans or who are irreligious, unmarried, and/or childless are more likely to do so. Drug use is “contained” by bonds with or adherence to conventional people, institutions, activities, and beliefs. To social control theorists, it is the attachment of people to conventionality that explains abstention from drugs; it is the absence or weakness of such attachments that explains drug use.

In support of social control theory, it is clear that criminal offending, illicit drug use included, varies enormously by involvement with conventional institutions and conventional others, independent of any stable, underlying traits or characteristics. For instance, men are less likely to commit crime, all other factors being held constant, when they are stably married and living with a wife. The same applies when persons are attending school. Both are independently related to the consumption of illegal psychoactive substances, and drug use, independent of any other factors, is related to criminal behavior (Horney, Osgood, and Marshall 1995). In short, “meaningful short-term change in involvement in crime”—and substance abuse as well— “is strongly related to variation in life circumstances” (p. 655). Marriage and school constitute social bonds that “contain” or inhibit deviant and criminal behavior, illicit drug use included.

Self-control theory agrees that it is conformity that needs to be explained, not normative violations or illegal behavior. But its explanation is very different, pushing its key factor, as it does, back to childhood. The factor that accounts for deviance and crime—drug use included— self-control theory argues, is low self-control. And its answer to the question of what accounts for low selfcontrol is poor, inadequate parenting. Children who grow up in a household in which their parents are unable or unwilling to monitor and control their untoward behavior early on will develop a pattern of engaging in uncontrolled, impulsive, hedonistic, high-risk, and, ultimately, shortterm, rewarding behavior that includes crime and drug use. People who lack self-control tend to be insensitive, self-centered, reckless, careless, short-sighted, nonverbal, inconsiderate, intolerant of frustration, and pleasure oriented. They are grabbers, cheats, liars, thieves, and exploiters. They act with no concern for the long-range consequences of their actions.

Drug use is simply one of many manifestations of their orientation to life, and that is to do whatever you want, whatever feels good, regardless of whether that causes harm to others or even, in the long run, to oneself. There is no need to explain the connection between drug use and crime, self-control theorists argue, because they are the same behavior, two sides of exactly the same low selfcontrol behavior. The usual controls that keep most individuals in check are inoperative in the lives of drug users. And according to the proponents of this theory, low selfcontrol can be traced back to bad parenting (Gottfredson and Hirschi 1990). The impulse to use drugs does not have to be learned, this perspective argues; hence, all learning theories of drug use—as well as all learning theories of crime and deviance—are in error. It is abstention from drugs that needs to be explained.

The “strong relationship” between criminal behavior and the use of psychoactive drugs has been shown to hold “regardless of age, race, gender, or country” (Uihlein 1994:149). Self-control theory argues that “they are consequences of common causal factors,” that the age curve for both follows the same trajectory, that both drug use and delinquency are relatively stable over time, that drug use, like delinquency and crime, is versatile rather than specialized, that “drug use” and “crime” variables “appear indistinguishable from one another” (Uihlein 1994:151, 153–54), and that both can be traced to poor, inadequate parenting. Since the “logical structure” of drug use and that of criminal behavior are identical—both being the “manifestations of an underlying tendency to pursue shortterm, immediate pleasure”—it follows that “crime and drug use are the same thing” and that research “designed to determine the causal relationship” between them “is a waste of time and money” (Gottfredson and Hirschi 1990:42, 93, 233–34).

Social learning theory emphatically disagrees with the control theories, arguing that people are not “naturally” predisposed to committing crimes or using drugs; instead, they have to specifically learn the positive value of nonnormative behaviors. The earliest sociological version of learning theory applies specifically to crime and is referred to as the theory of differential association (Sutherland 1939).

Learning theory argues that youngsters associate differentially with certain groups or social circles that provide “social environments for exposure” to definitions of correct or incorrect behavior, models of behavior to imitate, and opportunities to engage in certain kinds of behavior. These environments may discourage or encourage drug use. Family definitions, models, and opportunity are important in defining drug use one way or the other, but of course, they tend to discourage rather than encourage use. Additional agents of learning or socialization include other family members, neighbors, religious figures, teachers, and the mass media, each of whom has “varying degrees of effect on use and abstinence.” Typically, however, peers are most influential, the family is a distant second, and the other socializing agents trail far behind (Akers 1998:171–72).

Learning theory argues that the probability of the use of psychoactive substances increases to the extent that someone (a) is exposed to persons, especially peers, who use rather than abstain from drugs; (b) hears definitions favorable rather than unfavorable to use; and (c) finds such use pleasurable rather than neutral or unpleasant. In addition, use escalates to the extent that a person associates with heavier users and with parties who define heavier use in positive terms and who develop a pattern of heavy use that is reinforcing or pleasurable (Akers 1998:175–76).

Conflict theory argues that inequality is the root cause of drug use, at least the heavy, chronic abuse of and dependence on “hard” drugs such as crack cocaine and heroin. Such abuse, proponents of this theory argue, is strongly related to social class, income, power, and neighborhood. A significantly higher proportion of lower- and workingclass inner-city residents abuse the hard drugs than is true of more affluent members of the society. More important, this is the case because of the impact of a number of key structural conditions that have their origin in economics and politics (Hamid 1990; Levine 1991; Bourgeois 1995).

The conflict perspective argues that drug dealing is more likely to take root and flourish in poor, powerless, socially disorganized communities than in more affluent, powerful, organized communities. Where residents cannot mobilize the relevant political forces to act against undesirable activities in their midst, open, organized, and widespread drug dealing is extremely likely. In addition, in communities in which poverty is entrenched, the economic structure has never developed or has decayed and collapsed, and a feeling of hopelessness, depression, and anomie is likely to take hold, making drug abuse especially appealing and attractive, providing a means of “escaping from a dreadful condition into one that seems, temporarily at least, more pleasant” (Levine 1991:4). For some, getting high—and getting high frequently—has become an oasis of excitement, pleasure, and fantasy in lives that would otherwise feel psychically impoverished and alienated. Most of the residents of deteriorated communities resist such blandishments. But sufficient numbers succumb to drug abuse to make the lives of the majority unpredictable, insecure, and dangerous. A drug subculture flourishes in response to what some residents have come to see as the hopelessness and despair of the reality of their everyday lives. And it is poverty that generates these feelings. In the words of Harry Gene Levine (1991), “The three most important things to understand about the sources of long-term crack and heroin abuse are: poverty, poverty, poverty” (p. 3).

A crucial assumption of the conflict approach to drug abuse is that there are two overlapping but conceptually distinct forms or varieties of drug use. The first, which makes up the vast majority of illegal users, is “casual” or “recreational” use. It is engaged in by a broad spectrum of the class structure, the middle and upper-middle class included. This type of use ranges from experimental and episodic to regular but controlled use. Such users rarely become a problem for the society except insofar as they are regarded as a problem by others. “Middle class status,” says Harry Gene Levine (1991), “with its benefits and stability, tends to immunize people not against drug use, but against long-term, hard drug use ” (p. 4).

The second type of drug use is abuse—compulsive, chronic, or heavy use—drug use that often escalates to dependence and addiction. It is typically accompanied by social and personal harm. Chronic abuse is motivated by despair, alienation, poverty, and community disintegration. Experts argue that moving from the first type of drug use (recreational) to the second (abuse) is more likely to take place among the impoverished than among the affluent and to be indulged in by residents of disorganized rather than intact communities (Levine 1991).

Two of the largest, most nationally representative, and most valid drug use surveys are conducted in the United States: the National Survey on Drug Use and Health, based on a sample of the population as a whole (SAMHSA 2004), and the Monitoring the Future surveys, based on eighth, tenth, and twelfth graders, college students, and adults not in college of age 19 to 45. The results of these two yearly surveys, verified by others conducted in other countries, support the following generalizations or patterns in drug use.

The first pattern is that for all illicit drugs, experimental use is the rule. Most of the people who try a given illicit drug do not use it regularly; most in fact discontinue its use. The circle circumscribed by the universe of everyone who has ever taken a given drug at least once in their lives is much larger than the circle circumscribed by everyone who has taken it during the previous month.

The second pattern is that for all illicit drugs, irregular, episodic, occasional use is more common than heavy, chronic, compulsive abuse. The circle circumscribed by everyone who has used a given drug, say, less frequently than once a week in the past year is larger than the circle circumscribed by everyone who has used that drug more than 20 times a month—that is, more than 240 times in the past year.

The third pattern is that the use of the legal drugs, alcohol and tobacco, is vastly greater than the use of the illegal drugs. According to the most recent (2003) National Survey on Drug Use and Health, half of all Americans had consumed at least one alcoholic drink in the past month (50.1 percent) and a quarter had smoked one or more tobacco cigarettes (25.4 percent). But only 8 percent had used marijuana in the past 30 days, and just over one-half of 1 percent had used cocaine (0.6 percent).

Moreover—and this is the fourth pattern—the “loyalty” rate, the rate at which onetime users continue to use a drug, and use it regularly, is much greater for the legal drugs than for the illegal drugs. Six persons in 10 who ever drank alcohol (60.2 percent) had done so in the past month, and a third of persons who ever smoked a tobacco cigarette had done so in the past month (37.0 percent). But only one person in seven who had used marijuana at least one time in their lives (15.2 percent), and only 6.5 percent of those who had used cocaine one or more times in their lives did so in the past month. The comparable figures for PCP (0.8 percent) and LSD (0.5 percent) were much lower (SAMHSA 2004:188, 202). The more illicit the drug, the lower the continuance or loyalty rate it attracts among users.

The fifth pattern is that the correlation between the use of legal and illegal drugs is extremely strong. People who use alcohol and tobacco are much more likely to use any and all illicit drugs than people who do not do so. Moreover, the more they use the legal drugs, the greater is the likelihood that they use illegal drugs. Youths ages 12 to 17 who are both smokers and heavy drinkers are 20 times more likely to have used one or more illicit drugs (72.4 percent) than are youths who neither drink nor smoke (3.7 percent). Youths who drink heavily are 100 times more likely to have used cocaine in the past month (10.6 percent) than are nondrinkers (0.1 percent). The same generalizations prevail for all age groups, all drugs, legal and illegal, and all levels of use. The impulse to alter one’s consciousness with one substance—whether legal or illegal— is strongly related to altering it with other substances.

The sixth pattern is this: The use of psychoactive substances is strongly related to a person’s age. Drug use rises sharply from age 12 (the age at which most surveys begin asking respondents such questions) through adolescence, reaches a peak at about age 20, and then declines, year by year, after that. According to the 2003 National Survey on Drug Use and Health, only 2.7 percent of 12-year-olds say that they have used any illegal drug (excepting alcohol) in the past month. This rises to 24 percent for 20-year-olds and declines throughout the 20s and subsequently. It is 13.4 percent for persons in their late 20s (26–29); 8.4 percent for those in their late 30s (35–39); 6.8 percent for those in their late 40s (45–49); and only 2 percent for those in their late 50s. Only 0.6 percent of persons aged 65 or more said that they had used an illicit drug in the past month. For alcohol consumption, this curve is much flatter; the peak in consumption is reached between ages 21 and 22; use declines very slowly until age 60, and drops off more precipitously after that (SAMHSA 2004:193, 207).

The remaining patterns are the following. In addition to the young, and persons who use alcohol and smoke cigarettes, the categories in the population who have significantly higher-than-average likelihoods of using psychoactive substances include males (SAMHSA 2004:194); the unmarried, especially persons who cohabit without being married (Bachman et al. 2002:211–12); adolescents whose plans for the future do not include college (Johnston et al. 2004:452); and the unemployed (SAMHSA 2004:197). The categories in the population whose use of psychoactive substances is lower than the average include females (SAMHSA 2004:194); the married; women who are pregnant and couples with children; and persons who consider religion important in their lives and who frequently attend religious services. Persons who perceive great risks in drug use are more likely to disapprove of it and are less likely to indulge in drug use than are persons who do not perceive great risks in use (Bachman et al. 2002:121–55, 208–209, 211–12, 214–15).

These patterns, taken together, draw a consistent, coherent picture that provides a small number of generalizations about drug use as a form of behavior.

First generalization: Most people tend to be fairly cautious and temperate about their consumption of psychoactive substances. Heavy use is the exception, moderate use is the rule. This moderation extends to the relative avoidance of illicit drugs. Whether it is fear of arrest, the stigma of illegality, its deviant status, the inability to locate a dealer, or fear of physical harm, compared with alcohol and tobacco, the use of illegal drugs is relatively unpopular. And the more “illegal” and more deviant the use of the drug, the rarer its use is, and the less “loyal” users are to its use. The least stigmatized, the least deviant—and the least “criminal”—of the illicit drugs, marijuana, is by far the most popular, and the one users are most likely to “stick with” the longest. For the great majority of Americans— the same applies to the residents of the other countries in which drug surveys have been conducted—illicit drugs have less seductive appeal than do licit drugs.

And the second and closely related generalization: Unconventionality explains much of what we want to know about drug use. (An obvious but crucial point: Unconventionality is a matter of degree; it can be plotted along a continuum.) Unconventionality includes a broad range of associated and cognate characteristics, including experience and sensation seeking, low self-control, impulsivity, and the tendency to take risks. Most people do not take serious risks; hence, most people do not use illicit drugs that are perceived to be dangerous and harmful, and even fewer use them regularly. The minority who do so tend to be more unconventional than the majority who do not. Drug use is an aspect or manifestation of unconventionality. The dimension of unconventionality begs the question of causal origin; unconventionality has a variety of origins, and indeed, stressing its importance is consistent with all the theories spelled out in the foregoing. Certain social statuses foster or engender unconventionality. Their members have relatively few responsibilities, weak ties to conventional society, and few agents of social control monitoring and controlling their behavior, and hence there are relatively few harmful social consequences to the negative aspects of risk-taking. Hence, they are more likely to engage in unconventional, high-risk behavior than are persons in statuses or positions encumbered by stronger conventional social bonds. And people relatively slipped from the bonds of conventionality tend to congregate, thereby increasing the likelihood that they will violate the norms of society.

The late teens to the early 20s represents the peak years of drug use; it is the exact point of the trajectory combining diminished levels of parental supervision and as-yet low levels of adult responsibilities. Males are more likely to have been socialized to take greater risks and to violate the conventional norms of the society; hence, it should come as no surprise that they exhibit consistently higher levels of illicit drug use and heavy alcohol consumption. The unmarried tend to be less bonded to responsibility and convention than the married, and when children appear in the lives of the married, this difference widens—hence, the differences we observe in their illicit drug use. And persons who live together are already more unconventional compared with persons who are legally married; this unconventionality manifests itself in their higher rates of drug use. Adolescents with no college plans have less to lose through risky behavior than do those with plans to attend college—thus, their higher rates of drug use (although this difference decreases the closer the youngster is to actually attending college). The college experience itself generates a large, dense congregation of young people, and thus, college students have similar, or even slightly higher, rates of drug use than do young people who do not attend college, even though the former are more invested in the future than the latter. The more alienated people are from traditional religion, the greater the likelihood is that they use drugs; the more they attend religious services and say that religion is very important in their lives, the lower that likelihood is. Again, unconventionality rears its head in the drug picture. And last, perceived risk is not only a measure of rationality but of unconventionality as well: People who see greater risk in specific activities tend to be more unconventional than those who see less. And the perception of risk—or the lack thereof—is strongly related to drug use.

Drugs: Contemporary Issues and Concerns

The study by sociologists of drug use has become a substantial scholarly endeavor. More broadly, drug use constitutes a large conceptual and topical umbrella that attracts a collection of researchers with extremely diverse interests and concerns. The study of drug use is one of the more diffuse and incoherent fields in existence. Most of its researchers are not sociologists or even social scientists, and much of its data collection was not conducted for theoretical purposes. Drug-use surveys are extremely expensive to conduct, and hence, policy rather than theory tends to guide their direction. Many sociologists currently conducting research on drug use are members of a team made up of specialists working in other fields. Usually, sociologists offer methodological rigor to clinically oriented specialists. Even sociologists working on their own depend on the findings of research conducted by a scattering of nonsociological fields to a degree perhaps unprecedented in any subfield of sociology—these fields include pharmacology and psychopharmacology, medicine, psychiatry, epidemiology, the policy sciences, political science, history, anthropology, criminology, economics, cultural studies, and journalism. Sociologists are in a distinct minority among drug-use researchers. Many of the issues and questions that preoccupy contemporary sociologists of drug use are shaped outside their parent field.

In 2005, I mailed a questionnaire to the 120 members of the Society for the Study of Social Problems (SSSP), the majority of whom are sociologists, who list Drinking and Drugs as one of their division specialties, asking them about the topics that sociologists of drug use are most likely to investigate. Exactly half (60 members or 50 percent) responded. The topics respondents checked as most commonly investigated include the following.

More than half of the respondents of the survey said that policy-related issues are among the most frequently studied topics among sociologists of drug use. This finding is consistent with the work of MacCoun and Reuter (2001), who address much of the research on policy and legal issues. These issues include the consequences of imprisoning drug users and sellers; what other countries are doing about the drug problem; alternatives to strict prohibition; whether and to what extent the “war on drugs” is working, prohibition is causing more problems than it solves, some form of legalization can work; policy alternatives; whether strict prohibition is the best way of dealing with the problems posed by drug abuse; and learning about how to deal with suppressing drug abuse (MacCoun and Reuter 2001). More than half of the respondents (32 out of 60) said that policy-related issues are among the most frequently studied topics among sociologists of drug use.

At least from as far back as the 1930s, the causes of drug use and the distribution of drug use in the population have been a mainstay of sociological research on the abuse of psychoactive substances. Thirty-five of the 60 respondents said that the issues of who uses which drugs and why (Johnston et al. 2004) continue to engage sociological researchers.

Goldstein’s (1985) tripartite “drugs-violence nexus” has stimulated an enormous volume of commentary and research on the topic. In 2001, the National Institute of Justice (NIJ) invited three dozen experts to participate in a symposium titled “Toward a Drugs and Crime Research Agenda for the Twenty-First Century”; the presentations were published in 2003 (www.ojp.usdoj.gov/nij/ pub-sum/194616.htm). Although much work has been conducted in the area, the participants agreed that the drugs-and-crime link is unresolved and needs further research. In spite of the vagaries of funding, roughly threequarters of SSSP drug researchers (46 out of 60) believe that the drugs-crime nexus remains a central sphere of research attention for researchers.

Consistent with previous efforts of Hamid (1990), Bursik and Grasmick (1993), and Bourgeois (1995), 40 percent of the SSSP survey respondents believe the impact of drug use and extensive drug dealing on the viability of a community and whether and to what extent some communities are more vulnerable to the penetration of drug sellers into their midst offers a major topic of interest to sociologists and urban anthropologists who engage in drug research. “Drugs and the Community” is a specifically and distinctly sociological topic, one that has been on the subfield’s agenda for much of the past century.

Many researchers believe that a reliance on imprisonment is ineffective and counterproductive; hence, the research on alternatives, mainly drug treatment programs. The federal government has sponsored three waves of studies on drug treatment, the Drug Abuse Reporting Program (DARP), 1969 to 1972; the Treatment Outcome Prospective Study (TOPS), 1979 to 1981; and the Drug Abuse Treatment Outcome Study (DATOS), 1991 to 1993. These surveys, based on nationally representative samples, indicate that drug treatment is an effective means of addressing drug abuse and addiction. Currently, scores of smaller studies of treatment programs are ongoing. Sociologists continue to play a central role in conducting a substantial portion of these studies, a fact asserted by half (30 out of 60) of the survey respondents. In addition, preventing drug use, mainly by means of educational programs, is on the agenda of some researchers.

Research methods have been on the sociologist’s agenda since the field’s birth, and the study of drug use, which poses special methodological problems, exemplifies this principle, as asserted by a third of the respondents (19 out of 60). The best means of studying drug use and abuse, whether researchers get honest answers when asking respondents about their illicit, deviant behaviors, how the researcher addresses problems of validity and reliability, and how to conduct research among dangerous informants and subjects and access “hidden” populations of users and sellers are major topics that engage the field (Harrison and Hughes 1997; Dunlap and Johnson 1999; Wish et al. 2000).

The predisposition to use drugs does not explain use; it is a necessary but not sufficient condition for use. The availability of drugs is another precondition. How drugs are distributed, how drugs get from Point A to Point B, what is distinctive about buying and selling illicit products, and what the “social world” of the drug seller is like are frequently studied topics among sociologists and urban anthropologists engaged in studying drug use (Williams 1992; Bourgeois 1995; Jacobs 1999). These and related topics have offered intriguing strategic research issues to the drug researcher, a fact attested to by not quite half of our respondents (28 out of 60).

In addition to the forced-choice alternatives I offered, topics the survey respondents spontaneously wrote that attracted current sociological research interest include women and drug use; mothering and drug use; drugs and the family; HIV/AIDS; controlled or “functional” users of illicit drugs; the use of tobacco, especially by teenagers; drugs and health; the dangers of prescription and over-thecounter drugs; and cultural differences in drinking patterns.

Most of the SSSP/Drinking and Drugs Division respondents believe that the topics mentioned in the foregoing will remain on the subfield’s agenda. Furthermore, most respondents who answered the question specified their focus. Policy and legal questions will continue to engage sociologists of drug use, especially the decriminalization of marijuana; medical marijuana; the cost and impact of the “war on drugs,” especially on minorities; drug courts; the efficacy of harm reduction strategies; devising a “saner” drug policy; and control over the legal drug industry. Etiology remains central to the field, especially the impact of inadequate parenting on drug abuse. The effectiveness of drug treatment will continue to be studied, especially early intervention and drug education. The study of drug markets will remain important, including the diffusion of heroin and other narcotics into rural areas and the globalization of drug distribution.

Additional topics that will loom large in the twenty-first century include women and drug use; abuses by the pharmaceutical industry; teenagers and alcohol consumption; narcoterrorism; the spread of HIV/AIDS; the impact of drug abuse on the family; the use of performance-enhancing drugs; the use of drugs at work; drugs and health care; the use of medications and the development of neurological stimulation as a means of controlling deviant behavior; the reentry of released inmates into the general population; the misuse of prescription drugs; and smoking behavior and policies designed to control it.

Regardless of whether these predictions of future research enterprises will be borne out, the small, extremely eclectic field of the sociology of drug use will remain a dynamic component of drug-use research. Moreover, in the future, as in the present and the past, policy issues will influence the direction that research takes. In addition, sociologists of drug use will continue to be influenced by drug researchers in other disciplines more than they influence the field of sociology. A policy-oriented focus, theoretical eclecticism, interdisciplinary research, and the image of narrow specialization are the price the sociologist of drug use has to pay for conducting research on one of the most fascinating—and distinctively sociological—of human behaviors.

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Title: nutrition facts, drug facts, and model facts: putting ai ethics into practice in gun violence research.

Abstract: Objective: Firearm injury research necessitates using data from often-exploited vulnerable populations of Black and Brown Americans. In order to minimize distrust, this study provides a framework for establishing AI trust and transparency with the general population. Methods: We propose a Model Facts template that is easily extendable and decomposes accuracy and demographics into standardized and minimally complex values. This framework allows general users to assess the validity and biases of a model without diving into technical model documentation. Examples: We apply the Model Facts template on two previously published models, a violence risk identification model and a suicide risk prediction model. We demonstrate the ease of accessing the appropriate information when the data is structured appropriately. Discussion: The Model Facts template is limited in its current form to human based data and biases. Like nutrition facts, it also will require some educational resources for users to grasp its full utility. Human computer interaction experiments should be conducted to ensure that the interaction between user interface and model interface is as desired. Conclusion: The Model Facts label is the first framework dedicated to establishing trust with end users and general population consumers. Implementation of Model Facts into firearm injury research will provide public health practitioners and those impacted by firearm injury greater faith in the tools the research provides.

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Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials

Linked editorial.

Exercise for the treatment of depression

  • Related content
  • Peer review
  • Michael Noetel , senior lecturer 1 ,
  • Taren Sanders , senior research fellow 2 ,
  • Daniel Gallardo-Gómez , doctoral student 3 ,
  • Paul Taylor , deputy head of school 4 ,
  • Borja del Pozo Cruz , associate professor 5 6 ,
  • Daniel van den Hoek , senior lecturer 7 ,
  • Jordan J Smith , senior lecturer 8 ,
  • John Mahoney , senior lecturer 9 ,
  • Jemima Spathis , senior lecturer 9 ,
  • Mark Moresi , lecturer 4 ,
  • Rebecca Pagano , senior lecturer 10 ,
  • Lisa Pagano , postdoctoral fellow 11 ,
  • Roberta Vasconcellos , doctoral student 2 ,
  • Hugh Arnott , masters student 2 ,
  • Benjamin Varley , doctoral student 12 ,
  • Philip Parker , pro vice chancellor research 13 ,
  • Stuart Biddle , professor 14 15 ,
  • Chris Lonsdale , deputy provost 13
  • 1 School of Psychology, University of Queensland, St Lucia, QLD 4072, Australia
  • 2 Institute for Positive Psychology and Education, Australian Catholic University, North Sydney, NSW, Australia
  • 3 Department of Physical Education and Sport, University of Seville, Seville, Spain
  • 4 School of Health and Behavioural Sciences, Australian Catholic University, Strathfield, NSW, Australia
  • 5 Department of Clinical Biomechanics and Sports Science, University of Southern Denmark, Odense, Denmark
  • 6 Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, University of Cádiz, Spain
  • 7 School of Health and Behavioural Sciences, University of the Sunshine Coast, Petrie, QLD, Australia
  • 8 School of Education, University of Newcastle, Callaghan, NSW, Australia
  • 9 School of Health and Behavioural Sciences, Australian Catholic University, Banyo, QLD, Australia
  • 10 School of Education, Australian Catholic University, Strathfield, NSW, Australia
  • 11 Australian Institute of Health Innovation, Macquarie University, Macquarie Park, NSW, Australia
  • 12 Children’s Hospital Westmead Clinical School, University of Sydney, Westmead, NSW, Australia
  • 13 Australian Catholic University, North Sydney, NSW, Australia
  • 14 Centre for Health Research, University of Southern Queensland, Springfield, QLD, Australia
  • 15 Faculty of Sport and Health Science, University of Jyvaskyla, Jyvaskyla, Finland
  • Correspondence to: M Noetel m.noetel{at}uq.edu.au (or @mnoetel on Twitter)
  • Accepted 15 January 2024

Objective To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions.

Design Systematic review and network meta-analysis.

Methods Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool.

Data sources Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases.

Eligibility criteria for selecting studies Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression.

Results 218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges’ g −0.62, 95% credible interval −0.80 to −0.45), yoga (n=1047, κ=33, g −0.55, −0.73 to −0.36), strength training (n=643, κ=22, g −0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g −0.43, −0.61 to −0.24), and tai chi or qigong (n=343, κ=12, g −0.42, −0.65 to −0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments.

Conclusions Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression.

Systematic review registration PROSPERO CRD42018118040.

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Introduction

Major depressive disorder is a leading cause of disability worldwide 1 and has been found to lower life satisfaction more than debt, divorce, and diabetes 2 and to exacerbate comorbidities, including heart disease, 3 anxiety, 4 and cancer. 5 Although people with major depressive disorder often respond well to drug treatments and psychotherapy, 6 7 many are resistant to treatment. 8 In addition, access to treatment for many people with depression is limited, with only 51% treatment coverage for high income countries and 20% for low and lower-middle income countries. 9 More evidence based treatments are therefore needed.

Exercise may be an effective complement or alternative to drugs and psychotherapy. 10 11 12 13 14 In addition to mental health benefits, exercise also improves a range of physical and cognitive outcomes. 15 16 17 Clinical practice guidelines in the US, UK, and Australia recommend physical activity as part of treatment for depression. 18 19 20 21 But these guidelines do not provide clear, consistent recommendations about dose or exercise modality. British guidelines recommend group exercise programmes 20 21 and offer general recommendations to increase any form of physical activity, 21 the American Psychiatric Association recommends any dose of aerobic exercise or resistance training, 20 and Australian and New Zealand guidelines suggest a combination of strength and vigorous aerobic exercises, with at least two or three bouts weekly. 19

Authors of guidelines may find it hard to provide consistent recommendations on the basis of existing mainly pairwise meta-analyses—that is, assessing a specific modality versus a specific comparator in a distinct group of participants. 12 13 22 These meta-analyses have come under scrutiny for pooling heterogeneous treatments and heterogenous comparisons leading to ambiguous effect estimates. 23 Reviews also face the opposite problem, excluding exercise treatments such as yoga, tai chi, and qigong because grouping them with strength training might be inappropriate. 23 Overviews of reviews have tried to deal with this problem by combining pairwise meta-analyses on individual treatments. A recent such overview found no differences between exercise modalities. 13 Comparing effect sizes between different pairwise meta-analyses can also lead to confusion because of differences in analytical methods used between meta-analysis, such as choice of a control to use as the referent. Network meta-analyses are a better way to precisely quantify differences between interventions as they simultaneously model the direct and indirect comparisons between interventions. 24

Network meta-analyses have been used to compare different types of psychotherapy and pharmacotherapy for depression. 6 25 26 For exercise, they have shown that dose and modality influence outcomes for cognition, 16 back pain, 15 and blood pressure. 17 Two network meta-analyses explored the effects of exercise on depression: one among older adults 27 and the other for mental health conditions. 28 Because of the inclusion criteria and search strategies used, these reviews might have been under-powered to explore moderators such as dose and modality (κ=15 and κ=71, respectively). To resolve conflicting findings in existing reviews, we comprehensively searched randomised trials on exercise for depression to ensure our review was adequately powered to identify the optimal dose and modality of exercise. For example, a large overview of reviews found effects on depression to be proportional to intensity, with vigorous exercise appearing to be better, 13 but a later meta-analysis found no such effects. 22 We explored whether recommendations differ based on participants’ sex, age, and baseline level of depression.

Given the challenges presented by behaviour change in people with depression, 29 we also identified autonomy support or behaviour change techniques that might improve the effects of intervention. 30 Behaviour change techniques such as self-monitoring and action planning have been shown to influence the effects of physical activity interventions in adults (>18 years) 31 and older adults (>60 years) 32 with differing effectiveness of techniques in different populations. We therefore tested whether any intervention components from the behaviour change technique taxonomy were associated with higher or lower intervention effects. 30 Other meta-analyses found that physical activity interventions work better when they provide people with autonomy (eg, choices, invitational language). 33 Autonomy is not well captured in the taxonomy for behaviour change technique. We therefore tested whether effects were stronger in studies that provided more autonomy support to patients. Finally, to understand the mechanism of intervention effects, such as self-confidence, affect, and physical fitness, we collated all studies that conducted formal mediation analyses.

Our findings are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Network Meta-analyses (PRISMA-NMA) guidelines (see supplementary file, section S0; all supplementary files, data, and code are also available at https://osf.io/nzw6u/ ). 34 We amended our analysis strategy after registering our review; these changes were to better align with new norms established by the Cochrane Comparing Multiple Interventions Methods Group. 35 These norms were introduced between the publication of our protocol and the preparation of this manuscript. The largest change was using the confidence in network meta-analysis (CINeMA) 35 online tool instead of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines and adopting methods to facilitate assessments—for example, instead of using an omnibus test for all treatments, we assessed publication bias for each treatment compared with active controls. We also modelled acceptability (through dropout rate), which was not predefined but was adopted in response to a reviewer’s comment.

Eligibility criteria

To be eligible for inclusion, studies had to be randomised controlled trials that included exercise as a treatment for depression and included participants who met the criteria for major depressive disorder, either clinician diagnosed or identified through participant self-report as exceeding established clinical thresholds (eg, scored >13 on the Beck depression inventory-II). 36 Studies could meet these criteria when all the participants had depression or when the study reported depression outcomes for a subgroup of participants with depression at the start of the study.

We defined exercise as “planned, structured and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” 37 Unlike recent reviews, 12 22 we included studies with more than one exercise arm and multifaceted interventions (eg, health and exercise counselling) as long as they contained a substantial exercise component. These trials could be included because network meta-analysis methods allows for the grouping of those interventions into homogenous nodes. Unlike the most recent Cochrane review, 12 we also included participants with physical comorbidities such as arthritis and participants with postpartum depression because the Diagnostic Statistical Manual of Mental Health Disorders , fifth edition, removed the postpartum onset specifier after that analysis was completed. 23 Studies were excluded if interventions were shorter than one week, depression was not reported as an outcome, and data were insufficient to calculate an effect size for each arm. Any comparison condition was included, allowing us to quantify the effects against established treatments (eg, selective serotonin reuptake inhibitors (SSRIs), cognitive behavioural therapy), active control conditions (usual care, placebo tablet, stretching, educational control, and social support), or waitlist control conditions. Published and unpublished studies were included, with no restrictions on language applied.

Information sources

We adapted the search strategy from the most recent Cochrane review, 12 adding keywords for yoga, tai chi, and qigong, as they met our definition for exercise. We conducted database searches, without filters or date limits, in The Cochrane Library via CENTRAL, SPORTDiscus via Embase, and Medline, Embase, and PsycINFO via Ovid. Searches of the databases were conducted on 17 December 2018 and 7 August 2020 and last updated on 3 June 2023 (see supplementary file section S1 for full search strategies). We assessed full texts of all included studies from two systematic reviews of exercise for depression. 12 22

Study selection and data collection

To select studies, we removed duplicate records in Covidence 38 and then screened each title and abstract independently and in duplicate. Conflicts were resolved through discussion or consultation with a third reviewer. The same methods were used for full text screening.

We used the Extraction 1.0 randomised controlled trial data extraction forms in Covidence. 38 Data were extracted independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

For each study, we extracted a description of the interventions, including frequency, intensity, and type and time of each exercise intervention. Using the Compendium of Physical Activities, 39 we calculated the energy expenditure dose of exercise for each arm as metabolic equivalents of task (METs) min/week. Two authors evaluated each exercise intervention using the Behaviour Change Taxonomy version 1 30 for behaviour change techniques explicitly described in each exercise arm. They also rated the level of autonomy offered to participants, on a scale from 1 (no choice) to 10 (full autonomy). We also extracted descriptions of the other arms within the randomised trials, including other treatment or control conditions; participants’ age, sex, comorbidities, and baseline severity of depressive symptoms; and each trial’s location and whether or not the trial was funded.

Risk of bias in individual studies

We used Cochrane’s risk of bias tool for randomised controlled trials. 40 Risk of bias was rated independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

Summary measures and synthesis

For main and moderation analyses, we used bayesian arm based multilevel network meta-analysis models. 41 All network meta-analytical approaches allow users to assess the effects of treatments against a range of comparisons. The bayesian arm based models allowed us to also assess the influence of hypothesised moderators, such as intensity, dose, age, and sex. Many network meta-analyses use contrast based methods, comparing post-test scores between study arms. 41 Arm based meta-analyses instead describe the population-averaged absolute effect size for each treatment arm (ie, each arm’s change score). 41 As a result, the summary measure we used was the standardised mean change from baseline, calculated as standardised mean differences with correction for small studies (Hedges’ g). In keeping with the norms from the included studies, effect sizes describe treatment effects on depression, such that larger negative numbers represent stronger effects on symptoms. Using National Institute for Health and Care Excellence guidelines, 42 we standardised change scores for different depression scales (eg, Beck depression inventory, Hamilton depression rating scale) using an internal reference standard for each scale (for each scale, the average of pooled standard deviations at baseline) reported in our meta-analysis. Because depression scores generally show regression to the mean, even in control conditions, we present effect sizes as improvements beyond active control conditions. This convention makes our results comparable to existing, contrast based meta-analyses.

Active control conditions (usual care, placebo tablet, stretching, educational control, and social support) were grouped to increase power for moderation analyses, for parsimony in the network graph, and because they all showed similar arm based pooled effect sizes (Hedges’ g between −0.93 and −1.00 for all, with no statistically significant differences). We separated waitlist control from these active control conditions because it typically shows poorer effects in treatment for depression. 43

Bayesian meta-analyses were conducted in R 44 using the brms package. 45 We preregistered informative priors based on the distributional parameters of our meta-analytical model. 46 We nested effects within arms to manage dependency between multiple effect sizes from the same participants. 46 For example, if one study reported two self-reported measures of depression, or reported both self-report and clinician rated depression, we nested these effect sizes within the arm to account for both pieces of information while controlling for dependency between effects. 46 Finally, we compared absolute effect sizes against a standardised minimum clinically important difference, 0.5 standard deviations of the change score. 47 From our data, this corresponded to a large change in before and after scores (Hedges’ g −1.16), a moderate change compared with waitlist control (g −0.55), or a small benefit when compared with active controls (g −0.20). For credibility assessments comparing exercise modalities, we used the netmeta package 48 and CINeMA. 49 We also used netmeta to model acceptability, comparing the odds ratio for drop-out rate in each arm.

Additional analyses

All prespecified moderation and sensitivity analyses were performed. We moderated for participant characteristics, including participants’ sex, age, baseline symptom severity, and presence or absence of comorbidities; duration of the intervention (weeks); weekly dose of the intervention; duration between completion of treatment and measurement, to test robustness to remission (in response to a reviewer’s suggestion); amount of autonomy provided in the exercise prescription; and presence of each behaviour change technique. As preregistered, we moderated for behaviour change techniques in three ways: through meta-regression, including all behaviour change techniques simultaneously for primary analysis; including one behaviour change technique at a time (using 99% credible intervals to somewhat control for multiple comparisons) in exploratory analyses; and through meta-analytical classification and regression trees (metaCART), which allowed for interactions between moderating variables (eg, if goal setting combined with feedback had synergistic effects). 50 We conducted sensitivity analyses for risk of bias, assessing whether studies with low versus unclear or high risk of bias on each domain showed statistically significant differences in effect sizes.

Credibility assessment

To assess the credibility of each comparison against active control, we used CINeMA. 35 49 This online tool was designed by the Cochrane Comparing Multiple Interventions Methods Group as an adaptation of GRADE for network meta-analyses. 35 In line with recommended guidelines, for each comparison we made judgements for within study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Similar to GRADE, we considered the evidence for comparisons to show high confidence then downgraded on the basis of concerns in each domain, as follows:

Within study bias —Comparisons were downgraded when most of the studies providing direct evidence for comparisons were unclear or high risk.

Reporting bias —Publication bias was assessed in three ways. For each comparison with at least 10 studies 51 we created funnel plots, including estimates of effect sizes after removing studies with statistically significant findings (ie, worst case estimates) 52 ; calculated an s value, representing how strong publication bias would need to be to nullify meta-analytical effects 52 ; and conducted a multilevel Egger’s regression test, indicative of small study bias. Given these tests are not recommended for comparisons with fewer than 10 studies, 51 those comparisons were considered to show “some concerns.”

Indirectness — Our primary population of interest was adults with major depression. Studies were considered to be indirect if they focused on one sex only (>90% male or female), participants with comorbidities (eg, heart disease), adolescents and young adults (14-20 years), or older adults (>60 years). We flagged these studies as showing some concerns if one of these factors was present, and as “major concerns” if two of these factors were present. Evidence from comparisons was classified as some concerns or major concerns using majority rating for studies directly informing the comparison.

Imprecision — As per CINeMA, we used the clinically important difference of Hedges’ g=0.2 to ascribe a zone of equivalence, where differences were not considered clinically significant (−0.2<g<0.2). Studies were flagged as some concerns for imprecision if the bounds of the 95% credible interval extended across that zone, and they were flagged as major concerns if the bounds extended to the other side of the zone of equivalence (such that effects could be harmful).

Heterogeneity — Prediction intervals account for heterogeneity differently from credible intervals. 35 As a result, CINeMA accounts for heterogeneity by assessing whether the prediction intervals and the credible intervals lead to different conclusions about clinical significance (using the same zone of equivalence from imprecision). Comparisons are flagged as some concerns if the prediction interval crosses into, or out of, the zone of equivalence once (eg, from helpful to no meaningful effect), and as major concerns if the prediction interval crosses the zone twice (eg, from helpful and harmful).

Incoherence — Incoherence assesses whether the network meta-analysis provides similar estimates when using direct evidence (eg, randomised controlled trials on strength training versus SSRI) compared with indirect evidence (eg, randomised controlled trials where either strength training or SSRI uses waitlist control). Incoherence provides some evidence the network may violate the assumption of transitivity: that the only systematic difference between arms is the treatment, not other confounders. We assessed incoherence using two methods: Firstly, a global design-by-treatment interaction to assess for incoherence across the whole network, 35 49 and, secondly, separating indirect and direct evidence (SIDE method) for each comparison through netsplitting to see whether differences between those effect estimates were statistically significant. We flagged comparisons as some concerns if either no direct comparisons were available or direct and indirect evidence gave different conclusions about clinical significance (eg, from helpful to no meaningful effect, as per imprecision and heterogeneity). Again, we classified comparisons as major concerns if the direct and indirect evidence changed the sign of the effect or changed both limits of the credible interval. 35 49

Patient and public involvement

We discussed the aims and design of this study with members of the public, including those who had experienced depression. Several of our authors have experienced major depressive episodes, but beyond that we did not include patients in the conduct of this review.

Study selection

The PRISMA flow diagram outlines the study selection process ( fig 1 ). We used two previous reviews to identify potentially eligible studies for inclusion. 12 22 Database searches identified 18 658 possible studies. After 5505 duplicates had been removed, two reviewers independently screened 13 115 titles and abstracts. After screening, two reviewers independently reviewed 1738 full text articles. Supplementary file section S2 shows the consensus reasons for exclusion. A total of 218 unique studies described in 246 reports were included, totalling 495 arms and 14 170 participants. Supplementary file section S3 lists the references and characteristics of the included studies.

Fig 1

Flow of studies through review

Network geometry

As preregistered, we removed nodes with fewer than 100 participants. Using this filter, most interventions contained comparisons with at least four other nodes in the network geometry ( fig 2 ). The results of the global test design-by-treatment interaction model were not statistically significant, supporting the assumption of transitivity (χ 2 =94.92, df=75, P=0.06). When net-splitting was used on all possible combinations in the network, for two out of the 120 comparisons we found statistically significant incoherence between direct and indirect evidence (SSRI v waitlist control; cognitive behavioural therapy v tai chi or qigong). Overall, we found little statistical evidence that the model violated the assumption of transitivity. Qualitative differences were, however, found for participant characteristics between different arms (see supplementary file, section S4). For example, some interventions appeared to be prescribed more frequently among people with severe depression (eg, 7/16 studies using SSRIs) compared with other interventions (eg, 1/15 studies using aerobic exercise combined with therapy). Similarly, some interventions appeared more likely to be prescribed for older adults (eg, mean age, tai chi=59 v dance=31) or women (eg, per cent female: dance=88% v cycling=53%). Given that plausible mechanisms exist for these systematic differences (eg, the popularity of tai chi among older adults), 53 there are reasons to believe that allocation to treatment arms would be less than perfectly random. We have factored these biases in our certainty estimates through indirectness ratings.

Fig 2

Network geometry indicating number of participants in each arm (size of points) and number of comparisons between arms (thickness of lines). SSRI=selective serotonin reuptake inhibitor

Risk of bias within studies

Supplementary file section S5 provides the risk of bias ratings for each study. Few studies explicitly blinded participants and staff ( fig 3 ). As a result, overall risk of bias for most studies was unclear or high, and effect sizes could include expectancy effects, among other biases. However, sensitivity analyses suggested that effect sizes were not influenced by any risk of bias criteria owing to wide credible intervals (see supplementary file, section S6). Nevertheless, certainty ratings for all treatments arms were downgraded owing to high risk of bias in the studies informing the comparison.

Fig 3

Risk of bias summary plot showing percentage of included studies judged to be low, unclear, or high risk across Cochrane criteria for randomised trials

Synthesis of results

Supplementary file section S7 presents a forest plot of Hedges’ g values for each study. Figure 4 shows the predicted effects of each treatment compared with active controls. Compared with active controls, large reductions in depression were found for dance (n=107, κ=5, Hedges’ g −0.96, 95% credible interval −1.36 to −0.56) and moderate reductions for walking or jogging (n=1210, κ=51, g −0.63, −0.80 to −0.46), yoga (n=1047, κ=33, g=−0.55, −0.73 to −0.36), strength training (n=643, κ=22, g=−0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g=−0.43, −0.61 to −0.25), and tai chi or qigong (n=343, κ=12, g=−0.42, −0.65 to −0.21). Moderate, clinically meaningful effects were also present when exercise was combined with SSRIs (n=268, κ=11, g=−0.55, −0.86 to −0.23) or aerobic exercise was combined with psychotherapy (n=404, κ=15, g=−0.54, −0.76 to −0.32). All these treatments were significantly stronger than the standardised minimum clinically important difference compared with active control (g=−0.20), equating to an absolute g value of −1.16. Dance, exercise combined with SSRIs, and walking or jogging were the treatments most likely to perform best when modelling the surface under the cumulative ranking curve ( fig 4 ). For acceptability, the odds of participants dropping out of the study were lower for strength training (n=247, direct evidence κ=6, odds ratio 0.55, 95% credible interval 0.31 to 0.99) and yoga (n=264, κ=5, 0.57, 0.35 to 0.94) than for active control. The rate of dropouts was not significantly different from active control in any other arms (see supplementary file, section S8).

Fig 4

Predicted effects of different exercise modalities on major depression compared with active controls (eg, usual care), with 95% credible intervals. The estimate of effects for the active control condition was a before and after change of Hedges’ g of −0.95 (95% credible interval −1.10 to −0.79), n=3554, κ =113. Colour represents SUCRA from most likely to be helpful (dark purple) to least likely to be helpful (light purple). SSRI=selective serotonin reuptake inhibitor; SUCRA=surface under the cumulative ranking curve

Consistent with other meta-analyses, effects were moderate for cognitive behaviour therapy alone (n=712, κ=20, g=−0.55, −0.75 to −0.37) and small for SSRIs (n=432, κ=16, g=−0.26, −0.50 to −0.01) compared with active controls ( fig 4 ). These estimates are comparable to those of reviews that focused directly on psychotherapy (g=−0.67, −0.79 to −0.56) 7 or pharmacotherapy (g=−0.30, –0.34 to −0.26). 25 However, our review was not designed to find all studies of these treatments, so these estimates should not usurp these directly focused systematic reviews.

Despite the large number of studies in the network, confidence in the effects were low ( fig 5 ). This was largely due to the high within study bias described in the risk of bias summary plot. Reporting bias was also difficult to robustly assess because direct comparison with active control was often only provided in fewer than 10 studies. Many studies focused on one sex only, older adults, or those with comorbidities, so most arms had some concerns about indirect comparisons. Credible intervals were seldom wide enough to change decision making, so concerns about imprecision were few. Heterogeneity did plausibly change some conclusions around clinical significance. Few studies showed problematic incoherence, meaning direct and indirect evidence usually agreed. Overall, walking or jogging had low confidence, with other modalities being very low.

Fig 5

Summary table for credibility assessment using confidence in network meta-analysis (CINeMA). SSRI=selective serotonin reuptake inhibitor

Moderation by participant characteristics

The optimal modality appeared to be moderated by age and sex. Compared with models that only included exercise modality (R 2 =0.65), R 2 was higher for models that included interactions with sex (R 2 =0.71) and age (R 2 =0.69). R 2 showed no substantial increase for models including baseline depression (R 2 =0.67) or comorbidities (R 2 =0.66; see supplementary file, section S9).

Effects appeared larger for women than men for strength training and cycling ( fig 6 ). Effects appeared to be larger for men than women when prescribing yoga, tai chi, and aerobic exercise alongside psychotherapy. Yoga and aerobic exercise alongside psychotherapy appeared more effective for older participants than younger people ( fig 7 ). Strength training appeared more effective when prescribed to younger participants than older participants. Some estimates were associated with substantial uncertainty because some modalities were not well studied in some groups (eg, tai chi for younger adults), and mean age of the sample was only available for 71% of the studies.

Fig 6

Effects of interventions versus active control on depression (lower is better) by sex. Shading represents 95% credible intervals

Fig 7

Effects of interventions versus active control on depression (lower is better) by age. Shading represents 95% credible intervals

Moderation by intervention and design characteristics

Across modalities, a clear dose-response curve was observed for intensity of exercise prescribed ( fig 8 ). Although light physical activity (eg, walking, hatha yoga) still provided clinically meaningful effects (g=−0.58, −0.82 to −0.33), expected effects were stronger for vigorous exercise (eg, running, interval training; g=−0.74, −1.10 to −0.38). This finding did not appear to be due to increased weekly energy expenditure: credible intervals were wide, which meant that the dose-response curve for METs/min prescribed per week was unclear (see supplementary file, section S10). Weak evidence suggested that shorter interventions (eg, 10 weeks: g=−0.53, −0.71 to −0.35) worked somewhat better than longer ones (eg, 30 weeks: g=−0.37, −0.79 to 0.03), with wide credible intervals again indicating high uncertainty (see supplementary file, section S11). We also moderated for the lag between the end of treatment and the measurement of the outcome. We found no indication that participants were likely to relapse within the measurement period (see supplementary file, section S12); effects remained steady when measured either directly after the intervention (g=−0.59, −0.80 to −0.39) or up to six months later (g=−0.63, −0.87 to −0.40).

Fig 8

Dose-response curve for intensity (METs) across exercise modalities compared with active control. METs=metabolic equivalents of task

Supplementary file section S13 provides coding for the behaviour change techniques and autonomy for each exercise arm. None of the behaviour change techniques significantly moderated overall effects. Contrary to expectations, studies describing a level of participant autonomy (ie, choice over frequency, intensity, type, or time) tended to show weaker effects (g=−0.28, −0.78 to 0.23) than those that did not (g=−0.75, −1.17 to −0.33; see supplementary file, section S14). This effect was consistent whether or not we included studies that used physical activity counselling (usually high autonomy).

Use of group exercise appeared to moderate the effects: although the overall effects were similar for individual (g=−1.10, −1.57 to −0.64) and group exercise (g=−1.16, −1.61 to −0.73), some interventions were better delivered in groups (yoga) and some were better delivered individually (strength training, mixed aerobic exercise; see supplementary file, section S15).

As preregistered, we tested whether study funding moderated effects. Models that included whether a study was funded did explain more variance (R 2 =0.70) compared with models that included treatment alone (R 2 =0.65). Funded studies showed stronger effects (g=−1.01, −1.19 to −0.82) than unfunded studies (g=−0.77, −1.09 to −0.46). We also moderated for the type of measure (self-report v clinician report). This did not explain a substantial amount of variance in the outcome (R 2 =0.66).

Sensitivity analyses

Evidence of publication bias was found for overall estimates of exercise on depression compared with active controls, although not enough to nullify effects. The multilevel Egger’s test showed significance (F 1,98 =23.93, P<0.001). Funnel plots showed asymmetry, but the result of pooled effects remained statistically significant when only including non-significant studies (see supplementary file, section S16). No amount of publication bias would be sufficient to shrink effects to zero (s value=not possible). To reduce effects below clinical significance thresholds, studies with statistically significant results would need to be reported 58 times more frequently than studies with non-significant results.

Qualitative synthesis of mediation effects

Only a few of the studies used explicit mediation analyses to test hypothesised mechanisms of action. 54 55 56 57 58 59 One study found that both aerobic exercise and yoga led to decreased depression because participants ruminated less. 54 The study found that the effects of aerobic exercise (but not yoga) were mediated by increased acceptance. 54 “Perceived hassles” and awareness were not statistically significant mediators. 54 Another study found that the effects of yoga were mediated by increased self-compassion, but not rumination, self-criticism, tolerance of uncertainty, body awareness, body trust, mindfulness, and attentional biases. 55 One study found that the effects from an aerobic exercise intervention were not mediated by long term physical activity, but instead were mediated by exercise specific affect regulation (eg, self-control for exercise). 57 Another study found that neither exercise self-efficacy nor depression coping self-efficacy mediated effects of aerobic exercise. 56 Effects of aerobic exercise were not mediated by the N2 amplitude from electroencephalography, hypothesised as a neuro-correlate of cognitive control deficits. 58 Increased physical activity did not appear to mediate the effects of physical activity counselling on depression. 59 It is difficult to infer strong conclusions about mechanisms on the basis of this small number of studies with low power.

Summary of evidence

In this systematic review and meta-analysis of randomised controlled trials, exercise showed moderate effects on depression compared with active controls, either alone or in combination with other established treatments such as cognitive behaviour therapy. In isolation, the most effective exercise modalities were walking or jogging, yoga, strength training, and dancing. Although walking or jogging were effective for both men and women, strength training was more effective for women, and yoga or qigong was more effective for men. Yoga was somewhat more effective among older adults, and strength training was more effective among younger people. The benefits from exercise tended to be proportional to the intensity prescribed, with vigorous activity being better. Benefits were equally effective for different weekly doses, for people with different comorbidities, or for different baseline levels of depression. Although confidence in many of the results was low, treatment guidelines may be overly conservative by conditionally recommending exercise as complementary or alternative treatment for patients in whom psychotherapy or pharmacotherapy is either ineffective or unacceptable. 60 Instead, guidelines for depression ought to include prescriptions for exercise and consider adapting the modality to participants’ characteristics and recommending more vigorous intensity exercises.

Our review did not uncover clear causal mechanisms, but the trends in the data are useful for generating hypotheses. It is unlikely that any single causal mechanism explains all the findings in the review. Instead, we hypothesise that a combination of social interaction, 61 mindfulness or experiential acceptance, 62 increased self-efficacy, 33 immersion in green spaces, 63 neurobiological mechanisms, 64 and acute positive affect 65 combine to generate outcomes. Meta-analyses have found each of these factors to be associated with decreases in depressive symptoms, but no single treatment covers all mechanisms. Some may more directly promote mindfulness (eg, yoga), be more social (eg, group exercise), be conducted in green spaces (eg, walking), provide a more positive affect (eg, “runner’s high”’), or be more conducive to acute adaptations that may increase self-efficacy (eg, strength). 66 Exercise modalities such as running may satisfy many of the mechanisms, but they are unlikely to directly promote the mindful self-awareness provided by yoga and qigong. Both these forms of exercise are often practised in groups with explicit mindfulness but seldom have fast and objective feedback loops that improve self-efficacy. Adequately powered studies testing multiple mediators may help to focus more on understanding why exercise helps depression and less on whether exercise helps. We argue that understanding these mechanisms of action is important for personalising prescriptions and better understanding effective treatments.

Our review included more studies than many existing reviews on exercise for depression. 13 22 27 28 As a result, we were able to combine the strengths of various approaches to exercise and to make more nuanced and precise conclusions. For example, even taking conservative estimates (ie, the least favourable end of the credible interval), practitioners can expect patients to experience clinically significant effects from walking, running, yoga, qigong, strength training, and mixed aerobic exercise. Because we simultaneously assessed more than 200 studies, credible intervals were narrower than those in most existing meta-analyses. 13 We were also able to explore non-linear relationships between outcomes and moderators, such as frequency, intensity, and time. These analyses supported some existing findings—for example, our study and the study by Heissel et al 22 found that shorter interventions had stronger effects, at least for six months; our study and the study by Singh et al 13 both found that effects were stronger with vigorous intensity exercise compared with light and moderate exercise. However, most existing reviews found various treatment modalities to be equally effective. 13 27 In our review, some types of exercise had stronger effect sizes than others. We attribute this to the study level data available in a network meta-analysis compared with an overview of reviews 24 and higher power compared with meta-analyses with smaller numbers of included studies. 22 28 Overviews of reviews have the ability to more easily cover a wider range of participants, interventions, and outcomes, but also risk double counting randomised trials that are included in separate meta-analyses. They often include heterogeneous studies without having as much control over moderation analyses (eg, Singh et al included studies covering both prevention and treatment 13 ). Some of those reviews grouped interventions such as yoga with heterogeneous interventions such as stretching and qigong. 13 This practise of combining different interventions makes it harder to interpret meta-analytical estimates. We used methods that enabled us to separately analyse the effects of these treatment modalities. In so doing, we found that these interventions do have different effects, with yoga being an intervention with strong effects and stretching being better described as an active control condition. Network meta-analyses revealed the same phenomenon with psychotherapy: researchers once concluded there was a dodo bird verdict, whereby “everybody has won, and all must have prizes,” 67 until network meta-analyses showed some interventions were robustly more effective than others. 6 26

Predictors of acceptability and outcomes

We found evidence to suggest good acceptability of yoga and strength training; although the measurement of study drop-out is an imperfect proxy of adherence. Participants may complete the study without doing any exercise or may continue exercising and drop out of the study for other reasons. Nevertheless, these are useful data when considering adherence.

Behaviour change techniques, which are designed to increase adherence, did not meaningfully moderate the effect sizes from exercise. This may be due to several factors. It may be that the modality explains most of the variance between effects, such that behaviour change techniques (eg, presence or absence of feedback) did not provide a meaningful contribution. Many forms of exercise potentially contain therapeutic benefits beyond just energy expenditure. These characteristics of a modality may be more influential than coexisting behaviour change techniques. Alternatively, researchers may have used behaviour change techniques such as feedback or goal setting without explicitly reporting them in the study methods. Given the inherent challenges of behaviour change among people with depression, 29 and the difficulty in forecasting which strategies are likely to be effective, 68 we see the identification of effective techniques as important.

We did find that autonomy, as provided in the methods of included studies, predicted effects, but in the opposite direction to our hypotheses: more autonomy was associated with weaker effects. Physical activity counselling, which usually provides a great deal of patient autonomy, was among the lowest effect sizes in our meta-analysis. Higher autonomy judgements were associated with weaker outcomes regardless of whether physical activity counselling was included in the model. One explanation for these data is that people with depression benefit from the clear direction and accountability of a standardised prescription. When provided with more freedom, the low self-efficacy that is symptomatic of depression may stop patients from setting an appropriate level of challenge (eg, they may be less likely to choose vigorous exercise). Alternatively, participants were likely autonomous when self-selecting into trials with exercise modalities they enjoyed, or those that fit their social circumstances. After choosing something value aligned, autonomy within the trial may not have helpful. Either way, data should be interpreted with caution. Our judgement of the autonomy provided in the methods may not reflect how much autonomy support patients actually felt. The patient’s perceived autonomy is likely determined by a range of factors not described in the methods (eg, the social environment created by those delivering the programme, or their social identity), so other studies that rely on patient reports of the motivational climate are likely to be more reliable. 33 Our findings reiterate the importance of considering these patient reports in future research of exercise for depression.

Our findings suggest that practitioners could advocate for most patients to engage in exercise. Those patients may benefit from guidance on intensity (ie, vigorous) and types of exercise that appear to work well (eg, walking, running, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and be well tolerated (eg, strength training and yoga). If social determinants permit, 66 engaging in group exercise or structured programmes could provide support and guidance to achieve better outcomes. Health services may consider offering these programmes as an alternative or adjuvant treatment for major depression. Specifically, although the confidence in the evidence for exercise is less strong than for cognitive behavioural therapy, the effect sizes seem comparable, so it may be an alternative for patients who prefer not to engage in psychotherapy. Previous reviews on those with mild-moderate depression have found similar effects for exercise or SSRIs, or the two combined. 13 14 In contrast, we found some forms of exercise to have stronger effects than SSRIs alone. Our findings are likely related to the larger power in our review (n=14 170) compared with previous reviews (eg, n=2551), 14 and our ability to better account for heterogeneity in exercise prescriptions. Exercise may therefore be considered a viable alternative to drug treatment. We also found evidence that exercise increases the effects of SSRIs, so offering exercise may act as an adjuvant for those already taking drugs. We agree with consensus statements that professionals should still account for patients’ values, preferences, and constraints, ensuring there is shared decision making around what best suits the patient. 66 Our review provides data to help inform that decision.

Strengths, limitations, and future directions

Based on our findings, dance appears to be a promising treatment for depression, with large effects found compared with other interventions in our review. But the small number of studies, low number of participants, and biases in the study designs prohibits us from recommending dance more strongly. Given most research for the intervention has been in young women (88% female participants, mean age 31 years), it is also important for future research to assess the generalisability of the effects to different populations, using robust experimental designs.

The studies we found may be subject to a range of experimental biases. In particular, researchers seldom blinded participants or staff delivering the intervention to the study’s hypotheses. Blinding for exercise interventions may be harder than for drugs 23 ; however, future studies could attempt to blind participants and staff to the study’s hypotheses to avoid expectancy effects. 69 Some of our ratings are for studies published before the proliferation of reporting checklists, so the ratings might be too critical. 23 For example, before CONSORT, few authors explicitly described how they generated a random sequence. 23 Therefore, our risk of bias judgements may be too conservative. Similarly, we planned to use the Cochrane risk of bias (RoB) 1 tool 40 so we could use the most recent Cochrane review of exercise and depression 12 to calibrate our raters, and because RoB 2 had not yet been published. 70 Although assessments of bias between the two tools are generally comparable, 71 the RoB 1 tool can be more conservative when assessing open label studies with subjective assessments (eg, unblinded studies with self-reported measures for depression). 71 As a result, future reviews should consider using the latest risk of bias tool, which may lead to different assessments of bias in included studies.

Most of the main findings in this review appear robust to risks from publication bias. Specifically, pooled effect sizes decreased when accounting for risk of publication bias, but no degree of publication bias could nullify effects. We did not exclude grey literature, but our search strategy was not designed to systematically search grey literature or trial registries. Doing so can detect additional eligible studies 72 and reveal the numbers of completed studies that remain unpublished. 73 Future reviews should consider more systematic searches for this kind of literature to better quantify and mitigate risk of publication bias.

Similarly, our review was able to integrate evidence that directly compared exercise with other treatment modalities such as SSRIs or psychotherapy, while also informing estimates using indirect evidence (eg, comparing the relative effects of strength training and SSRIs when tested against a waitlist control). Our review did not, however, include all possible sources of indirect evidence. Network meta-analyses exist that directly focus on psychotherapy 7 and pharmacotherapy, 25 and these combined for treating depression. 6 Those reviews include more than 500 studies comparing psychological or drug interventions with controls. Harmonising the findings of those reviews with ours would provide stronger data on indirect effects.

Our review found some interesting moderators by age and sex, but these were at the study level rather than individual level—that is, rather than being able to determine whether women engaging in a strength intervention benefit more than men, we could only conclude that studies with more women showed larger effects than studies with fewer women. These studies may have been tailored towards women, so effects may be subject to confounding, as both sex and intervention may have changed. The same finding applied to age, where studies on older adults were likely adapted specifically to this age group. These between study differences may explain the heterogeneity in the effects of interventions, and confounding means our moderators for age and sex should be interpreted cautiously. Future reviews should consider individual patient meta-analyses to allow for more detailed assessments of participant level moderators.

Finally, for many modalities, the evidence is derived from small trials (eg, the median number of walking or jogging arms was 17). In addition to reducing risks from bias, primary research may benefit from deconstruction designs or from larger, head-to-head analyses of exercise modalities to better identify what works best for each candidate.

Clinical and policy implications

Our findings support the inclusion of exercise as part of clinical practice guidelines for depression, particularly vigorous intensity exercise. Doing so may help bridge the gap in treatment coverage by increasing the range of first line options for patients and health systems. 9 Globally there has been an attempt to reduce stigma associated with seeking treatment for depression. 74 Exercise may support this effort by providing patients with treatment options that carry less stigma. In low resource or funding constrained settings, group exercise interventions may provide relatively low cost alternatives for patients with depression and for health systems. When possible, ideal treatment may involve individualised care with a multidisciplinary team, where exercise professionals could take responsibility for ensuring the prescription is safe, personalised, challenging, and supported. In addition, those delivering psychotherapy may want to direct some time towards tackling cognitive and behavioural barriers to exercise. Exercise professionals might need to be trained in the management of depression (eg, managing risk) and to be mindful of the scope of their practice while providing support to deal with this major cause of disability.

Conclusions

Depression imposes a considerable global burden. Many exercise modalities appear to be effective treatments, particularly walking or jogging, strength training, and yoga, but confidence in many of the findings was low. We found preliminary data that may help practitioners tailor interventions to individuals (eg, yoga for older men, strength training for younger women). The World Health Organization recommends physical activity for everyone, including those with chronic conditions and disabilities, 75 but not everyone can access treatment easily. Many patients may have physical, psychological, or social barriers to participation. Still, some interventions with few costs, side effects, or pragmatic barriers, such as walking and jogging, are effective across people with different personal characteristics, severity of depression, and comorbidities. Those who are able may want to choose more intense exercise in a structured environment to further decrease depression symptoms. Health systems may want to provide these treatments as alternatives or adjuvants to other established interventions (cognitive behaviour therapy, SSRIs), while also attenuating risks to physical health associated with depression. 3 Therefore, effective exercise modalities could be considered alongside those intervention as core treatments for depression.

What is already known on this topic

Depression is a leading cause of disability, and exercise is often recommended alongside first line treatments such as pharmacotherapy and psychotherapy

Treatment guidelines and previous reviews disagree on how to prescribe exercise to best treat depression

What this study adds

Various exercise modalities are effective (walking, jogging, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and well tolerated (especially strength training and yoga)

Effects appeared proportional to the intensity of exercise prescribed and were stronger for group exercise and interventions with clear prescriptions

Preliminary evidence suggests interactions between types of exercise and patients’ personal characteristics

Ethics statements

Ethical approval.

Not required.

Acknowledgments

We thank Lachlan McKee for his assistance with data extraction. We also thank Juliette Grosvenor and another librarian (anonymous) for their review of our search strategy.

Contributors: MN led the project, drafted the manuscript, and is the guarantor. MN, TS, PT, MM, BdPC, PP, SB, and CL drafted the initial study protocol. MN, TS, PT, BdPC, DvdH, JS, MM, RP, LP, RV, HA, and BV conducted screening, extraction, and risk of bias assessment. MN, JS, and JM coded methods for behaviour change techniques. MN and DGG conducted statistical analyses. PP, SB, and CL provided supervision and mentorship. All authors reviewed and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: None received.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Data sharing Data and code for reproducing analyses are available on the Open Science Framework ( https://osf.io/nzw6u/ ).

The lead author (MN) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: We plan to disseminate the findings of this study to lay audiences through mainstream and social media.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Nanoparticles in Drug Delivery: From History to Therapeutic Applications

Obaid afzal.

1 Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia

Abdulmalik S. A. Altamimi

Muhammad shahid nadeem.

2 Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

Sami I. Alzarea

3 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia

Waleed Hassan Almalki

4 Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia

5 Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore 54000, Pakistan

Bismillah Mubeen

Bibi nazia murtaza.

6 Department of Zoology, Abbottabad University of Science and Technology (AUST), Abbottabad 22310, Pakistan

Saima Iftikhar

7 School of Biological Sciences, University of Punjab, Lahore 54000, Pakistan

8 Department of Pharmacy, COMSATS University, Abbottabad 22020, Pakistan

Imran Kazmi

Associated data.

Not applicable.

Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. This paper reviews the various conventionally used and current used carriage system to deliver drugs. Due to numerous drawbacks of conventional DDSs, nanocarriers have gained immense interest. Nanocarriers like polymeric nanoparticles, mesoporous nanoparticles, nanomaterials, carbon nanotubes, dendrimers, liposomes, metallic nanoparticles, nanomedicine, and engineered nanomaterials are used as carriage systems for targeted delivery at specific sites of affected areas in the body. Nanomedicine has rapidly grown to treat certain diseases like brain cancer, lung cancer, breast cancer, cardiovascular diseases, and many others. These nanomedicines can improve drug bioavailability and drug absorption time, reduce release time, eliminate drug aggregation, and enhance drug solubility in the blood. Nanomedicine has introduced a new era for drug carriage by refining the therapeutic directories of the energetic pharmaceutical elements engineered within nanoparticles. In this context, the vital information on engineered nanoparticles was reviewed and conferred towards the role in drug carriage systems to treat many ailments. All these nanocarriers were tested in vitro and in vivo. In the coming years, nanomedicines can improve human health more effectively by adding more advanced techniques into the drug delivery system.

1. Introduction

Drug delivery systems (DDSs) have been used in past eras to treat numerous ailments. All medicines rely on pharmacologic active metabolites (drugs) to treat diseases [ 1 ]. Some of the drugs are designed as the inactive precursor, but they become active when transformed in the body [ 2 ]. Their effectiveness depends on the route of administration. In conventional drug delivery systems (CDDSs), drugs were delivered usually via oral, nasal, inhaled, mucosal, and shot methods [ 3 ]. The conventionally delivered drugs were absorbed less, distributed randomly, damaged unaffected areas, were excreted early, and took a prolonged time to cure the disease [ 4 ]. They were less effective due to many hurdles like their enzymatic degradation or disparity in pH, many mucosal barriers, and off-the-mark effects, and their immediate release enhanced toxicity in blood [ 5 ].

Due to all such reasons, the controlled-release drug delivery system was developed. Such evolution in the DDS enhances drug effectiveness in many ways [ 6 ]. DDSs have been engineered in recent years to control drug release [ 7 ]. Such engineered DDSs used various novel strategies for controlled drug release into the diseased areas. These strategies were erodible material, degradable material, matrix, hydrogel, osmotic pump, and reservoir [ 8 ]. They all provided a medium for the medicines to deliver at the desired sites like tissues, cells, or organs. In these approaches, drugs are often available for many diseases [ 9 ]. Such strategies were unsuccessful due to lower distribution, less solubility, higher drug aggregation, less target selection, and poor effects for disease treatment [ 10 ]. Moreover, drug development is the most expensive, intricate, and time-consuming process [ 5 ]. The innovative drug findings involved the identification of new chemical entities (NCEs), [ 11 ] having the vital distinguishing characteristics of drug capacity and pharmaceutical chemistry. This methodology, however, was confirmed to be less effective in terms of the overall attainment percentage [ 12 ], as 40% of drug development was botched due to its changeable responses and unpredicted noxiousness in humans [ 13 ]. From past decades until now, drug development and its delivery are shifting from the micro to the nano level to prolong life expectancy by revolutionizing drug delivery systems ( Figure 1 ) [ 14 ].

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Illustration of how traditional medications were administered without the use of nanocarriers and harm was done to healthy organs or cells. In contrast, modern procedures use nanomedicines to transport medications to specific parts of the body.

In 1959, Feynman was the first physicist to introduce the notion of nanotechnology in the lecture entitled “There’s Plenty of oom at the Bottom”. This concept initiated remarkable developments in the arena of nanotechnology [ 15 ]. Nanotechnology is the study of extremely tiny things and is basically the hub of all science disciplines including physics, chemistry, biology, engineering, information technology, electronics, and material science [ 16 ]. The structures measured with nanotechnology range from 1–100 nm at the nanoscale level [ 17 ]. Nanoparticles have different material characteristics because of submicroscopic size and also provide practical implementations in a wide range of fields including engineering, drug delivery, nanomedicine, environmental indemnification, and catalysis, as well as target diseases such as melanoma and cardiovascular diseases (CVD), skin diseases, liver diseases, and many others [ 18 ].

Therefore, medicines linked with nanotechnology can enhance efficiency of medicines and their bioavailability [ 19 ]. The relation of nanoparticles to biomedicine was demonstrated in late the 1970s, and over 10,000 publications have referred to this association with the term “nanomedicine”. Almost thirty papers on this term were accessible by 2005 [ 20 ].

After 10 to 12 years, Web of Science published more than 1000 nanomedicine articles in 2015 and most of the articles relating nanoparticles (NPs) for biomedical usage [ 21 ]. Nanocarriers such as dendrimers, liposomes, peptide-based nanoparticles, carbon nano tubes, quantum dots, polymer-based nanoparticles, inorganic vectors, lipid-based nanoparticles, hybrid NPs, and metal nanoparticles are the advanced forms of NPs [ 22 ]. Nanoparticles are nowadays a growing arena for drug delivery, microfluidics, biosensors, microarrays, and tissue micro-engineering for the specialized treatment of diseases [ 23 , 24 , 25 ].

Nanoparticles are less effective and can treat cancer by selectively killing all cancerous cells [ 26 ]. In 2015, the Food and Drug Administration (FDA) approved the clinical trials of onivyde nanomedicine in the treatment of cancer [ 27 ]. The characteristic properties of nanocarriers are physicochemical properties, supporting the drugs by improving solubility, degradation, clearance, targeting, theranostics, and combination therapy [ 28 ]. Studies on nanomedicine based on protein used for drug delivery in which various protein subunits combine to deliver medicine on site to a specific tumor have been reported [ 29 ]. Many altered kinds and forms of nanocarriers arranged to carry medicine are protein-based podiums, counting several protein coops, nanoparticles, hydrogels, films, microspheres, tiny rods, and minipellets [ 30 ]. All proteins, including ferritin–protein coop, the small heat shock protein (sHsp) cage, plant-derived viral capsids, albumin, soy and whey protein, collagen, and gelatin-implemented proteins are characterized for drug carriage [ 31 ].

The nanomedicines are escorted in a new-fangled epoch, meant for drug carriage by refining the therapeutic directories of the energetic pharmacological elements engineered inside nanoparticles [ 32 ]. In this epoch, nanomedicine-based targeted-design structures can deliver multipurpose freight with favorable pharmacokinetics and capitalized so as to enhance drug specificity, usefulness, and safety, as shown in ( Figure 2 ) [ 33 ]. The failure of chemotherapeutic approaches has increased the recurrence chances of disease, which enhances the complexity of lethal diseases [ 34 ].

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Aids of using nanomedicine platform for delivering drugs to the tumor complex.

Petros and his colleague reported a study about mid-19th century work on nanotechnology. As they reported, polymers and drugs were conjugated in 1955 [ 35 ], the first controlled-release polymer device appeared in 1964, the liposome was discovered by Bangham in 1965, albumin-based NPs were reported in 1972, liposome-based drugs were formulated in 1973, the first micelle was formulated and approved in 1983, the FDA approved the first controlled formulation in 1989, and first polyethylene glycol (PEG) conjugated with protein entered the market in 1990 [ 36 ]. Further studies have produced incredibly encouraging results for treating a variety of disorders ( Table 1 ).

Evolution of nanoparticles from 1991 to 2022 in detail discussed here.

3. Recent Approaches Used in Drug Carriage System for Treatment of Various Diseases

3.1. brain drug delivery system and its types.

Under the most pathological circumstances of diseases such as strokes, seizures, multiple sclerosis, AIDS, diabetes, glioma, Alzheimer’s disease, and Parkinson’s disease, the blood–brain barrier (BBB) is disrupted [ 103 ]. An important reason for the breakdown of the blood–brain barrier is the remodeling of the protein complex in intra-endothelial junctions under the pathological conditions [ 104 ]. Normally, the blood–brain barrier acts to maintain blood–brain homeostasis by preventing entry of macromolecules and micromolecules from the blood [ 105 ]. If a drug crosses the BBB, it restricts accumulation of the drug in the intracerebral region of brain, and bioavailability is reduced, due to which brain diseases cannot be treated [ 106 ]. Therefore, the optimal drug delivery system (DDS) is a cell membrane DDS, virus-based DDS, or exosome-based DDS designed for BBB penetrability, lesion-targeting ability, and standard safety [ 107 ]. For the cure of brain diseases, the nanocarrier-assisted intranasal drug carriage system is widely used [ 108 ]. Now, at the advanced level, drugs poorly distributed to the brain can be loaded into a nanocarrier-based system, which would interact well with the endothelial micro vessel cells at the BBB and nasal mucosa to increase drug absorption time and the olfactory nerve fibers to stimulate straight nose-to-brain delivery [ 109 ], thus greater drug absorption in brain parenchyma through the secondary nose-to-blood-to-brain pathway [ 110 ]. The current strategies used are viral vectors, nanoparticles, exosomes, brain permeability enhancers, delivery through active transporters in the BBB, alteration of administration route, nanoparticles for the brain, and imaging/diagnostics under diseased conditions [ 111 ].

3.1.1. Role of Nanocarriers in Alzheimer’s Disease

Alzheimer’s disease is one of the fastest growing neurodegenerative diseases in the elderly population. Clinically, it is categorized by abstraction, damage to verbal access, and diminishing in spatial skills and reasoning [ 112 ]. Furthermore, engrossment of amyloid β (Aβ) aggregation and anxiety in the brain have significant parts [ 113 ]. The treatment of different diseases with nanotechnology-based drug delivery uses nanotechnology-based approaches [ 114 ]. In Alzheimer’s diseases, polymeric nanoparticles, liposomes, solid lipid nanoparticles, nano-emulsions, micro-emulsions, and liquid-crystals are used for treatment.

Polymeric Nanoparticles

  • I. The drug Tacrine was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced the concentration of tacrine inside the brain and also reduced the whole-dose quantity [ 115 ].
  • II. Rivastigmine drug was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced learning and memory capacities [ 116 ].

Solid Lipid Nanoparticles (SLNPs)

SLNPs enhanced drug retention in the brain area, raising absorption across the BBB [ 117 ]. Some of the drug’s effects are listed below.

  • I. Piperine drug is loaded on solid lipid nanoparticles through an intraperitoneal route inside the brain to decrease plaques and masses and to increase AChE enzyme activity [ 118 ].
  • II. Huperzine A improved cognitive functions. No main irritation was detected in rat skin when the drug was loaded on SLNPs in an in vitro study [ 119 ].

In recent reports, the coating of SLNPs with polysorbate enhances drug bioavailability [ 120 , 121 ]. Some of the coated NPs are listed below.

  • I. The drug clozapine was loaded on a Dynasan 116 [Tripalmitin] lipid matrix coated with surfactant Poloxamer 188, Epikuron 200 to unload the drug safely into the brain microenvironment [ 122 , 123 ].
  • II. Vitamin A was loaded on a lipid matrix Glyceryl behenate with coated surfactant hydroxypropyl distarch to unload the drug safely across the BBB [ 124 , 125 ].
  • III. Diminazine was loaded on a stearic acid matrix coated with polysorbate 80 to deliver to an infected area safely [ 126 , 127 ].
  • IV. Doxorubicin was loaded on stearic acid SLNs coated with Taurodeoxycholate surfactant to deliver the drug without reducing its effectiveness [ 128 , 129 ].

Liposomes have gained attention as auspicious tactics for brain-targeted drug delivery [ 130 ]. The recorded beneficial features of liposomes are their capacity to integrate and carry a large quantity of drugs and their likelihood to adorn their exterior with diverse ligands [ 131 , 132 ].

  • Curcumin–PEG derivative was loaded on liposomes and showed high affinity on senile plaques in an ex vivo experiment. Furthermore, in vitro it demonstrated the ability for Aβ aggregation and was taken inside by the BBB in a rat model [ 133 ].
  • Folic acid was loaded on liposomes, administered through an intranasal route and absorbed through the nasal cavity [ 134 ].

Nanoemulsions

  • I. Beta-Asarone was loaded on nanoemulsions, administered through an intranasal route, and enhanced bioavailability [ 130 ].

Micro Emulsion

  • I. Tacrine was loaded on a microemulsion and improved memory. Such nanoparticles absorbed rapidly via the nose to the brain through an intranasal route [ 135 ].

Liquid Crystals

  • I. T. divaricate was loaded on liquid crystals and injected through a transdermal route. It increased permanency of the drug in designs and also increased skin infusion and retention [ 136 ].

3.1.2. Role of Nanocarriers in Parkinson’s Disease (PD)

Parkinson’s disease is considered the second most common neurological ailment, and it faces problems in reliable drug delivery for treatment and diagnosis [ 137 ]. The conventional anti-Parkinson’s drug is Levodopa , but it experiences low bioavailability and deprived transfer to the brain; this is the most thought-provoking problem [ 138 ]. To solve this problem, nanotechnology comes to the fore with insightful solutions to solve this problem. Various nanoparticles like metal nanoparticles, quantum dots, cerium oxide nanoparticles, organic nanoparticles, liposomes, and gene therapy are used in PD treatment [ 139 ]. All these nanoparticles enable drugs to enter through numerous ways across the blood–brain barrier (BBB) [ 140 ]. In the current study, Bhattamisra et al. reported Rotigotine drug loaded on chitosan NPs in human SH-SY5Y neuroblastoma cells and delivered from the nose to the brain in rat model of Parkinson’s disease. A study of the pharmacokinetic data proposed that the intranasal route is the best path for a straight channel of rotigotine to the brain [ 125 ].

Ropinirole (RP)

Ropinirole (RP) is a dopamine agonist used for Parkinson’s treatment. RP-loaded solid lipid nanoparticles (RP-SLNs) with nanostructured lipid carriers (RP-NLCs) comprising hydrogel (RP-SLN-C and RP-NLC-C) formulations are better for oral and topical distribution [ 141 ]. Generally, the results confirmed that lipid nanoparticles and consistent hydrogel formulations can be measured as another carriage methodology for the upgraded oral and topical delivery of RP for the active treatment of PD [ 142 ]. Neurodegenerative pathologies such as AD and PD can be treated with solid lipid nanoparticles, as this permits the drug to cross the BBB and reach the damaged area of the central nervous system [ 143 ].

3.2. Mechanism of Nanoparticles’ Brain Drug Delivery (across BBB)

The NPs are commonly administered via intranasal, intraventricular, intraparenchymal routes. All these routes enabled nanoparticles to cross the BBB due to their small size. When nanoparticles reach the BBB, several mechanisms are used, like receptor-mediated mechanisms, active transport, and passive transport to deliver nanoparticles into the brain. Nanoparticles are small in size, can diffuse passively across the endothelial cells of the BBB, and can interact favorably with brain receptors and recognize ligands for interaction ( Figure 3 ) [ 144 ].

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Diagram showing the mechanism of targeted drug delivery across BBB in brain microenvironment. Piperine loaded on SLNPs is injected intraperitonially, across BBB efferently to stop plaque formation. Polymeric nanoparticles are used for Tacrine delivery inside the brain, folic acid are loaded on the liposomes crossing blood–brain barrier to treat Alzheimer’s disease, while nanoemulsions and SLNP are loaded with drugs used to deliver medicines inside the targeted brain area to cure Parkinson’s disease.

3.3. Advantages and Disadvantages of Nanomedicines

When employed for brain illnesses, nanomedicines have both benefits and drawbacks ( Table 2 ).

Advantages and disadvantages of nanomedicine.

4. Nanocarriers Role in Major Cancers

4.1. brain cancer.

Brain malignancy is the most critical disease in the sense of treatment [ 150 ]. Malignancies of the brain are most difficult to treat due to limits imposed by the blood–brain barrier [ 151 ]. The brain microvascular endothelium is present in the BBB and creates barriers that distinguish blood from the neural tissues of the brain [ 152 ]. The BBB prevents the entry of harmful toxins, xenobiotic and other metabolites from entering the brain [ 153 ]. The majority of brain cancers include glioma and glioblastoma. Both of these are among the most lethal forms of brain cancer [ 154 ]. The annual occurrence is 5.26 per 100,000 people or 17,000 new diagnoses each year. The most common treatment is radiation surgery and chemotherapy, usually implemented with with temozolomide (TMZ) [ 155 ]. Nanoparticles have a high potential to treat brain cancer because of their small size in nm, tissue-specific targeting properties, and ease in crossing the BBB [ 156 ] ( Table 3 ).

Various nanoparticles involved in brain cancer treatment in recent era.

4.2. Breast Cancer

Cancer causes major deaths all over the world. Tumors spread due to the proliferation of cells [ 171 ], which invade through the lymphatic system to various parts of the body if they becomes malignant [ 172 ]. According to WHO, the ratio of deaths globally due to cancer is assessed to be 13%, attributing 8.2 million deaths every year [ 173 ]. Breast cancer is the most recorded type of melanoma present in only females, and its severity leads to mortality more often than lung cancer [ 174 ]. In 2012, estimated female breast cancer cases were 1.7 million, with 25% of deaths all over the world [ 175 ]. In a recent study, a report published in the name of Global Cancer Statistics 2020: GLOBOCAN estimates the incidence and mortality worldwide for 36 cancers in 185 countries and provides an update on cancer internationally [ 176 ]. A reported estimate is 19.3 million new cancer cases (18.1 million excluding non-melanoma skin cancer) and almost 10 million cancer deaths (9.9 million without non-melanoma skin cancer) occurring in 2020 worldwide. Female breast cancer has exceeded lung cancer as the most frequently diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), prostate (7.3%), colorectal (10%), and stomach (5.6%) cancers [ 177 ]. For the effective treatment of breast cancer, surgery, chemotherapy, radiation therapy, hormonal therapy, and targeted therapy are performed [ 178 ]. However, nowadays, nanotechnology has gained interest for breast cancer treatment. Various organic and inorganic nanocarriers are used to deliver drugs to the specific target site [ 179 ]. Nanocarriers enhance the hydrophobicity of the anticancer drugs and promote specific target drug delivery [ 180 ]. Organic nanocarriers include polymeric nanocarriers, liposome nanocarriers, and solid lipid nanocarriers, while inorganic nanocarriers include magnetic nanocarriers, quantum dots, and carbon nanotubes (CNTs); both categories show great results towards treatment of heart diseases ( Table 4 ) [ 181 ]. The mechanism of drug delivery in breast cancer is shown in Figure 4 .

An external file that holds a picture, illustration, etc.
Object name is nanomaterials-12-04494-g004.jpg

Schematic representation of mechanism of drug letrozol loaded on solid lipid nanoparticles (SLNs) and folic acid coupled to SLNs. The whole carrier was delivered inside the animal rat model to treat effects on breast cancer cell lines. Inside cytoplasm, biodegradation occurred, as well as drug release and caspases’ activation inside nucleus, causing apoptosis.

Nanoparticles’ role in treatment of breast cancer.

4.3. Lung Cancer

Lungs are basically responsible for inhalation [ 194 ]. The lung is composed airways (conveying the air inside and outside of the lungs) and alveoli (gas exchange zones) [ 195 ]. In fact, airways are comparatively tough barriers for particles to enter through, while the barrier along the alveolar wall and the capillaries is relatively fragile in the gas exchange component [ 196 ]. The huge exterior area of the alveoli and deep air blood exchange cause the alveoli to be less healthy when affected by environmental injuries. Such injuries may be the reason for some pulmonary illnesses, including lung malignancy [ 197 ]. Several nanoparticles are now being established for respiratory applications that aim at eliminating the restrictions of orthodox drugs [ 198 ] ( Table 5 ). Nanoparticles aid the cure of many lung diseases, such as asthma, tuberculosis, emphysema, cystic fibrosis, and cancer [ 199 ].

Recent discovered nanoparticle’s role in lung cancer treatment.

5. Drug Delivery Approach in Heart Diseases

Cardiovascular diseases include myocardial infraction (MI) [ 213 ], ischemic impairment, coronary artery disease (CAD), heart arrhythmias, pericardial disease, cardiomyopathy (heart muscle disease), and congenital heart disease [ 214 , 215 ]. All these illnesses are the basic main cause of mortality and morbidity in the world [ 216 ]. Cardiac diseases in humans involve incongruity in the morphogenesis of heart arrangement, functionality, and the healing and periodic shrinkage of cardiac muscles [ 217 , 218 ]. Around 50% of patients suffering from MI die within five years [ 216 ]. The insistence for a novel and effective remedy has brought about progress in direct drug carriage to the heart [ 219 ]. Modern therapeutic approaches have been developed to stop the incidence of heart failure after myocardial infarction [ 220 ]. Liposomes, silica NPs, dendrimers, cerium oxide NPs, micelles, TiO 2 NPs, stents with nano-coatings, microbubbles, and polymer–drug conjugates are used for drug delivery. Magnetic nanoparticles like magnetoliposomes (MLs) are made up of the union of liposomes and magnetic nanoparticles. They are used as magnetic-targeted drug delivery [ 221 ]. The PEGylation of MLs increases their rate of flow in the blood, and pairing of the MLs with antibodies raises the rate of active target to pretentious positions [ 222 ]. Namdari and his co-workers performed experiments in a mice model afflicted with myocardial infraction (MI). Liposomes are used with various modifications and in different ways; they are adapted to load drugs on NPs for efficient delivery inside the cell. Cationic liposomes, perfluorocarbon nanoparticles, polyelectrolyte nanoparticles, and polymeric nanoparticles are the modified forms of nanocarriers [ 223 ] ( Table 6 ).

Different forms of NPs; their experiment studies show its role in treatment of heart diseases.

6. Drug Delivery Approach in Skin Diseases

Skin diseases are follicular and cutaneous. These dermatological diseases are treated nowadays with nanotechnology. Nanoparticle delivery for cutaneous disease treatment is preferred, with minor side effects. The conventionally used creams, gels, and ointments are insufficient for delivering drugs due to low penetration in skin tissues. To address this, polymeric, lipid, and surfactant nanocarriers are used. The polymeric micelles enhance drug penetration into the skin tissue to treat skin cancer. As in this reported study, chitosan polymeric NPs, liposomes, and gold nanoparticles can treat atopic dermatitis by improving drug penetration into the dermal and epidermal layers [ 246 ]. Gold nanoparticles are extremely small in size and can penetrate easily and effectively with very low toxicity and no skin damage. As such, they are used widely in nanocarrier formulations for skin diseases.

7. Drug Delivery Approach in Bone Diseases

Bone diseases includes bone defects due to many pathological factors, such as fracture, trauma, osteoporosis, arthritis, infections, and many other diseases. In fact, bone regeneration as a disease treatment is a very complex process, due to which nanomaterials and biological materials are fused to repair bones effectively. The combination of biomaterial and nanomaterial has reduced bone implantation through the development of bone bioscaffolds [ 247 ].

Mechanism of Drug Delivery

The drugs encapsulated inside the nanoparticle is delivered through blood to the targeted area in the bones. The management of the sending nanoparticles as shown herenin ( Figure 5 ).

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Object name is nanomaterials-12-04494-g005.jpg

Mechanism of nanomedicine delivery in bone diseases.

8. Drug Delivery Approach in Blood Diseases

There are various types of blood diseases, like hemopoietic blood disorder, as well as iron deficiency, leukemia, anemia, hemophilia, platelet diseases, and blood cancer. The conventionally used chemotherapeutic system causes damage to the immune system, with high risk of mortality. Bone marrow transplant is also an expensive and intricate process. For example, thalassemia is treated with deferoxamine, a chelating agent to treat excessive iron in the blood. The siRNA-coated nanocomposite has the inhibitory activity for tumor cells in vivo [ 248 ]. The treatment of blood disorders with nanomedicine is still under investigation.

9. Future Challenges of Nanomedicines

In the field of nanomedicine, there are many innovations which show its importance in clinical and other medical aspects. Many scientists have investigated in their research how nanomedicine is involved in treating malignancies and reducing mortality and morbidity rates. However, there are also future challenges that nanomedicines have been facing until now [ 249 ]. The implementation of nanomedicine in clinical practice will face many issues with insurance companies, regulatory agencies, and the public health sector. Until now, the FDA has not developed any specific regulation for the products containing nanomaterials. Due to a lack of nanomaterial standardization and other safety issues, US agencies, such as the EPA and NIOSH, are giving less funding to these research endeavors.

10. Conclusions

Nanotechnology-based nanomedicine is a diverse field for disease treatment. Nowadays, in every sort of disease, nanotechnology is emerging as the best therapeutic to cure disease. At California University, researchers are developing methods to deliver cardiac stem cells to the heart. They attached nanovesicles that directly target injured tissue to increase the amount of stem cells there. Thus, the involvement of stem cells with nanotechnology will develop many solutions for the disease-based queries in the medical arena. However, nanomedicine and nano drugs deal with many doubts. Irregularities and toxicity and safety valuations will be the topic of development in the future. Nanotechnology will be in high demand. Nowadays, drug-targeted delivery through nanoparticles is catching the attention of pharmaceutical researchers all over the world. Nanomedicine will overcome all the side effects of traditional medicines. This nanoscale technology will be incorporated in the medical system to diagnose, transport therapeutic drugs, and detect cancer growth, according to the National Cancer Institute. Experts are trying to treat SARS-CoV-2 with nanomedicine, as nanoparticles with 10–200 nm size can detect, for site-specific transfer, SARS-CoV-2, exterminate it, and improve the immune system of the body. Nanotechnology could help to combat COVID-19 by stopping viral contamination. Highly accurate nano-based sensors will be made in the future that will quickly recognize the virus and act by spraying to protect frontline doctors and the public. Furthermore, many antiviral disinfectants are being developed through nanobiotechnology to stop virus dissemination. In the future, nanotechnology will evolve to develop drugs with high activity, less toxicity, and sustained release to target tissue. Therefore, personalized medicine and nanomedicine both will be potential therapies to treat COVID-19 successfully, as well as to treat upcoming diseases in future.

Acknowledgments

The authors are thankful to Umm Al-Qura University, Makkah, Saudi Arabia, for supporting this project (Project number 224UQU4310387DSR40).

Funding Statement

The Project was funded by Deanship of Scientific Research at Umm Al-Qura University, and this work was supported by Grant Code (Project Code: 22 UQU4310387DSR40).

Author Contributions

Conceptualization, M.S.N. and I.K.; original draft, O.A., M.S.N., B.M. and O.A.; writing—review and editing, O.A., S.I.A., A.S.A.A., A.T., B.M., B.N.M., S.I. and N.R.; funding acquisition, W.H.A. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Reproductive rights in America

Research at the heart of a federal case against the abortion pill has been retracted.

Selena Simmons-Duffin

Selena Simmons-Duffin

research papers on drugs

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy. Anna Moneymaker/Getty Images hide caption

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy.

A scientific paper that raised concerns about the safety of the abortion pill mifepristone was retracted by its publisher this week. The study was cited three times by a federal judge who ruled against mifepristone last spring. That case, which could limit access to mifepristone throughout the country, will soon be heard in the Supreme Court.

The now retracted study used Medicaid claims data to track E.R. visits by patients in the month after having an abortion. The study found a much higher rate of complications than similar studies that have examined abortion safety.

Sage, the publisher of the journal, retracted the study on Monday along with two other papers, explaining in a statement that "expert reviewers found that the studies demonstrate a lack of scientific rigor that invalidates or renders unreliable the authors' conclusions."

It also noted that most of the authors on the paper worked for the Charlotte Lozier Institute, the research arm of anti-abortion lobbying group Susan B. Anthony Pro-Life America, and that one of the original peer reviewers had also worked for the Lozier Institute.

The Sage journal, Health Services Research and Managerial Epidemiology , published all three research articles, which are still available online along with the retraction notice. In an email to NPR, a spokesperson for Sage wrote that the process leading to the retractions "was thorough, fair, and careful."

The lead author on the paper, James Studnicki, fiercely defends his work. "Sage is targeting us because we have been successful for a long period of time," he says on a video posted online this week . He asserts that the retraction has "nothing to do with real science and has everything to do with a political assassination of science."

He says that because the study's findings have been cited in legal cases like the one challenging the abortion pill, "we have become visible – people are quoting us. And for that reason, we are dangerous, and for that reason, they want to cancel our work," Studnicki says in the video.

In an email to NPR, a spokesperson for the Charlotte Lozier Institute said that they "will be taking appropriate legal action."

Role in abortion pill legal case

Anti-abortion rights groups, including a group of doctors, sued the federal Food and Drug Administration in 2022 over the approval of mifepristone, which is part of a two-drug regimen used in most medication abortions. The pill has been on the market for over 20 years, and is used in more than half abortions nationally. The FDA stands by its research that finds adverse events from mifepristone are extremely rare.

Judge Matthew Kacsmaryk, the district court judge who initially ruled on the case, pointed to the now-retracted study to support the idea that the anti-abortion rights physicians suing the FDA had the right to do so. "The associations' members have standing because they allege adverse events from chemical abortion drugs can overwhelm the medical system and place 'enormous pressure and stress' on doctors during emergencies and complications," he wrote in his decision, citing Studnicki. He ruled that mifepristone should be pulled from the market nationwide, although his decision never took effect.

research papers on drugs

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017. AP hide caption

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017.

Kacsmaryk is a Trump appointee who was a vocal abortion opponent before becoming a federal judge.

"I don't think he would view the retraction as delegitimizing the research," says Mary Ziegler , a law professor and expert on the legal history of abortion at U.C. Davis. "There's been so much polarization about what the reality of abortion is on the right that I'm not sure how much a retraction would affect his reasoning."

Ziegler also doubts the retractions will alter much in the Supreme Court case, given its conservative majority. "We've already seen, when it comes to abortion, that the court has a propensity to look at the views of experts that support the results it wants," she says. The decision that overturned Roe v. Wade is an example, she says. "The majority [opinion] relied pretty much exclusively on scholars with some ties to pro-life activism and didn't really cite anybody else even or really even acknowledge that there was a majority scholarly position or even that there was meaningful disagreement on the subject."

In the mifepristone case, "there's a lot of supposition and speculation" in the argument about who has standing to sue, she explains. "There's a probability that people will take mifepristone and then there's a probability that they'll get complications and then there's a probability that they'll get treatment in the E.R. and then there's a probability that they'll encounter physicians with certain objections to mifepristone. So the question is, if this [retraction] knocks out one leg of the stool, does that somehow affect how the court is going to view standing? I imagine not."

It's impossible to know who will win the Supreme Court case, but Ziegler thinks that this retraction probably won't sway the outcome either way. "If the court is skeptical of standing because of all these aforementioned weaknesses, this is just more fuel to that fire," she says. "It's not as if this were an airtight case for standing and this was a potentially game-changing development."

Oral arguments for the case, Alliance for Hippocratic Medicine v. FDA , are scheduled for March 26 at the Supreme Court. A decision is expected by summer. Mifepristone remains available while the legal process continues.

  • Abortion policy
  • abortion pill
  • judge matthew kacsmaryk
  • mifepristone
  • retractions
  • Abortion rights
  • Supreme Court

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