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Following an extensive review of the current data collection instrument on drugs, the Annual Report Questionnaire, the UNODC, in consultation with experts from the Member States and international organisations, is preparing a revised Annual Report Questionnaire, which will be implemented from 2021.

28-30 August 2019 ,  Second Expert Working Group on improving drug statistics and strengthening the Annual Report Questionnaire (ARQ)

29-31 January 2018 ,  Expert Working Group on Improving Drug Statistics and Strengthening the Annual Report Questionnaire (ARQ)

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• Published: 20 September 2021

Research led by people who use drugs: centering the expertise of lived experience

• Zach R. Salazar   ORCID: orcid.org/0000-0002-6211-835X 1 ,
• Louise Vincent 1 ,
• Mary C. Figgatt 2 , 3 ,
• Michael K. Gilbert 4 &
• Nabarun Dasgupta 2 , 3  

Substance Abuse Treatment, Prevention, and Policy volume  16 , Article number:  70 ( 2021 ) Cite this article

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Research collaborations between people who use drugs (PWUD) and researchers are largely underutilized, despite the long history of successful, community-led harm reduction interventions and growing health disparities experienced by PWUD. PWUD play a critical role in identifying emerging issues in the drug market, as well as associated health behaviors and outcomes. As such, PWUD are well positioned to meaningfully participate in all aspects of the research process, including population of research questions, conceptualization of study design, and contextualization of findings.

We argue PWUD embody unparalleled and current insight to drug use behaviors, including understanding of novel synthetic drug bodies and the dynamics at play in the drug market; they also hold intimate and trusting relationships with other PWUD. This perfectly situates PWUD to collaborate with researchers in investigation of drug use behaviors and development of harm reduction interventions. While PWUD have a history of mistrust with the medical community, community-led harm reduction organizations have earned their trust and are uniquely poised to facilitate research projects. We offer the North Carolina Survivors Union as one such example, having successfully conducted a number of projects with reputable research institutions. We also detail the fallacy of meaningful engagement posed by traditional mechanisms of capturing community voice. As a counter, we detail the framework developed and implemented by the union in hopes it may serve as guidance for other community-led organizations. We also situate research as a mechanism to diversify the job opportunities available to PWUD and offer a real-time example of the integration of these principles into public policy and direct service provision.

In order to effectively mitigate the risks posed by the fluid and volatile drug market, research collaborations must empower PWUD to play meaningful roles in the entirety of the research process. Historically, the most effective harm reduction interventions have been born of the innovation and heart possessed by PWUD; during the current overdose crisis, there is no reason to believe they will not continue to be.

Research collaborations between people who use drugs (PWUD) and researchers are underacknowledged, misinterpreted, and undervalued. The most effective evidence-based harm reduction interventions, such as needle-exchange [ 1 ], peer-delivered naloxone [ 2 ] and community-based drug checking [ 3 ], were designed and implemented by PWUD well before they had the backing of the greater public health community. PWUD play significant roles in identifying cross-disciplinary issues of import and contextualizing significance of findings. Therefore, collaborations with PWUD are necessary to produce effective and relevant research. Ultimately, we aim to argue the necessity of research collaborations with PWUD; detail the optimal positioning of harm reduction organizations in facilitating research projects; provide a framework for successfully conducting these partnerships; propose a potential career path for PWUD; and provide real-world application of the presented concepts.

Community contextualization

PWUD are experiencing a fluid illicit drug market where changes to products and potency can be extremely volatile, posing a series of unpredictable, and potentially deadly, risks to the consumer. The recent increase in novel synthetic drug types bodes ill for public health and safety because new psychoactive substances (e.g., fentanyl analogs) are frequently unknown by law enforcement and undetected by conventional drug screens, with associated health risks unfamiliar to public health. Evidently, though, people who consume these substances know what they are, or what they are intended to imitate, including what they look like, the places where they are sold, how much they cost, who is using them, methods and techniques for using (e.g., routes of administration), and the social network dynamics that facilitate contacts between consumers (i.e., dyadic pairings) [ 4 ].

The knowledge inhabited by PWUD, and the trusting and intimate relationships they have with other PWUD and their social networks, begs for collaboration in all areas of research involving illicit drug use or the population of PWUD. PWUD are needed at all stages of the research process: from conceptualizing ideas and constructing research questions to interpreting study findings and helping develop effective responses.

Situatedness of harm reduction organizations

PWUD are conventionally mistrusting and skeptical of medical professionals and social workers, and rightfully so, due to a long history of mistreatment and deeply ingrained stigma. Harm reduction organizations, such as syringe service programs (SSPs), and the workers who deliver services have secured the trust and respect of participants and have a unique opportunity to provide health care services and mobilize community involvement in research [ 5 , 6 ].

When researchers view PWUD solely as research subjects and within a strict binary of researcher/researched—where PWUD are interpolated as either vectors of information or a means to recruit study participants—they fail to recognize (or communicate) how circumstantial complications can influence health outcomes and how the combined factors of agent, host, and environment contribute to disease transmission and/or acquisition of injury. By collaborating with people who actually perform the drug use behaviors under investigation in a genuine and transparent relationship, all components of the research process described above are enhanced. For example, the North Carolina Survivors Union (NCSU), a robust, drug-user union in central North Carolina, maintains strong professional relationships with researchers and academic institutions and welcomes collaboration. NCSU has served as a subcontractor on numerous NIH, FDA, and industry-funded research projects. The union has been involved in cutting edge research led by PWUD, including hepatitis testing and linkage-to-care, fentanyl test strip distribution [ 3 ], and community-based drug checking. Successful collaboration between NCSU and external research organizations has been driven by attainment of genuine “meaningful collaboration.”

Tokenistic attempts at involving PWUD in research (i.e., advisory boards) might look good at face value, but refuse to give community members the power needed to make change and offer consequential insight to the research process. In fact, advisory boards can cause more harm than good, furthering the divide between PWUD and researchers. With this considered, NCSU has installed processes, largely informed by the principles of community driven research (CDR) [ 7 ], to avoid such experiences. Research collaborations begin with an informal meeting between NCSU and researchers to discuss objectives, methods, findings dissemination, party responsibilities, and other logistics. Project ideas are born out of mutual collaboration, as opposed to researchers approaching the organization with a fully developed project in hand. Instead, the proposed framework encourages community-initiated research questions, centering the needs of those performing the behaviors in question. This meeting lays the groundwork for a mutually beneficial and respectful collaboration, while developing relevant research ideas aimed to directly benefit the community. As projects materialize, infrastructure is created to allow for expression of needed modifications and expectations. Collaborations have resulted in conducting on-site needs assessment surveys, in-person interviews, development of health education materials, and more. Following project implementation, dispersal of results prioritizes community-based utilization. NCSU, along with its research partners, ensures undertaken projects will be as beneficial for community members as they are for academics.

Many other harm reduction programs like NCSU exist across the country. These organizations present a unique opportunity for collaborations between researchers and PWUD. In fact, researchers and PWUD should not be considered as two mutually exclusive roles. Rather, research institutions should make a concerted effort to hire PWUD and create opportunities for career growth. This may be sought through a number of potential paths, including collaboration with community-led organizations who can facilitate ongoing, mutually beneficial relationships between PWUD and research institutions, and emphasis on recruiting PWUD who are in pursuit of careers in research through traditional channels (i.e., higher education and formal research training) to join staff. However, it is important to note institutional barriers lock many PWUD out of conventional mechanisms of research training, and consequently long-term employment in the field of research. Obstructions are frequently due to prior felony convictions, as the war on drugs has pushed so many PWUD into encounters with the criminal justice system. As such, it is imperative to the growth of the field of substance use research that research institutions learn to better navigate the line between accountability and flexibility. As long as research institutions uphold these obstacles to the advancement of PWUD in the field of research, they amplify the influence of the criminalization of substance use and inhibit maximized benefit of research efforts on public health. Still, we caution researchers from simply hiring or collaborating with PWUD without thorough thought about how to establish and maintain a relationship grounded in respect and openness, in addition to holding a mission to improve the health and wellbeing of PWUD.

Research as a career path for PWUD

Currently, the common career paths for PWUD accepted by society are limited to those serving other PWUD in social service settings, such as peer support specialists. While providing services to others can be beneficial to both the persons receiving and delivering the services, these jobs are often underpaid and can lack critical benefits that traditionally accompany other types of full-time employment (e.g., health insurance, retirement benefits) [ 8 ]. We argue research is another field in which employment of PWUD would be mutually beneficial. The field of research is filled with many accomplished individuals with respective areas of expertise. PWUD, too, hold their own area of expertise: drug use and the many related health factors and outcomes. Rather than stigmatize PWUD for their use, we should see them for their value as experts. Due to long held stigmatization of drug use, discrimination can present in the researcher themselves, their organizations, and the policies that fund research. Researchers may even suppress or withhold information about their own drug use in order to protect their professional reputation and employment status from drug-related stigma. Therefore, to change the landscape of drug use research, we argue it is the responsibility of researchers to enact change by creating employment opportunities for PWUD in which their expertise is valued and respected and where they are seen as equals with their colleagues [ 9 ].

To this end, the power imbalances between PWUD and formally trained researchers must be dismantled. While we would certainly encourage PWUD hoping to pursue research as a career path to follow continuing education and relevant certification opportunities, barriers to these formalized systems of education must be acknowledged. Furthermore, a credential or degree does not replace the invaluable experiential knowledge held by PWUD. As such, credentials and degrees should not serve as the standard by which we judge a person’s capacity to contribute to the research process. Rather, it is the responsibility of the researcher, and relevant partnering organizations, to empower PWUD to participate in the research process in a meaningful way. Dependent upon the research project, we recommend project and role specific training for PWUD, as well as equitable allocation of legitimate decision-making power. Likewise, it is essential researchers nurture long-lasting relationships with non-profits and other community-led organizations they intend to work with. As opposed to only interacting during the project period, which is not conducive to ongoing training for PWUD, enduring relationships foster continuing professional development as well as collaborations built in trust. These strategies will furnish PWUD with the skills and opportunities necessary to genuinely influence the research process.

To be clear: we are not suggesting researchers include any and all people who have used drugs. Instead, we are advocating for increasing the participation of PWUD who have the relevant experience and expertise with the drug types, consumption techniques, and environments being investigated. Particularly given the current fluidity of the drug market, those actively engaged are best situated to speak to present-day trends. Moreover, it is vital PWUD included in the research process possess the situational understanding to critically assess the current use environment and contribute to impactful investigation. These individuals are well positioned to provide accurate and timely information that can strengthen analyses of the drug, set, and setting factors that influence consumption behavior and negative health outcomes [ 10 ]. Drug user unions like NCSU are already playing an integral role in public health research by aiding researchers to better involve PWUD in research efforts. Concisely stated: something can be statistically meaningful when chasing p -values but be socially and medically irrelevant for effectiveness and successful implementation.

Representation and guidance from PWUD is also critical to translating scientific knowledge gained through research into improved public policies and direct service practices. Some public health authorities approach that translation process through advisory boards or other bodies with a nominal ‘voice’, but the inclusion of PWUD among bodies with a formal ‘vote’ remains rare. Oregon’s Drug Addiction Treatment and Recovery Act of 2020, passed by ballot initiative in November 2020, decriminalized possession of small amounts of controlled substances and redirected cannabis tax revenues to an Oversight and Accountability Council tasked with overseeing grants to implement Addiction Recovery Centers and increase access to community care [ 11 ]. The Oversight and Accountability Council is required to include at least two members, “who suffered or suffer from substance use disorder,” and while that language would be improved by centering on members’ lived experience without the characterization of ‘suffering’, the inclusion of people who use(d) drugs as voting members of a body empowered to direct public funding for drug-related health and social services provides an opportunity for increasingly equitable structures of public policy and governance.

Conclusions

If the goal, especially during a lethal overdose epidemic, is to conduct research that can contribute to the development of useful, evidence-based interventions the likes of needle exchange, lay naloxone distribution, onsite wound care, safer injection education, fentanyl test strips, and peer navigation, then it is plainly obvious researchers need to include and expand efforts to collaborate with PWUD. Given the rising rates of drug-involved morbidity and mortality, it is high time to include people who use drugs in public health efforts. Our lives depend on it.

Availability of data and materials

Not applicable.

Abbreviations

• People who use drugs
• Syringe service programs

North Carolina Survivors Union

National Institutes of Health

U.S. Food and Drug Administration

• Community driven research

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Acknowledgements

We are appreciative of Dr. Jon E. Zibbell, who offered critical review and formative conversation in development of this article.

This project was supported in part through a U.S. Food and Drug Administration contract to the University of North Carolina (HHSF223201810183C). The funding organization was not involved in any aspect of the development, writing, or submission of this manuscript.

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All authors contributed significantly to the conceptualization of this manuscript. ZS led drafting, assisted by MF and MG. ZS and MF conducted literature searches. All authors revised and approved the final manuscript.

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ND’s participation in this research was conducted solely as part of academic duties as a member of the faculty at the University of North Carolina at Chapel Hill. ND is a part-time methods consultant to the RADARS System, which was not involved in nor had knowledge of this manuscript. The RADARS System is supported by subscriptions from pharmaceutical manufacturers, governmental and non-governmental agencies for data, research and reporting services. RADARS System is the property of Denver Health and Hospital Authority, a political subdivision of the State of Colorado (United States of America). Subscribers do not participate in data collection nor do they have access to raw data; Denver Health retains exclusive ownership of all data, databases and systems. Employees are prohibited from personal financial relationships with any biopharmaceutical company. The other authors declare that they have no competing interests.

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Salazar, Z.R., Vincent, L., Figgatt, M.C. et al. Research led by people who use drugs: centering the expertise of lived experience. Subst Abuse Treat Prev Policy 16 , 70 (2021). https://doi.org/10.1186/s13011-021-00406-6

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Single-cell RNA sequencing of human tissue supports successful drug targets

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Early characterization of drug targets associated with disease can greatly reduce clinical failures attributed to lack of safety or efficacy. As single-cell RNA sequencing (scRNA-seq) of human tissues becomes increasingly common for disease profiling, the insights obtained from this data could influence target selection strategies. Whilst the use of scRNA-seq to understand target biology is well established, the impact of single-cell data in increasing the probability of candidate therapeutic targets to successfully advance from research to clinic has not been fully characterized. Inspired by previous work on an association between genetic evidence and clinical success, we used retrospective analysis of known drug target genes to identify potential predictors of target clinical success from scRNA-seq data. Particularly, we investigated whether successful drug targets are associated with cell type specific expression in a disease-relevant tissue (cell type specificity) or cell type specific over-expression in disease patients compared to healthy controls (disease cell specificity). Analysing scRNA-seq data across 30 diseases and 13 tissues, we found that both classes of scRNA-seq support significantly increase the odds of clinical success for gene-disease pairs. We estimate that combined they could approximately triple the chances of a target reaching phase III. Importantly, scRNA-seq analysis identifies a larger and complementary target space to that of direct genetic evidence. In particular, scRNA-seq support is more likely to prioritize therapeutically tractable classes of genes such as membrane-bound proteins. Our study suggests that scRNA-seq-derived information on cell type- and disease-specific expression can be leveraged to identify tractable and disease-relevant targets, with increased probability of success in the clinic.

Competing Interest Statement

ED has consulted for Ensocell Therapeutics. ET, GG, FN, EdR are employees of Sanofi and own Sanofi stock. VS has been leading the application of single-cell biology for drug development at Sanofi since 2018 and owns Sanofi stock. RE is a co-founder and employee of Ensocell Therapeutics. SAT has consulted for or been a member of scientific advisory boards at Qiagen, Sanofi, GlaxoSmithKline and ForeSite Labs. She is a consultant and equity holder for TransitionBio and Ensocell Therapeutics.

Funding Statement

ED, KBM and SAT. acknowledge Wellcome Sanger core funding (WT206194).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

https://cellxgene.cziscience.com/collections

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data availability

All scRNA-seq data analysed in this study is available via the CZ CellxGene Discover database and CxG Census API ( https://chanzuckerberg.github.io/cellxgene-census/ , version: 2023-07-25). Data on clinical precedence for known drugs for each target-disease pair, as well as gene-disease genetic association scores, was downloaded from Open Targets (version 23.02, https://platform.opentargets.org/downloads/data ). Data on gene tolerance to loss-of-function mutations (LOEUF, loss-of-function observed/expected upper bound fraction) was extracted from gnomAD.v2.1’s pLoF metrics by gene data [ 80 ] ( https://gnomad.broadinstitute.org/downloads ). Gene sets used as universes for association analysis are available at https://github.com/emdann/sc_target_evidence/blob/master/data/universe_genes.csv . Processed datasets and analysis outputs are available as supplementary tables and via figshare (doi:10.6084/m9.figshare.25360129).

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2 (page 15) p. 15 How drugs work

• Published: June 2016
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‘How drugs work’ outlines the basic mechanisms of pharmacology. Drugs are chemicals that can be naturally occurring or man-made, and which can be administered in a variety of ways. They can act on receptors—often highly specific proteins in cells which can up-regulate or down-regulate processes—or on other targets, such as DNA or enzymes. The molecular action of drugs can be investigated in a lab, but the effects on the whole organism are more important. Effective doses need to be determined, taking into account metabolic rates, drug interactions, and side effects. Prolonged drug use can cause tolerance and substance addiction.

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• Published: 19 October 2023

Drug repurposing: a nexus of innovation, science, and potential

• Maria Cristina De Rosa   ORCID: orcid.org/0000-0002-9611-2490 1 ,
• Rituraj Purohit 2 , 3 &
• Alfonso T. García-Sosa   ORCID: orcid.org/0000-0003-0542-4446 4  

Scientific Reports volume  13 , Article number:  17887 ( 2023 ) Cite this article

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The urgency of finding therapeutic solutions for emerging and existing health challenges has never been more pronounced. In the pursuit of this goal, the value of a strategy that makes use of existing resources is being recognized: drug repurposing or repositioning of compounds for new indications. Such approaches are employed against cancer, rheumatoid arthritis, multiple sclerosis, HIV/AIDS, and many other diseases. This Collection, aptly titled “Drug Repurposing”, includes research and perspectives from scientists at the forefront of this innovative field.

Reinvigorating the drug discovery pipeline

In the traditional drug discovery pipeline, the journey from an idea to an approved therapy is long, costly, and fraught with uncertainty. The failure rate is high, and the financial and temporal investments are significant. Drug repurposing is an alternative strategy that allows to reduce the time and costs of pharmaceutical research in which new uses are identified for drugs already approved or under investigation. In the last decades, many successful examples of repositioning have been reported for the treatment of different pathologies 1 . Through the strategic redirection of existing drugs, molecules, or compounds that have already passed safety tests, in fact, drug repurposing or repositioning accelerates the pace of discovery. The research presented in this Collection illuminates various facets of experimental and computational drug repurposing, reflecting its complexity, potential, and burgeoning maturity.

A Tapestry of techniques and targets

What strikes the reader of this Collection is the diversity of techniques and targets that may be involved in drug repurposing. From machine learning (ML)-driven frameworks for kinase inhibitor repositioning, to the utilization of natural products as potential therapeutics against viral infections, the methodologies are as varied as they are inventive. The Collection also showcases the integration of multi-disciplinary sciences. Computational techniques, pharmacological insights, and molecular biology interweave to form a cohesive picture of a promising and dynamic field.

Leveraging artificial intelligence

Several papers in this Collection highlight the role of artificial intelligence (AI) and machine learning in drug repurposing. These advanced computational methods allow researchers to sift through vast amounts of data, identify hidden patterns, and generate insights that would be very difficult to uncover through traditional means. The KUALA framework is a prime example, automating the identification of kinase active ligands and prioritizing multi-target scores for best repurposable molecules 2 . Emphasizing the high similarity of kinase binding sites, the research underscores its dual role in drug selectivity and poly-pharmacology. Leveraging this similarity, De Simone et al. explore the potential for drug repositioning on analogous targets 2 . KUALA, which employs 12 different machine learning methods for classification, successfully assigned kinase inhibitors currently in clinical trials, to each of the known targets in 84% of cases.

In two other papers published as part of this Collection, Hetmann et al. 3 and Pirolli et al. 4 successfully combined physics-based computational methods with deep learning models showing how science adapts and evolves to meet the challenges of drug repurposing. The novel computational pipeline CavitomiX 3 , based on active site cavity comparisons, was capable of identifying inhibitors for selected target enzymes. This technology offers a novel drug repurposing approach, independent of structure and sequence alignments, identifying two approved drugs, fusidic and flufenamic acid, as exhibiting anti-viral activity against SARS-CoV-2. Notably, the established computational pipeline can be quickly modified to address new pathogens.

Expanding the scope of repurposing

Scientists contributing to the Collection address diverse therapeutic needs. This Collection illustrates how repurposed drugs can be explored for COVID-19, Alzheimer’s disease (AD), and infectious diseases. Parolo et al. present a comprehensive study on AD, for which, despite significant investments in drug development, only one disease-modifying treatment has been recently approved 5 . The researchers introduce a single cell-led systems biology pipeline for identifying drug repurposing candidates. By leveraging single-cell RNA sequencing data from brain tissues of AD patients, genome-wide association study results, and multiple gene annotation resources, they constructed a multi-cellular AD disease molecular network. This network provided cell-specific insights into AD pathophysiology and identified 54 candidate drugs, primarily targeting MAPK and IGF1R signaling pathways, for potential AD therapy.

Another study addressed the urgency to discover solutions for antibiotic resistance with innovative approaches that explore the therapeutic potential of natural products and their synthetic derivatives 6 . These efforts reflect a broader shift in thinking, where drug repurposing is not merely a tactic but a holistic strategy to respond to global health concerns.

Schake et al. delve into the role of the gut microbiota in modulating the effects of dietary polyphenols on human health 7 . The study highlights the bidirectional interactions between polyphenols and gut microbiota, emphasizing the importance of microbial metabolism in determining the bioavailability and bioactivity of polyphenols. The researchers provide insights into the potential health benefits of polyphenols, including anti-inflammatory, antioxidant, and anti-cancer properties. They also discuss the challenges in studying polyphenol-microbiota interactions and suggest future research directions to harness the therapeutic potential of dietary polyphenols.

Navigating challenges

The path to successful drug repurposing is not without challenges. Issues of selectivity, toxicity, and the intricate balance between binding site similarity and the number of targets are just a few of the complex considerations that must be navigated. The provision of experimental results can, as ever, help to make predictions stronger and better focused and explainable. Despite this, a drug may be effective in a different application case, but at doses that render it unusable or ineffective for another indication due to issues of efficacy or side-effects, the most common obstacles to drug approvement 8 . However, there is a long and solid history of off-label use of pharmaceutical products in the clinic for indications other than the primary or listed case. Another avenue for possible development is finding new targets that have not been described or targeted yet but may have clinical use such as in the illuminating the druggable genome project 9 with compounds that are already known to be safe. In addition, companies are in some cases donating some of their libraries or collaborating with institutions such as the DNDi to help make compounds accessible for vector-based diseases 10 . The research within this Collection does not shy away from these opportunities and challenges, providing valuable insights and analytical rigor to guide future efforts.

Pushpakom, S. et al. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 18 , 41–58. https://doi.org/10.1038/nrd.2018.168 (2019).

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Hetmann, M. et al. Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX. Sci. Rep. 13 , 11783. https://doi.org/10.1038/s41598-023-39071-z (2023).

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Pirolli, D. et al. Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface. Sci. Rep. 13 , 1494. https://doi.org/10.1038/s41598-023-28716-8 (2023).

Parolo, S. et al. Single-cell-led drug repurposing for Alzheimer’s disease. Sci. Rep. 13 , 222. https://doi.org/10.1038/s41598-023-27420-x (2023).

Rossiter, S., Fletcher, M. & Wuest, W. Natural products as platforms to overcome antibiotic resistance. Chem. Rev. 117 , 12415–12474. https://doi.org/10.1021/acs.chemrev.7b00283 (2017).

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Schake, P. et al. An interaction-based drug discovery screen explains known SARS-CoV-2 inhibitors and predicts new compound scaffolds. Sci. Rep. 13 , 9204. https://doi.org/10.1038/s41598-023-35671-x (2023).

Yang, H. et al. In silico prediction of chemical toxicity for drug design using machine learning methods and structural alerts. Front. Chem. 6 , 30. https://doi.org/10.3389/fchem.2018.00030 (2018).

Nguyen, D. T. et al. Pharos: Collating protein information to shed light on the druggable genome. Nucleic Acids Res. 45 , D995–D1002. https://doi.org/10.1093/nar/gkw1072 (2017).

Drugs for Neglected Diseases initiative, https://dndi.org/research-development/treatments-delivered/ . Last website visit 22.09.2023.

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Acknowledgements

ATG-S thanks the EU COST (European Cooperation in Science and Technology) Action 21111 OneHealthDrugs, EU Partnerships in Health (2021) (HORIZON-HLTH-2021-ENVHLTH-03) Partnership for the Assessment of Risk from Chemicals (PARC), as well as the Estonian Research Council (grant PRG1509) for support.

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Maria Cristina De Rosa

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Rituraj Purohit

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ATG-S wrote the first draft; MCDR and ATG-S wrote the second draft; MCDR, RP, and ATG-S wrote the final draft. All authors contributed to revisions.

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De Rosa, M.C., Purohit, R. & García-Sosa, A.T. Drug repurposing: a nexus of innovation, science, and potential. Sci Rep 13 , 17887 (2023). https://doi.org/10.1038/s41598-023-44264-7

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This outdated diabetes drug still has something to offer

By learning how an old diabetes drug works, researchers are discovering new, safer treatment options.

Thiazolidinediones (TZDs) are a class of drug that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main hallmarks of the disease. While TZDs were extremely popular in the 1990's and early 2000's, they have fallen out of use among physicians in recent decades because they were discovered to cause unwanted side effects, including weight gain and excess fluid accumulation in body tissues.

Now, researchers at University of California San Diego School of Medicine are exploring how to isolate the positive effects of these drugs, which could help yield new treatments that don't come with the old side effects. In a new study published in Nature Metabolism , the researchers discovered how one of the most well-known TZD drugs works at the molecular level and were able to replicate its positive effects in mice without giving them the drug itself.

"For decades, TZDs have been the only drugs we have that can reverse insulin resistance, but we seldom use them anymore because of their side effects profile," said Jerrold Olefsky, M.D., a professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences. "Impaired insulin sensitivity is the root cause of type 2 diabetes, so any treatment we can develop to safely restore this would be a major step forward for patients."

The main driver of insulin resistance in type 2 diabetes is obesity, which currently affects more than 40 percent of Americans and in 2021 bore an annual medical cost of nearly $173 billion. In addition to causing adipose tissue (fat) to expand, obesity also causes low levels of inflammation. This inflammation causes immune cells, called macrophages, to accumulate in adipose tissue, where they can comprise up to 40 percent of the total number of cells in the tissue.

When adipose tissue is inflamed, these macrophages release tiny nanoparticles containing instructions for surrounding cells in the form of microRNAs, small fragments of genetic material that help regulate gene expression. These microRNA-containing capsules, called exosomes, are released into the circulation and can travel through the bloodstream to be absorbed by other tissues, such as the liver and muscles. This can then lead to the varied metabolic changes associated with obesity, including insulin resistance. For the current study, the researchers wanted to understand how TZD drugs, which restore insulin resistance, affect this exosome system.

The researchers treated a group of obese mice with rosiglitazone, a type of TZD drug. Those mice became more sensitive to insulin, but they also gained weight and retained excess fluid, known side effects of rosiglitazone. However, by isolating exosomes from the adipose tissue macrophages of the mice who had received the drug and injecting them into another group of obese mice that had not received it, the researchers were able to deliver the positive effects of rosiglitazone without transferring the negative effects.

"The exosomes were just as effective in reversing insulin resistance as the drug itself but without the same side effects," said Olefsky. "This indicates that exosomes can ultimately link obesity-related inflammation and insulin resistance to diabetes. It also tells us that we may be able to leverage this system to boost insulin sensitivity."

The researchers were also able to identify the specific microRNA within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone. This molecule, called miR-690, could eventually be leveraged into new therapies for type 2 diabetes.

"It's likely not practical to develop exosomes themselves as a treatment because it would be difficult to produce and administer them, but learning what drives the beneficial effects of exosomes at the molecular level makes it possible to develop drugs that can mimic these effects," said Olefsky. "There's also plenty of precedent for using microRNAs themselves as drugs, so that's the possibility we're most excited about exploring for miR-690 going forward."

• Personalized Medicine
• Colon Cancer
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• Diet and Weight Loss
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• Diabetes mellitus type 1
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Materials provided by University of California - San Diego . Original written by Miles Martin. Note: Content may be edited for style and length.

Journal Reference :

• Theresa V. Rohm, Felipe Castellani Gomes Dos Reis, Roi Isaac, Cairo Murphy, Karina Cunha e Rocha, Gautam Bandyopadhyay, Hong Gao, Avraham M. Libster, Rizaldy C. Zapata, Yun Sok Lee, Wei Ying, Charlene Miciano, Allen Wang, Jerrold M. Olefsky. Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization . Nature Metabolism , 2024; DOI: 10.1038/s42255-024-01023-w

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A systematic analysis of FDA-approved anticancer drugs

Jingchun sun.

1 School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030 USA

2 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China

Jingqi Wang

3 Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37203 USA

Associated Data

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

The discovery of novel anticancer drugs is critical for the pharmaceutical research and development, and patient treatment. Repurposing existing drugs that may have unanticipated effects as potential candidates is one way to meet this important goal. Systematic investigation of efficient anticancer drugs could provide valuable insights into trends in the discovery of anticancer drugs, which may contribute to the systematic discovery of new anticancer drugs.

In this study, we collected and analyzed 150 anticancer drugs approved by the US Food and Drug Administration (FDA). Based on drug mechanism of action, these agents are divided into two groups: 61 cytotoxic-based drugs and 89 target-based drugs. We found that in the recent years, the proportion of targeted agents tended to be increasing, and the targeted drugs tended to be delivered as signal drugs. For 89 target-based drugs, we collected 102 effect-mediating drug targets in the human genome and found that most targets located on the plasma membrane and most of them belonged to the enzyme, especially tyrosine kinase. From above 150 drugs, we built a drug-cancer network, which contained 183 nodes (150 drugs and 33 cancer types) and 248 drug-cancer associations. The network indicated that the cytotoxic drugs tended to be used to treat more cancer types than targeted drugs. From 89 targeted drugs, we built a cancer-drug-target network, which contained 214 nodes (23 cancer types, 89 drugs, and 102 targets) and 313 edges (118 drug-cancer associations and 195 drug-target associations). Starting from the network, we discovered 133 novel drug-cancer associations among 52 drugs and 16 cancer types by applying the common target-based approach. Most novel drug-cancer associations (116, 87%) are supported by at least one clinical trial study.

Conclusions

In this study, we provided a comprehensive data source, including anticancer drugs and their targets and performed a detailed analysis in term of historical tendency and networks. Its application to identify novel drug-cancer associations demonstrated that the data collected in this study is promising to serve as a fundamental for anticancer drug repurposing and development.

In the last 50 years, numerous remarkable achievements have been made in the fight against cancer, starting from understanding cancer mechanisms to patient treatment. However, cancer remains as one of the leading causes of death in the world, which places a heavy burden on health services and society. Cancer involves abnormal cell growth with the potential to invade or spread to other parts of the body and encompasses more than 100 distinct diseases with diverse risk factors and epidemiology. Over the past five decades, scientific discoveries and technological advances, including modern molecular biology methods, high-throughput screening, structure-based drug design, combinatorial and parallel chemistry, and the sequencing of the human genomes have improved the drug discovery. However, the increasing cost of new drug development and decreasing number of truly efficient medicines approved by the US Food and Drug Administration (FDA) present unprecedented challenges for the pharmaceutical industry and patient healthcare, including the oncology [ 1 , 2 ]. As the increasing availability of FDA-approved drugs and quantitative biological data from the human genome project, multiple strategies have been proposed to shorten the drug development process and significantly lower costs, including drug repurposing [ 3 , 4 ] and network pharmacology [ 5 , 6 ].

With advances in anticancer drug discovery and development in the last several decades, more than 100 anticancer drugs have been discovered and approved by the FDA [ 7 , 8 ]. These drugs can be broadly classified into two basic categories: cytotoxic and targeted agents based on their mechanisms of action [ 9 – 11 ]. The cytotoxic agents can kill rapidly dividing cells by targeting components of the mitotic and/or DNA replication pathways. The targeted agents block the growth and spread of cancer through interacting with molecular targets that are involved in the pathways relevant to cancer growth, progression, and spread [ 12 ]. Those successful agents and their related data may provide valuable clues for further identification of novel drug targets, the discovery of novel anticancer drug combinations, drug repurposing, and computational pharmacology. Several reviews have provided the historical summary of these drugs, which revealed the trends of increasing proportion of targeted agents, particularly monoclonal antibodies [ 7 , 8 ]. Recently network pharmacology has successfully applied in multiple fields such as target identification, prediction of side effects, and investigation of general patterns of drug actions [ 5 , 13 , 14 ]. Therefore, besides of updating the FDA-approved anticancer drugs, analysis of drug-disease/target networks will significantly increase our understanding of the molecular mechanisms underlying drug actions and provide valuable clues for drug discovery.

Thus, in this study, we first comprehensively collected the FDA-approved anticancer drugs by the end of 2014 and curated their related data, such as initial approval years, action mechanisms, indications, delivery methods, and targets from multiple data sources. According to their action mechanisms, we classified them into two groups: cytotoxic and targeted drugs. Then, we analyzed these data to reveal the different trends between the two groups. Besides, we analyzed the drug targets by investigating their subcellular locations, functional classifications, and genetic mutations. Finally, we generated anticancer drug-disease and drug-target networks to capture the common anticancer drugs across different types of cancer and to reveal how strongly the anticancer drugs and targets interact or drug-target networks. The network-assisted investigation provides us with novel insights into the relationships among anticancer drugs and disease or drugs and targets, which may provide valuable information for further understanding anticancer drugs and the development of more efficient treatments.

Collection of FDA-approved anticancer drugs and their relation information

We have collected anticancer drugs approved by FDA since 1949 to the end of 2014 from multiple data sources. We started the collection of the anticancer drugs from anticancer drug-focused websites, including National Cancer Institute (NCI) drug information [ 15 ], MediLexicon cancer drug list [ 16 ], and NavigatingCancer [ 17 ]. Then, we employed the tool MedEx-UIMA, a new natural language processing system, to retrieve the generic names for these drugs [ 18 ]. Using the generic names, we searched Drug@FDA [ 19 ] and downloaded their FDA labels. For those that cannot be found in the drugs@FDA, we obtained their labels from Dailymed [ 20 ] or DrugBank [ 21 ]. From the drug label, we manually retrieved the initial approval year, drug action mechanism, drug target, delivery method, and indication for each drug. We further checked the multiple sources such as the MyCancerGenome [ 22 ], DrugBank, and the several publications [ 4 , 23 ] to obtain the drug targets. For drug category, we manually checked the ChemoCare [ 24 ] to assign the drugs as cytotoxic or targeted agents. In our curated drug list, we did not include the medicines to treat drug side effects, cancer pain, other conditions, or cancer prevention.

Classes of drug targets and cancer

For these targeted agents, we collected their targets from FDA drug labels, DrugBank, and MyCancerGenome. We then manually curated the primary effect-mediating targets for each drug. We further retrieved the gene annotation from Ingenuity Pathway Analysis (IPA) [ 25 ] to obtain their subcellular location and family classes. For the indication, we first collected the detail information from FDA drug labels and then manually classified them into higher-level class for the purpose of data analysis. For example, drug idelalisib can be used to treat relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), relapsed small lymphocytic lymphoma (SLL) from FDA labels. In our data analysis, we recorded the drug’s therapeutic classes as leukemia and lymphoma.

Cancer genes and somatic mutations of the cancer genome

The cancer gene set contains 594 genes from the Cancer Gene Census, which have been implicated in tumorigenesis by experimental evidence in the literature (July 14, 2016) [ 26 ]. We obtained 50 oncogenes (OCGs) and 50 tumor suppressor genes (TSGs) with high confidence from Davioli et al. [ 27 ]. The somatic mutations were obtained from Supplementary Table 2 in one previous work [ 28 ]. The table contains the somatic mutations in 3268 patients across 12 types of cancer. They are bladder urothelial carcinoma (BLCA), breast adenocarcinoma (BRCA), colon and rectal adenocarcinoma (COAD/READ), glioblastoma (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian cancer (OV), and uterine corpus endometrioid carcinoma (UCEC). The mutations include missense, silent, nonsense, splice site, readthrough, frameshift indels (insertions/deletions) and inframe indels [ 28 ].

Network analysis

We built two networks based on our curated data, drug-cancer and drug-cancer-target networks. In the drug-cancer network, there are two types of nodes representing drug or cancer types and edges suggesting drug as the approved treatment for the cancer. In the drug-cancer-target network, there are three types of nodes representing cancer types, drug or drug target and edges indicating cancer-drug associations or drug-target interactions. The network degree is used to assess the toplogical feature of each cancer type and drug, i.e., the number of edges of each node in the network.

Common target-based approach

We used common target-based approach to discover novel drug-cancer associations [ 29 ]. It is one of the “guilt-by-association” strategies based on the knowledge that whether the drugs shared common targets or not. If two drugs A and B have a common target, drug A is in current use for treating cancer type C and drug B is used for cancer type D, it is highly likely to be effective for drug A-cancer type D and drug B-cancer type C associations.

Results and Discussion

Fda-approved anticancer drugs.

From 1949 to 2014, a total of 150 medicines has been approved with an indication for at least one type of cancer (Table ​ (Table1). 1 ). Notably, in this study, we did not include the drugs used to treat side effects of cancer treatment, cancer pain, and other conditions. Based on the mechanism of action (MOA), we grouped them into two groups: 61 cytotoxic drugs and 89 targeted drugs. Most of the cytotoxic drugs are alkylating agents, anti-microtubule agents, topoisomerase inhibitors while most of the targeted drugs belong to signal transduction inhibitors, gene expression modulators, apoptosis induces, hormone therapies, and monoclonal antibodies. Figure ​ Figure1 1 shows that the number of approved drugs in cancer treatment had a gradual increase. In the later years (1991–2014), the number of approved anticancer (116 drugs) extremely increased compared to that of the previous five decades (1941–1990, 34 drugs). Even in the recent years (2011–2014), the annual average number was 9, which was about 2.5 times of that in 1991–2000 (3.8) or 2001–2010 (4.2). From 1991 to 2000, the number of anticancer targeted drugs (17) was similar to that of cytotoxic drugs (21). However, since the 2000s, the number of targeted drugs (65) was significantly higher than that of the cytotoxic drugs (13), which was about five times.

Summary of FDA-approved anticancer drugs from 1949 to 2014

Number of anticancer drugs approved by FDA from 1949 to 2014. Approval dates were retrieved from FDA drug labels. Drugs were divided into two categories according to their action mechanisms. The inserted table is the summary of drug numbers for each decade

Among 89 targeted drugs, 18 are antibodies, of which two (rituximab and trastuzumab) were approved in 1990, eight in the 2000s (gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab and iodine I 131 tositumomab, bevacizumab, cetuximab, panitumumab, and ofatumumab) and seven from 2010 to 2014 (denosumab, brentuximab vedotin, ipilimumab, pertuzumab, ado-trastuzumab emtansine, obinutuzumab, and pembrolizumab). The trend was consistent with previous observations [ 7 ], which indicated that the advanced molecular understanding of cancer during the period had contributed substantially to the development of the anticancer drug, especially targeted drugs [ 30 ].

According to the drug delivery method administered to the patient, one drug can be categorized as a cancer single (individual) drug or a cancer combination drug. A combination drug is a drug that makes up a cancer drug combination that several individual drugs are administered to the patient. Though the targeted agents have become the primary focus of the therapeutic cancer research, investigation of their combined use with other targeted drugs or with cytotoxic drugs has become promising for the development of the effective cancer treatment [ 31 , 32 ]. Among the 150 drugs, 96 drugs could be given to patients one at a time, 22 could be given in combination with other cancer drugs to patients, and 32 drugs could be delivered to patients as the combination drugs or single drugs (Fig. ​ (Fig.2). 2 ). The targeted drugs tended to be delivered as signal drugs (Pearson’s correlation: r  = 0.92, P  < 2.2 × 10 −26 ) while cytotoxic drug tended to be delivered as combination drugs ( r  = 0.43, P  = 0.002) or by both methods ( r  = 0.44, P  = 0.001).

Delivery methods of anticancer drugs approved by FDA from 1949 to 2014

Subcellular location and function of drug targets

In our curated data set, among the 150 anticancer FDA-approved drugs, 89 were targeted drugs that could be used to treat 23 types of cancer and acted on 102 protein targets (Tables ​ (Tables1, 1 , ​ ,2). 2 ). To comprehensively understand the target functions and their genetic roles in cancer, we performed a survey from the perspectives of subcellular location, functional classification, and genetic mutations. These insights might be valuable for further understanding of molecular mechanisms of cancer and the advanced development of cancer therapy [ 30 , 33 , 34 ].

Subcellular location and function classification of targeted drug targets

We retrieved the target’s subcellular information and function classification from IPA and manually reviewed for each target (Table ​ (Table2). 2 ). The result shows that most of the drug targets (45, 44%) located in the plasma membrane, 27 (26%) in the cytoplasm, 23 (23%) in the cell nucleus, and only seven (7%) in the extracellular space (Fig. ​ (Fig.3a). 3a ). Among the 45 targets in the plasma membrane, 21 were tyrosine kinases, 12 were transmembrane receptors, five were antigens, and five were G-protein coupled receptors. Among the 27 targets in the cytoplasm, 23 were enzymes and four were others. Among the 23 targets in the nucleus, 13 were enzymes and 10 were receptors. The observation indicates that, to date, the most successful anticancer drugs target the plasma membrane proteins.

Anticancer drug target percentage of subcellular locations a and function families b and c

The data set showed that enzymes made up the largest groups of drug targets (58, 57%) while receptors were the second largest group of anticancer target proteins (27, 26%) (Fig. ​ (Fig.3b). 3b ). Of these enzymes, 28 (27%) were tyrosine kinases, eight (8%) were the serine/threonine kinases, six (6%) were peptidases, and five (5%) were epigenetic enzymes (Fig. ​ (Fig.3c). 3c ). Of these receptors, 12 (12%) were transmembrane receptors, 10 (10%) were ligand-dependent nuclear receptors, and five (5%) were G-protein coupled receptors (Fig. ​ (Fig.3c 3c ).

Genetic pattern of targeted anticancer targets

To check if these targets are the cancer candidate genes, we compared them with the cancer gene set which contains 594 genes from the Cancer Gene Census [ 26 ]. Among 102 target genes, 32 genes are cancer genes. Compared to all the protein-coding genes in the human (20,729), the anticancer drug targets were significantly enriched with cancer genes (Hypergeometric test, P -value = 3.57 × 10 −25 ). Among the 32 cancer genes, 16 were oncogenes while none were tumor suppressor genes according to the the high confidence TSGs and OCGs from Davioli et al. [ 27 ].

To further explore the mutation pattern of the anticancer drug targets, we utilized the somatic mutations in 3268 patients across 12 types of cancer from TCGA Pan-Cancer [ 28 ]. Among 102 drug targets, 32 were cancer genes. Thus we compared the mutation frequency of four gene sets: 32 genes belonging to drug targets and cancer genes (TargetCancer genes), 70 genes only belonging to genes encoding drug targets (TargetOnly genes), 537 cancer genes only belonging to cancer genes and with mutation data (CancerOnly genes), and 20,308 genes with mutation data excluding the genes from above three gene sets (Other genes). To compare the distribution of mutation frequency of the tumor samples among the four gene sets, we performed the Kolmogorov-Smirnor (K-S) tests. Figure ​ Figure4a 4a shows the comparison of mutation percentage of all samples in each gene set. The TargetCancer genes had the highest average mutation frequency (2.41%), which was significantly higher than that of TargetOnly (1.19%, K-S test: P  = 4.79 × 10 −5 ), CancerOnly (1.85%, P  = 0.0005), and Other genes (0.97%, P  = 1.31 × 10 −9 ). The CancerOnly genes had the second highest average mutation frequency (1.85%), which was significantly higher than that of of TargetOnly ( P  = 0.0275) and other genes ( P  < 2.2× 10 −17 ). The TargetOnly genes had the third highest average mutation frequency, which was significantly higher than that of other genes ( P  = 0.0134).

Mutation pattern of drug target genes belonging to cancer genes. The TargetCancer represented the common genes between anticancer drug targets and cancer genes. The TargetOnly represented the genes only belonging to genes encoding drug targets with mutation data. The CancerOnly represented the genes only belonging to cancer genes with mutation data. The Other represented genes with mutation data excluding the genes from above three gene sets. a Comparison of average mutation frequency of four gene sets. b Percentage of genes with at least 2% mutation frequency in the Pan-Cancer. c The function classification, mutation frequency in individual cancer type and Pan-Cancer, and numbers of drugs of 32 TargetCancer genes. We highlighted the mutation frequency higher than 5% of samples in “TargetCancer” genes with red color

Notably, among the 32 TargetCancer genes, 18 genes (56%) had at least 2% mutation frequency across the Pan-Cancer collection (Fig. ​ (Fig.4b). 4b ). Compared to that of TargetOnly genes (39%), CancerOnly (29%), or Other gene sets (10%), the percentage was significantly higher (Chi-squared test P -values: 0.0002, 0.002, 2.48 × 10 −16 , respectively). Figure ​ Figure4c 4c shows the percentage of samples with mutations of the 32 TargetCancer genes, their function classification, and number of targeting drugs. Indeed, for the 32 Target Cancer genes, there was a significant correlation between the percentages of samples with mutations and numbers of targeted drugs (Pearson’s correlation: r  = 0.40, P  = 0.0230). Among the 32 genes, the most frequently mutated gene in the Pan-Cancer cohort was EGFR (6.2%). Its mutations significantly occur in the brain cancer GBM (27.1%), lung cancer (13.5%), COAD/READ (5.8%), HNSC (6.2%). Among the seven drugs targeting the gene, three (afatinib, erlotinib, and gefitinib) were used to treat lung cancer, two (cetuximab and panitumumab) were used to treat colorectal cancer, and one (cetuximab) was used to treat head and neck cancer.

Drug-cancer network

To explore the associations between the drugs and cancer types, we generated a drug-cancer network, which comprised 183 nodes (150 drugs and 33 cancer types) and 248 drug-cancer associations (Fig. ​ (Fig.5) 5 ) based on the FDA-approved drug-cancer associations in our curated data.

Drug-cancer network. The red ellipse represents the cancer; the green rectangle represents the cytotoxic drug; the green diamond represents the targeted drug. The cancer abbreviations included in the Table ​ Table3 3

In the drug-cancer network, the degree (number of cancer types) of the 150 drugs ranged from one to eleven, and the average degree was 1.65. The degree distribution of these drugs was strongly right-skewed, indicating that most drugs had a low degree and only a small portion of the nodes had a high degree. The degree of the cytotoxic drugs was 2.13, which was significantly higher than that of the targeted drugs (1.33, K-S test: P  = 0.0378). Most of them (105, 70%) could be used to treat only one cancer type. Among the 105 drugs, 35 belonged to the cytotoxic drugs while 70 belonged to the targeted drugs. Among the rest 45 drugs, 24 (16%) could be used to treat two cancer types and 21 drugs (14%) could be used to treat at least three cancer types. Among the 21 drugs, 15 were cytotoxic drugs while six were targeted drugs. Most of the 21 drugs (16, 76%) were approved by FDA before 2000. The most commonly used drug was doxorubicin that could be used to treat 11 cancer types, including leukemia, breast cancer, stomach cancer, lymphoma, ovarian cancer, lung cancer, sarcoma, thyroid cancer, bladder cancer, kidney cancer, and brain cancer. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius, which binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix [ 35 ]. The result indicated that the cytotoxic drugs tended to be used to treat more cancer types than targeted drugs.

In the drug-cancer network, the degree (number of drugs) of the 33 cancer types ranged from one to 40 and the average degree was 7.52. The degree distribution of the cancer types was not obviously right-skewed. Among the 33 cancer types, 11 had one drug, 12 had at least two drugs and less than 10 drugs, and ten had at least ten drugs (Table ​ (Table3). 3 ). They were leukemia (number of drugs: 40), lymphoma (28), breast cancer (27), lung cancer (17), prostate cancer (15), ovarian cancer (12), melanoma (11), colorectal cancer (10), kidney cancer (10), and stomach cancer (10). Among the 40 drugs used to treat leukemia, 24 belonged to cytotoxic drugs while 16 drugs were the targeted drugs. Similarly, the numbers of cytotoxic drugs and targeted drugs were similar to each other for lymphoma, breast cancer, and lung cancer. However, for prostate cancer, melanoma, and kidney cancer, the numbers of targeted drugs were significantly higher than those of cytotoxic drugs.

Cancer classes, their abbreviations, and number of anticancer drugs

Network of targeted drugs, targets, and cancer

Besides the drug-cancer network, we generated a specific network for targeted drugs, their targets, and their indications. The network contained 214 nodes (89 drugs, 102 targets, and 23 cancer types) and 313 edges (118 drug-cancer associations and 195 drug-target associations) (Fig. ​ (Fig.6) 6 ) based on the FDA-approved targeted drug-cancer associations and targeted drug-target associations in our curated data.

Network of targeted drugs, targets, and cancer types. The red rectangle represents the cancer; the green rectangle represents the targeted drug, the blue rectangle represents the drug target. The cancer abbreviations included in the Table ​ Table3 3

In the network, drugs had two types of neighbors: drug target and drug indication (cancer type). The target degree (number of targets) of the 89 drugs ranged from one to 18, and the average degree was 2.19. The cancer degree (number of cancer types) of the 89 drugs ranged from one to four and the average degree was 1.33. Among the 89 drugs, 22 had more than two targets. The drug regorafenib had 18 targets, which was approved by FDA to treat gastrointestinal stromal tumors and metastatic colorectal cancer. Among the 89 drugs, 19 drugs could be used to treat more than one cancer types. Four drugs bevacizumab, everolimus, hydroxyurea, and recombinant interferon Alfa-2b could be used to treat four types of cancer. The degree (number of drugs) of targets ranged from one to seven and the average degree was 1.91. The EGFR (epidermal growth factor receptor) and KDR (kinase insert domain receptor) were the most popular targets and both could be targeted by seven drugs, separately. The EGFR-related seven drugs could be used to treat six cancer types, while KDR-related drugs could be used to treat seven types of cancer. There were three common cancer types: colorectal cancer, thyroid cancer, pancreatic cancer. The degree (number of drugs) of cancer types ranged from one to 16 and the average degree was 5.13. As we discussed before, leukemia had 16 targeted drugs can be used to treat.

The common target-based approach, namely, the drugs that shared common targets could be used to treat the same disease, is one of the “guilt-by-association” strategies to identify the novel drug-disease associations [ 29 ]. During the analysis, we noticed that, among the 89 drugs, 70 drugs had at least one common target. Applying the common target-based approach, we discovered 133 novel drug-cancer associations among 52 drugs and 16 cancer types. To evaluate the novel drug-cancer associations, we utilized the clinical trial studies to see if the drug had been investigated in the corresponding cancer type. After searching using the 52 drugs and their predicted cancer types against ClinivalTrials.gov , we found that most of the drug-cancer associations (116) have been investigated in at least one clinical trial (Table ​ (Table4) 4 ) while the 17 had not been investigated in clinical trials. The later part of novel drug-cancer associations might provide valuable clues for drug repurposing. The most well-studied association was the thalidomide-lymphoma, which had 174 clinical trial studies, including 15 Phase III clinical trial studies and one Phase IV clinical trial study. The drug thalidomide was approved to treat multiple myeloma. Recently its combination with other drugs entered to treat the peripheral T-cell lymphoma in the Phase 4 study ( ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01664975","term_id":"NCT01664975"}} NCT01664975 ).

Potential drug-cancer associations with numbers of clinical trials

a obtained from ClinivalTrials.gov

FDA-approved anticancer medicines play important roles in the successful cancer treatment and novel anticancer drug development. In this study, we comprehensively collected 150 FDA-approved anticancer drugs from 1949 to 2014. According to their action mechanisms, we groups them into two sets: cytotoxic and targeted agency. Then we performed a comprehensive analysis from the perspective of drugs, drug indications, drug targets, and their relationships. For drugs, we summarized their historical characteristics and delivery methods. For targets, we surveyed their cellular location, functional classification, genetic patterns. We further applied network methodology to investigate their relationships. In this study, we provided a comprehensive data source, including anticancer drugs and their targets and performed a detailed analysis in term of historical tendency and networks. Its application to discover novel drug-cancer associations demonstrated that the data collected in this study is promising to serve as a fundamental for anticancer drug repurposing and development.

Acknowledgements

We thank Dr. Anupama E. Gururaj for manually check cancer classification.

This project was supported by Cancer Prevention & Research Institute of Texas (CPRIT R1307) Rising Star Award to Dr. Hua Xu.

Availability of data and materials

About this supplement.

This article has been published as part of BMC Systems Biology Volume 11 Supplement 5, 2017: Selected articles from the International Conference on Intelligent Biology and Medicine (ICIBM) 2016: systems biology. The full contents of the supplement are available online at < https://bmcsystbiol.biomedcentral.com/articles/supplements/volume-11-supplement-5> .

Abbreviations

Authors’ contributions.

JS and YZ collected data for the study. JS and QL performed data analysis. JS and HX conceived and designed the study. QW prepared the figs. JS and HX wrote the manuscript. JS, QW, YZ, QL and HX revised the manuscript. All the authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Competing interests.

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Jingchun Sun, Email: [email protected] .

Qiang Wei, Email: [email protected] .

Yubo Zhou, Email: nc.ca.cnchs.liam@uohzby .

Jingqi Wang, Email: [email protected] .

Qi Liu, Email: [email protected] .

Hua Xu, Email: [email protected] .

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• Published: 14 October 2023

Harm reduction social work with people who use drugs: a qualitative interview study with social workers in harm reduction services in Sweden

• Torkel Richert 1 ,
• Anke Stallwitz 2 &
• Johan Nordgren 1  

Harm Reduction Journal volume  20 , Article number:  146 ( 2023 ) Cite this article

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Social work with people who use drugs (PWUD) has traditionally focused on abstinence and rehabilitation. In recent years, harm reduction has gained an increasingly more important role in social work with PWUD, and social workers are key professionals in many harm reduction services. This study investigates how social workers in harm reduction services for PWUD in Sweden understand the concept of harm reduction and how it relates to goals of rehabilitation, and how they assess and deal with dilemmas and challenges in everyday work.

The study is based on interviews with 22 social workers in harm reduction services for PWUD in the Scania region of Sweden. A thematic analysis in three steps was used in coding and processing the data.

The social workers pointed to similar values between social work and harm reduction and argued for combining the two fields to improve services for PWUD. Three overarching principles for Harm Reduction Social Work (HRSW) were developed based on the social workers accounts: (1) Harm reduction is a prerequisite for rather than a counterpoint to rehabilitation and recovery, (2) motivational work must be non-mandatory and based on the client’s goals, (3) a holistic perspective is crucial for Harm Reduction Social Work. Challenges in doing HRSW concerned restrictive laws, policies, and guidelines, resistance from managers, difficulties in setting boundaries between client autonomy and life-saving interventions, and the risk of normalizing high-risk behaviors.

Conclusions

We use the concept of Harm Reduction Social Work to show how social work with PWUD can have a primary focus on reducing harm and risks, while at the same time it involves a holistic perspective that facilitates motivation and change. The suggested principles of HRSW can provide guidance in practical social work with vulnerable PWUD. Social workers can have important roles in most harm reduction settings and may act to enable recovery.

Introduction

Social work with people who use drugs (PWUD) has traditionally focused on abstinence and rehabilitation with the goal of helping clients to stop using drugs, change their lifestyle and be reintegrated into society [ 1 , 2 ]. In recent years, harm reduction has gradually entered social work discourse and practice and is now seen as a promising approach for helping and treating individuals with drug and alcohol problems [ 3 ]. Harm reduction refers to a broad set of goals, strategies, and services which aim to minimize the social and physical harms of substance use, without necessarily aiming for abstinence. Important harm reduction services for PWUD include needle and syringe exchange programs, overdose prevention, drug consumption rooms, opioid substitution treatment (OST), low-threshold housing, and drug checking [ 4 ].

Harm reduction approaches have been described as an alternative to the moral and disease models of addiction that have dominated substance use treatment, and as a means of reducing problematic power dynamics in social work practice [ 3 ]. Social work, especially that which is carried out by employees within state or municipal authorities, includes to varying extents a power hierarchy of social worker over client, as well as practices of surveillance and control [ 5 ]. Proponents of a harm reduction perspective in social work with PWUD argue that this could reduce moralism, imply a reduced focus on abstinence, lower thresholds, and increase equality in the relationship between client and professional [ 1 , 6 , 7 , 8 ].

On the other hand, social workers and social science researchers have raised concerns about what too strong or narrow a focus on harm reduction in the work with PWUD could lead to. The development of harm reduction has been associated with individualization and medicalization of the drug problem, and with addressing short-term issues and symptoms of complex problems, rather than the broader social, political, and economic context that creates these problems [ 9 , 10 ]. This also relates to the risk of health-related goals being prioritized over goals such as social integration and rehabilitation [ 11 ]. Critics have also argued that harm reduction can be a cynical strategy that shows too little faith in people’s ability to change [ 12 ], that harm reduction practitioners accept the client’s engagement in high-risk substance use rather than imposing the safest alternative: abstinence [ 13 ], and that harm reduction can imply fatalism in the form of a “palliative care model” [ 9 ].

A further area of controversy between those who advocate for total abstinence and harm reductionists is the conceptualization of recovery. The recovery-based treatment system, in which social workers can have important roles, is traditionally oriented toward achieving complete abstinence among clients, responsibility and a drug free society. This stands in contrast to the harm reduction perspective which focuses on the client’s own goals without demanding abstinence or lifestyle change. However, more recent definitions of recovery incline toward inclusiveness, well-being, and improved quality of life and acknowledges that recovery is something that is made in practice and can take multiple forms [ 14 ]. The introduction of the concept recovery capital has meant a stronger focus on the individuals’ different strengths and needs and on community-based recovery sources. Recovery capital usually involves the sum of the individual’s social, physical, human, and cultural capital that can be decisive in the initiation and maintenance of substance misuse cessation [ 15 ]. A resent proposal of an assemblage approach to recovery highlights that recovery should not be seen as a separate, post-drug use phase, but rather should be treated as part of drug use and in the relation to drug use [ 14 ]. These developments show that recovery can have multiple meanings and implications that may conflict or harmonize with a harm reduction perspective. Lancaster and colleagues state that the polarization of the field between harm reduction and abstinence-based approaches in Britain, and a shift toward a recovery-oriented drug policy has created a concern about how this might affect the continued provision of harm reduction [ 16 ].

Although there are some dividing lines between social work and harm reduction, the two fields also share many core values, and could be combined to provide a more comprehensive continuum of services [ 1 ]. The harm reduction model has even been put forward as an ideal framework for social work practice in a wide variety of settings and as something that should be a fully integrated component of social work education [ 2 ]. Vakharia and Little [ 3 ] state that harm reduction and social work are “natural partners” with similar core values, including a client-centered and strengths-based approach, and a focus on developing a working alliance and supporting the client’s self-efficacy. Given these similar values they believe that “ it is only a matter of integrating the specific framework and treatment interventions for social workers to be leaders in harm reduction practice” [ 3 , p 67].

Even though harm reduction increasingly has been suggested as a constructive perspective for social work, few guidelines for clinical practice have been detailed in the social work literature, something that limits the potential implementation of the model into day-to-day social work practice [ 3 ]. There is little knowledge about social workers’ roles in harm reduction settings, and about what they see as the dilemmas and advantages of doing social work with a focus on harm reduction . There is also a lack of knowledge about what social workers, or a social work perspective, contribute to harm reduction services.

This study aims to investigate how professional social workers in harm reduction services for PWUD understand the concept of harm reduction and how the concept relates to rehabilitation, as well as how they assess and deal with various dilemmas and challenges in everyday work with PWUD. The study is based on semi-structured interviews with 22 social workers in harm reduction services for PWUD in the Scania region of Sweden.

Social work and harm reduction in Sweden

In Sweden, healthcare and social services have a shared responsibility for treatment and support for PWUD. The healthcare sector primarily provides medically oriented efforts, while social services are responsible for non-medical treatment, accommodation, social support, and rehabilitation as well as the investigation of care needs of PWUD. Social workers are represented in most services for PWUD, including harm reduction programs such as OST, housing, and needle and syringe exchange programs. Social workers are thus one of several key actors in the work with PWUD in Sweden, and the social work perspective has been important in the development of drug policy and interventions within the addiction field [ 17 ].

Since the 1980s, Swedish drug policy has been based on a zero-tolerance approach with the stated aim of creating a “drug-free society” [ 18 ]. Although the strategy has been built on three pillars—control, prevention, and treatment—a proportionally large focus has been placed on various control efforts [ 19 ]. Historically, harm reduction has developed relatively slowly in Sweden since interventions primarily aimed at reducing risks and harms of drug use, without the goal or requirement of abstinence, have been considered controversial. When introduced, harm reduction services have been met with resistance and have been forced to incorporate strict regulations and controls as well as, in some cases, requirements for motivational work toward treatment or abstinence [ 20 , 21 ]. This has led to some PWUD being excluded from OST or choosing not to start treatment, instead self-medicating with illegal substances [ 22 ]. Social workers have historically had an active role in the resistance toward harm reduction. For example, both OST and needle and syringe exchange programs were initially opposed by individuals in the social work profession [ 23 , 24 , 25 ]. In the last decade, however, the harm reduction perspective has gained ground, and existing harm reduction services have expanded and become less regulated, and new services have been introduced. Access to OST has gradually increased, the number of syringe exchange programs has increased significantly, and take-home naloxone programs have been initiated and developed in most regions [ 19 , 26 , 27 ]. Housing first programs and low-threshold housing with an acceptance of drug use have been introduced in some municipalities. However, interventions such as heroin-assisted treatment, drug consumption rooms, and drug testing have still not been introduced in any regions in Sweden [ 19 , 28 ].

Harm reduction measures have been geographically unevenly developed in the country [ 29 ]. This is also reflected in social workers’ attitudes. Although social workers now generally tend to have positive attitudes toward harm reduction, social workers in regions with low access to services tend to be more negative toward harm reduction goals and specific services in comparison with social workers in regions with high access [ 30 ]. Scania, Sweden’s most southerly region and the location for this study, stands out when it comes to harm reduction services for PWUD. Two syringe exchange programs started as pilot projects in 1986 and 1987, 20 years before a new law made it possible to start programs in other parts of the country. Scania was also one of the first regions to implement a take-home naloxone project [ 26 ] and was the first region in the country to implement a choice of care for OST, which led to increased accessibility and freedom of choice for people with an opioid addiction [ 27 ]. In Malmö, the largest city of the region, the first low-threshold accommodation in Sweden with a clear harm reduction focus was started, allowing residents to use illegal drugs in their rooms. A recent study from Malmö [ 31 ] showed that police officers largely supported harm reduction services in the city and refrained from enforcing drug laws in their vicinity.

Many of the harm reduction services and initiatives in the region have broken new ground and were initially perceived as controversial. Social workers are employed in all the services, and many of them have also been active in pushing forward the boundaries of harm reduction. This is interesting and points to a possible shift in the focus of social work, since addiction-related interventions from the social services in Sweden have traditionally had abstinence and social integration as their main goals [ 32 ]. These goals are also emphasized in the Social Services Act (Chapter 5, section 9), which states that municipal social services have an obligation to ensure that “the individual addict receives the help and care he or she needs to recover from the addiction” .

The Swedish case, where social workers have a central role in addiction care and rehabilitation in general and in harm reduction services specifically, can provide important insights into experiences of and challenges for social workers in harm reduction settings, and about what a social work perspective can contribute in harm reduction services.

Recruitment and sample

We conducted semi-structured in-depth interviews with 22 social workers employed at harm reduction services for PWUD in Scania County in the south of Sweden. The interviewees were recruited through a purposive sampling approach [ 33 ], aiming to reach a broad group of social workers in terms of age, gender, number of working years and different types of workplaces and work tasks. Our long-standing contacts with services for PWUD in the region facilitated this recruitment process. For several years, we have led a research study circle with social workers who work with PWUD in Malmö. This means that we have good contact with staff and managers from various low-threshold operations in the city. Several circle participants were asked if they themselves wanted to participate in the study and if they had suggestions for other possible participants.

The interviewees were recruited on the basis that they were professional social workers working within harm reduction services for PWUD within the region. The services included low-threshold accommodations where drug use is permitted, OST clinics, needle exchange programs, an outreach team for homeless PWUD, and an NGO providing food, social activities, and health services for PWUD and people experiencing homelessness.

Eighteen of the interviewees were female and four were male. All interviewees were professional social workers, which in Sweden means that they have completed a bachelor’s degree in social work of at least 3.5 years. Their average age was 40.5 years, with a range between 25 and 62. The median number of years of practice as social workers was 12 years, with a range between one and 31 years.

Due to the Covid-19 pandemic, the interviews were conducted in two waves, one in 2019 and one in 2022. We conducted the interviews face to face at the interviewees’ respective workplaces. The majority of the interviews were conducted individually, but in two cases they were conducted as pair-interviews at the request of the interviewees. The interviews were recorded, and they lasted between 40 and 110 min.

All interviewees gave informed oral and written consent to take part in the study. To ensure the anonymity of the interviewees, we have changed their names and anonymized their organizations.

We used a semi-structured interview guide to allow a focused conversation about the interviewees’ practices, experiences, and attitudes. The interview guide contained sections about; (a) background information (age, gender, educational background), (b) their views of drug use problems, drug scenes and services for PWUD in the region, (c) assessments of PWUDs’ vulnerability and the possibility of receiving help, (d) professional role and work situation, (e) opinions of Swedish drug policy, (f) views on conflicts and similarities between social work and harm reduction, (g) possibilities and risks in conducting motivational work, (h) views on challenges and opportunities in their harm reduction work. In this paper, we focus primarily on responses from sections d, e, f, g and h.

The interviews were transcribed verbatim by a research assistant and checked for accuracy by the first author. Our approach to analyzing the empirical material was based on qualitative text analysis and aimed at interpreting meaning from the empirical material [ 34 ]. Coding was carried out by the first author in a three-step process, influenced by Braun and Clarke’s thematic analysis [ 35 ]. The first step consisted of reading the transcribed interviews, with the aim of obtaining a holistic view of the material. In the next step, the material was categorized into broad themes relating to the overall focus of the study such as “similarities and differences between social work and harm reduction”, “difficulties and dilemmas in doing harm reduction work”, “what social work can contribute within harm reduction services”. In a later stage, “Harm Reduction Social Work” gradually emerged as a core theme. In further analysis of the data, the overall themes were categorized into more specific subthemes. In the third step, quotations that represented the identified themes were chosen as analytical points and interpreted for meaning. The interview excerpts were translated from Swedish to English by the first author and then checked by a professional proofreader to ensure that the meaning of the quotations was retained.

Harm reduction social work: principles and strategies

The interviewed social workers all stated that harm reduction should be a natural part of social work with PWUD. They believed that there are great similarities in the basic ideology behind harm reduction and social work, such as the importance of “ meeting the person with respect and dignity ”, “ meeting the person where they are at ” and “ starting from the client’s own goals ”. At the same time, some of the social workers pointed out that their work differed from what they called “traditional social work” which includes a stronger focus on long-term abstinence, rehabilitation, and self-sufficiency, but also differed from more medically oriented harm reduction work which they believed could lack a holistic perspective and social dimensions.

The social workers saw great advantages in their work being oriented toward harm reduction and at the same time believed that as social workers they could add important dimensions to the harm reduction perspective. Their descriptions can be summarized in three overarching principles and strategies where harm reduction and social work can be combined in what we define as Harm Reduction Social Work (HRSW).

Harm reduction is a prerequisite for rather than a counterpoint to rehabilitation and recovery

The social workers emphasized that harm reduction must come first and permeate the work with vulnerable PWUD. This was motivated by the fact that for most people, lifestyle change is only possible if they have a basic level of security, somewhat stable health, and a reasonably stable social situation. At the same time, they pointed out that harm reduction does not oppose motivational work or rehabilitation and that social workers have an important function in making possible alternatives and room for action visible to clients.

Marcus, a social worker in low-threshold housing, clarified their priorities: The focus of our service is harm minimization, so we have the three directions: number one is to save lives by offering a safe place, number two is to minimize harm, and number three is to help the client further in the direction the person wants.

When asked how a social worker in a low-threshold service should relate to the overarching political goal of a drug-free society and to the Social Services Act’s stated goal of helping people with addiction stop using drugs and rehabilitate, Peter, a supervisor at a low-threshold residence, answered:

A drug-free society will never happen anyway, so you can just drop that goal, that’s what makes it [the drug policy] so repressive. The second part, helping to stop [using drugs], yes, but to be able to stop, you have to be alive and the less harm you get from the use, the better chance you have of coming back. That is the kind of harm reduction that we do here, we give people the energy to be able to make a choice. So, if you sleep, eat, have an ID card, if you have your medicines, yes, but then you can at least start thinking about “Do I want to live like this or do I want to reduce…” If you are on the street and are being chased [by the police], never have money and inject as many drugs as you can just to last another day, yeah but then, that's no help to stop using.

The quote points out that a repressive drug policy can increase vulnerability and risks for PWUD and reduce the possibilities for rehabilitation. In contrast, according to Peter, a harm reduction approach can reduce suffering and increase the chances for the person to be able to decrease drug use and change their life situation in the long term. In this sense harm reduction is a prerequisite for, rather than a counterpoint to, rehabilitation and recovery.

The interviewees said that with most people they could work in parallel with harm reduction and gradual rehabilitation. In some cases, however, the work was almost exclusively about keeping the person alive and reducing risks as much as possible. The social workers argued for a broad concept of harm reduction that included for instance: treating wounds or injuries, efforts to improve physical and mental health, working with strategies to reduce exposure to violence or sexual abuse, counteracting loneliness, improving sexual health, working with overdose prevention, educating in safer ways to use drugs, and offering food, clothing and a safe place to sleep.

Motivational work must be non-mandatory and based on the client’s goals

A harm reduction perspective—where you meet individuals where they are at, without demands for abstinence or lifestyle change—was described as crucial for creating a trusting relationship and for being able to carry out motivational work. Hanna, who worked at a low-threshold housing unit, talked about the great advantages of working primarily from a harm reduction approach:

You increase the chance of building an alliance and trust in the person. There are no controls or any control function that make the person in question need to deceive, lie, manipulate… also by showing that I want to help you regardless of what you want help with, regardless of whether you choose to use drugs or not, I’m here to help you and care about you, I want to listen to what you have to say.

The quote shows the importance of not making unreasonable demands or controlling clients and of basing the work on the client's goals. According to Hanna, this is crucial for a trusting and honest relationship and for the possibility of conducting motivational work.

Another central theme from the interviews was that motivational work can never be imposed. Moa, a social worker who did outreach work with socially vulnerable PWUD, said the following about the opportunity to work with motivation for change:

We definitely engage in motivational work and try to motivate them to dare to seek help, but then it is more if the person wants but maybe doesn't dare. But we don’t have goals for our clients; they have to set them themselves, so in that way there isn’t much work toward change if the person doesn’t initiate it themselves. And sometimes there really isn’t any change-work at all, but just making sure the person doesn’t perish.

The quote points out that working toward change or recovery is not always possible. At the same time, it shows the importance of analyzing possible obstacles to clients’ motivation and change. It was considered common that clients themselves did not believe that change was possible, that they did not dare to seek help or “open up” due to feelings of shame or the risk of being poorly treated or met with prejudice. Helping clients to overcome these obstacles and making visible alternative courses of action were seen as important tasks for social work with PWUD.

Pia, a social worker in a low-threshold housing unit, described how staff working close to PWUD with great vulnerability develop a different perspective on what constitutes positive change or success. Changes could involve the client switching from a more dangerous drug to a less dangerous one, injecting with sterile equipment instead of used, starting to eat more regularly, or making an initial contact with health care or psychiatric services. These types of changes were considered major successes by the staff but were rarely seen as decisive by outsiders. Pia said: “ We see changes all the time, which we think are good for the client in the long run but which society may not appreciate.” She further explained that from society’s perspective, everything about addiction is black or white, “Is he an addict or a non-addict , everything in between doesn’t matter”.

According to the interviewed social workers, harm-reducing social work must be based on an understanding that lifestyle change is not always possible or desirable, that it can take a long time, and that even small changes can be of great significance. The general view was that professionals must be sensitive to their clients’ motivation to change and facilitate this change without being intrusive.

A holistic perspective is crucial for harm reduction social work

Something that was stated in many interviews was that a holistic perspective should be a starting point for harm reduction social work with PWUD. Although all social workers agreed that harm reduction is part of social work with PWUD, several said that social work in some respects can also be said to be “more than harm reduction” , that social work with PWUD means something “in addition to reducing harm and vulnerability” . A holistic approach was described as seeing the individual in a larger context, analyzing possible underlying causes of the drug addiction, acknowledging the individual's strengths, enabling enjoyment and pleasure, and involved counteracting structural obstacles to change for the individual. Several social workers believed that this holistic perspective could add important dimensions to what was, in some cases, a rather narrow or medical harm reduction perspective.

Anna, who worked in a low-threshold housing unit, developed the notion of what a holistic perspective can mean when working with PWUD.

Many people have the opinion that you have to fix the problem [drug abuse] first and then you can work on other things such as rehabilitation and strengthening different life areas. But you can turn the tables and do exactly the opposite, you focus on everything else so that the drug use does not become as important anymore. So that it gets less space or less focus, so that other things in life become more positive, so that you either cut back or stop using, or stop using a certain drug, maybe change social interactions, make new friends.

Anna pointed to the importance of looking beyond drug addiction and the consequences connected to this and instead focusing on the individual as a person. By strengthening the individual’s resources, skills, and networks, Anna believed that the individual’s opportunities to see other possibilities for action become greater. The “drug-free life” must, according to Anna, offer something that replaces not only the psychological functions of the drug but also the social life, income strategies, and skills that have been linked to a lifestyle where the person organizes their everyday life and interactions largely around drugs.

An additional dimension of a holistic perspective highlighted was mapping which resources, networks, and services the person might need. Some described this as “being the spider in the web” or “building bridges” to different services. It could be about accompanying the person to a doctor’s visit, to the social services or to the employment agency, or about making contact with a user organization or activity center. Bridge-building was considered particularly important when working with PWUD who had limited social abilities or very low trust in authorities. Hanna, a social worker at one of the low-threshold housing units in the city, described this work in terms of being a “middle ground”:

And the biggest gain [of a harm reduction approach] is that you can often motivate the person to accept help from others as well. You can be a bit of a middle ground, between different [services], yes, but if they have confidence in me, if I say it’s fine to go to this doctor, we can go to that doctor together. And also, if any problems arise in the contact with this doctor, you can stand up for the person and so on.

In other words, a holistic perspective also involved helping the client navigate a help system that can sometimes be bureaucratic and difficult to access; it was about mediating contacts and, in some cases, about standing up for the client's social and human rights.

The holistic perspective relates to a broad perspective on harm reduction, which can be about reducing risks and vulnerability in many different areas of life, including medical, psychological, and social aspects.

In more medically oriented services such as OST and needle and syringe exchange programs, social workers were considered to have a particularly important role in ensuring that the holistic perspective was represented. It could involve having time for more “in-depth conversations where you can process various problems” , to focusing on “social network, housing and other issues in life” in addition to illnesses, health problems, and medications. Without this broadened focus, there is a risk that, OST clinics, as Malin expressed it, “only become a place where you get medicine without the possibility of additional support” .

Challenges in doing harm reduction social work

The interviewed social workers all talked about challenges in doing HRSW with PWUD. The most important challenges can be summarized in two overarching themes: (1) professional, organizational, and policy limitations, (2) setting boundaries and dealing with normalization of risk.

Professional, organizational, and policy limitations

At a policy level, legislation and guidelines were described as obstacles to carrying out or developing harm reduction work. In general, harm reduction services in Sweden have had high requirements for enrollment, clear goals for motivational work, strict rules and low thresholds for dischargement. This has gradually changed over the past 10–15 years, although some restrictive rules and control efforts remain. Examples of policy level limitations that were raised concerned legal barriers to handing out syringes (except in needle and syringe exchange programs) or implementing safe consumption rooms, laws that means needle and syringe exchange programs have age limits and that require visitors to show identification, and legal barriers to social workers being allowed to carry naloxone.

Another example that was raised was that certain harm reduction services have guidelines or legal requirements that the staff must carry out motivational work. Although a focus on motivational work was generally seen as positive, it was believed that stated requirements for this could involve problems. Fredrik, a counselor at a syringe exchange program saw the risk that social workers would “force motivational talk on clients” as relatively small, but at the same time pointed to problems with this type of statutory requirement:

If you are exposed to motivational work when you do not want it then it contributes to a feeling of stigmatization that you often may already have. I can imagine that this can be very difficult for the patients. It is difficult to know, but perhaps there is such a risk [to force motivational talk on clients] if it says in the legislation that you must do it [motivational work], if you then interpret it literally, then perhaps there is such a risk. Then you probably lose some patients because of that.

On an organizational level, limitations could entail resistance from the higher management in being allowed to push harm reduction as far as they wanted, not least within municipally organized services. Examples were a stalled initiative to establish “locker rooms” where homeless PWUD could store belongings, and a resistance to publishing brochures with information on safer injecting practices and overdose prevention at a low-threshold accommodation. Many of the interviewed social workers had themselves pushed for further development of harm reduction in the city, despite opposition.

On a professional level, limitations concerned unreasonable expectations and demands placed on the social work with PWUD from colleagues in social services. Svea, who worked as a counselor at an OST clinic, believed that some social workers who had “their” clients at the clinic had a poor understanding of the client’s situation and unreasonable expectations of lifestyle change. This included, for example, the expectation of “total abstinence from illegal drugs” or a clearer “focus on employment and rehabilitation” in the work with the clients:

Some social workers can push this issue quite far. And be assertive about it, like—‘how can you allow my client to be so intoxicated?’ And so on. They have somehow not understood that this is a long process that can take up to two years, perhaps, before a person becomes stable.

A few social workers also talked about clients having expectations that meetings with social workers must involve talking about motivation to change, something that could negatively affect the relationship. Fredrik, a counselor at a syringe exchange program, said that some patients experienced ambivalence about contacting him because he was a social worker “ Why should I see a counselor, I have no plans to stop using drugs”. He further stated that “ there is still a notion among some drug users that there is an expectation from us [social workers] that the purpose of the contact is for them to quit [using drugs]”.

Another challenge related to professionality concerned social workers lacking the medical competence or legitimacy required for certain harm reduction tasks. In some services, for example a residence for PWUD, all the staff were social workers. This meant that they experienced certain limitations in their daily work, not being able to handle prescriptions, medication, or serious medical injuries. The staff also did not have the legal right to carry naloxone, despite overdoses occurring among their clients. Some of these challenges could be solved through close cooperation with health centers or the syringe exchange program and through the residents themselves sharing naloxone with the staff. In services with only one or two social workers, such as syringe exchange programs or OST clinics, they could sometimes feel alone in representing a social perspective within a more medical context.

Setting boundaries and dealing with normalization of risk

The social workers agreed that harm reduction interventions for PWUD should have “low thresholds in , high thresholds out” and have as few rules as possible. At the same time, certain rules and restrictions were considered necessary for protecting clients from themselves or from each other, for protecting staff, or for protecting the reputation and legitimacy of the services. The social workers presented several examples of ethical dilemmas and difficulties around setting boundaries in the work.

One example concerned client inclusion criteria. This is partly regulated in laws and guidelines, but services also set their own boundaries. For example, some accommodations and low-threshold services did not enroll young people or people early in their ‘addiction career’ because it was considered that there was a risk of their situation worsening. However, it was seen as difficult to determine what “young” and “early in the addiction career” meant and what the consequences would be for PWUD who were not enrolled.

Other boundaries concerned when to discharge clients or when to make a report of concern for compulsory care (something that social services in Sweden can suggest if the drug addiction poses a life-threatening danger to the individual), or even call the police. In general, it was agreed that these measures should be avoided as far as possible and that there must be a high level of acceptance for risky behavior, rule-breaking and “disorderliness”, considering that most clients had a long-term drug addiction in combination with mental illness. In addition, there were few other options for the clients, and a discharge from, for example, a low-threshold housing unit or OST clinic would very likely mean that the person ended up in a worsened life situation with increased exposure to risk.

Examples of situations that were considered difficult to handle were when patients were psychotic or aggressive, when they had repeated overdoses or life-threatening health problems, and when they sold drugs in or in connection with the services. In some cases, especially concerning aggressiveness or violence directed at other clients or staff, patients could be discharged from the service or referred to another agency. In general, however, very few violent incidents were described. Drug sales were not allowed at OST clinics, syringe exchange programs or low-threshold housing. The main reasons for this were that this could pose a problem for clients trying to reduce or stop using drugs and that the services would risk criticism from politicians or be visited more frequently by the police.

Several social workers talked about gradually moving boundaries or increasing their acceptance of risky situations and behaviors. This is how Peter, a supervisor at a low-threshold residence reasoned about this risk.

I was lucky enough to work with a Danish [social worker], quite early in my career, who talked a lot about co dependency in terms of us becoming tolerant of overdoses, threats and violence, because we dealt with these matters a lot and we stopped reacting to them. And it became food for thought, so I try, I talk to the staff here about it. That you should be aware of these things.

The quote points to the importance of the staff constantly reflecting on whether boundaries or acceptance are beginning to shift. The quote also highlights the risk of what is referred to as “codependency” and the difficulty in determining when and how to act on clients' vulnerability and risk-taking, which could, for example, involve overdoses, self-harming behavior, deteriorating physical or mental health or living in a very destructive and violent relationship. This points to difficulties setting boundaries due to the need to consider the client’s privacy and autonomy on the one hand, and protection and care on the other. Witnessing people in a very destructive and vulnerable situation was also experienced by some social workers as psychologically stressful.

Stella, who worked at an OST clinic, talked about the difficulty in deciding when to intervene and make a report of concern and suggest compulsory care:

If we see that they have been in the hospital, had overdoses or infected injection wounds… And they don’t take care of themselves, if we don't see any positive change, they just keep falling, falling, falling…. Yes, when we are really worried about their lives and health. You could say that is the limit.

Other social workers were of the same opinion and believed that the acceptance must generally be high in harm reduction services, that the general rule must be to respect the person's autonomy and integrity, but that you have an obligation to intervene in life-threatening situations, or when you see that the individual is on a path toward increasingly poor physical and mental health.

Social work with PWUD has traditionally focused on rehabilitation, with abstinence as a primary goal. This can be something positive if the work is in line with the client’s goals but can also be problematic if it is perceived as forced or intruding. In recent years, harm reduction has gained an increasingly more important role in the work with PWUD, and social workers are key professionals in many low-threshold facilities and harm reduction services for PWUD in Sweden, as well as in other countries. This raises questions about how social workers understand the concept of harm reduction in relation to rehabilitation.

Social workers are important professionals for PWUD as they influence both what interventions are provided and how they are carried out [ 32 , 36 ]. Social workers have a large degree of discretion in their work, and they can thus act as both gatekeepers, hindering the development of harm reduction, and as pioneers breaking new ground. The social workers we interviewed had a very positive attitude toward a harm reduction perspective and saw this as a natural part of social work with PWUD. Some had themselves shown “moral courage” [ 37 ] by pushing for further development of harm reduction in the region, by criticizing existing zero-tolerance policies, or by introducing new harm reduction initiatives despite opposition. This is interesting since, historically, social workers in Sweden have opposed the development of important harm reduction services. A recent survey study from three different regions of Sweden also showed that the social workers generally had positive attitudes toward harm reduction, which, in line with our study, indicates that there has been a change in attitudes over time [ 30 ].

Scholars have argued that a harm reduction perspective in social work with PWUD could imply a reduced focus on abstinence, lowering thresholds, and increasing equality in the relationship between client and professional [ 1 , 3 , 6 , 7 , 8 ]. Several of these advantages were also highlighted by our interviewees, not least a more honest, genuine relationship with clients and an opportunity to focus on goals other than abstinence. There seems to be a great deal of agreement about the benefits of a harm reduction perspective within social work with PWUD. However, there is a lack of discussion about what a social work perspective could contribute to harm reduction services. In line with Vakharia and Little [ 3 ], we argue that social workers can have important or leading roles in many harm reduction services [ 3 ]. Based on the accounts of the social workers interviewed, we use the concept of Harm Reduction Social Work (HRSW, in Swedish: skadereducerande socialt arbete ) to show how social work and harm reduction, through a number of common principles and strategies, can be combined to broaden and improve services for PWUD.

In doing HRSW the social workers expressed the importance of having low thresholds for services and of “meeting the client where they are at”, without demands for lifestyle change or abstinence. They pointed to the importance of primarily focusing on saving lives and reducing risks and vulnerability. At the same time, HRSW involved a holistic perspective on the individual’s life situation and opportunities that can make a new scope of actions visible to the client. The social workers talked about the importance of strengthening the individual’s resources, skills, and networks. This is in line with the concept of recovery capital and a person-in-environment approach, where focus is put on helping individuals to develop their social, physical, human, and cultural capital to enhance quality of life and gain control over drug use [ 15 , 38 ].

Social workers are trained to see the individual in a larger context and to understand and navigate society’s various support systems and bureaucratic processes, something the interviewed social workers talked about in terms of being “the spider in the web” and “building bridges”. This can create an opportunity to guide and support clients in their contacts with authorities and safeguard their social and human rights [ 39 ]. Several social workers also highlighted the importance of a good working alliance, focusing on the individuals’ strengths, skills, and goals, as well as enabling enjoyment and pleasure. This focus has similarities with strengths-based approaches or strengths-based case management. This approach has been described as central in social work practice and as particularly important in the work with marginalized people with mental health and/or drug use problems. Harm reduction services have been pointed out as one central domain for strength-based approaches [ 40 ]. The holistic perspective that characterizes social work speaks for the importance of including social workers in most harm reduction services.

In doing HRSW the social workers recognized the importance of helping clients to improve their life situation and to facilitate motivation and change, as long as this is in line with the clients’ goals. They also argued for that harm reduction in many situations is a prerequisite for, rather than a counterpoint to, rehabilitation, recovery or abstinence. More recent conceptualizations of recovery acknowledge that abstinence does not have to be a final goal and that recovery can take place within the context of continued drug use [ 14 ]. This is in line with the perspective of many of the interviewed social workers, indicating that social workers are professionals who have the right competence to work with recovery and rehabilitation within a harm reduction framework.

Some of the interviewed social workers referred to the holistic perspective and motivational work as doing “more than harm reduction” . This focus can have several explanations. The social workers seemed to view motivational work as crucial both in relation to the target group's situation and needs and in relation to their own professional competence and ethics. They also saw a need to broaden the focus and range of services within certain harm reduction services where health-related goals were being prioritized too strongly in relation to goals such as social integration and rehabilitation [ 11 ]. Allowing for harm reduction services to also incorporate strategies to facilitate rehabilitation and abstinence has been suggested on the basis that many PWUD that reach out to harm reduction services hope to achieve lifelong abstinence [ 41 ]. The social workers’ focus on motivational work and change can also be interpreted as a way to legitimize activities that are not in line with the zero-tolerance drug policy model or social workers’ overall statutory mission to help PWUD to become abstinent and reintegrated into society [ 20 ]. The idea of doing more than harm reduction, for instance in terms of motivational work, can generally be seen as something positive, but it could also pose a risk of clients ending the contact if they perceive this work as coercive or intruding.

Based on our interviews, it is clear that harm reduction as a starting point is far from obvious for all social workers or managers. This has also been discussed in other contexts, such as Canada [ 36 ]. As some interviewees pointed out, harm reduction must not become the only solution or out-compete other efforts such as prevention, in-patient treatment or housing first; there must also be room for social work with other goals and perspectives. Many help-seeking PWUD have abstinence as a primary goal and demand treatment and services with this orientation. Some social institutions or referral agents, such as probation services, child protection services, work training programs, etc., may mandate abstinence-only treatment and requirements for control [ 3 ]. Although some harm reduction principles and strategies can be useful in all types of social work, the term HRSW can be used to describe social work in harm reductions settings or social work with a clear focus on reducing harm, especially in contexts such as Sweden, where social work traditionally has had clear focus on abstinence.

The fact that harm reduction and recovery are contested and ambiguous concepts points to the importance of discussing the meanings of and relationship between these in practical social work, as well as in social work education. This can reduce the risk of reproducing simplistic notions of the concepts and show how it is possible to combine principles of harm reduction and recovery in social work with PWUD. How social workers conceptualize substance use problems, rehabilitation and recovery, will affect the types of interventions that they suggest or provide, including harm reduction services [ 42 ]. Scholars in social work have argued for the need to include topics such as substance use problems and harm reduction to a greater extent within the curriculum of social work education, as doing so can enhance students’ knowledge and prepare them to practice social work with PWUD in a more pragmatic and humanistic way [ 2 , 43 ]. Discussing some of the challenges that the social workers faced in doing HRSW could also provide a good opportunity for social work students to prepare for dealing with dilemmas in social work practice with vulnerable PWUD.

Doing HRSW has its challenges, which can vary depending on the local context. The social workers defined challenges on both the macro and the micro levels, but also described strategies to deal with some of them. Macro level challenges concerned national legislation and guidelines hindering harm reduction, and negative attitudes to or lack of knowledge of harm reduction among professionals and senior officials. The social workers illustrated how they could act as agents of change by arguing for the importance of harm reduction to managers or by introducing small-scale efforts or strategies with a harm reduction focus. This might in the long term also influence changes at the policy level.

On a micro level, challenges were, for example, about the lack of legitimacy of social workers in performing certain medical tasks, and about difficulties in setting boundaries and making trade-offs between the client’s privacy and autonomy on the one hand and protection, care, and motivational work on the other. Other challenges concerned not accepting or normalizing violence, life-threatening behaviors, and not becoming “codependent” with one’s clients. Although a contested concept, the notion of codependency was developed within the 12-step movement and is usually used to describe problematic behaviors of spouses or relatives of people who use drugs, such as an extreme focus on others’ needs, being self-sacrificing, and adopting dysfunctional coping aimed at preventing conflict [ 44 ]. The concept seems useful for some social workers in describing strategies to handle boundaries toward clients in their professional work. The use of the concept by the interviewees suggests that they try to balance the need for empathy and closeness to their clients with keeping a professional sense of distance. Discussing “codependency” and boundaries may be a strategy used by social workers to engage in self-care practices to reduce stress and enhance well-being [ 45 ]. This might be particularly important in low threshold harm reduction services, where clients experience high degrees of vulnerability.

The social workers generally saw their work as important, rewarding, and fun. Some social workers however struggled to find strategies to cope with the psychological stress of witnessing long-term suffering and destructive behaviors, something that has also been discussed in a study of ‘wet’ eldercare facilities in Nordic countries [ 46 ]. Accepting destructive or risky behaviors may, in addition to constituting a moral challenge, also clash with policies of social work, since Swedish social services are generally regarded as having a moral and legal imperative to act if witnessing or suspecting self-destructive or life-threatening behavior [ 46 ].

Some of the challenges outlined above might be reduced with increased professional supervision, introducing methods or guidelines for how to deal with threats and conflicts, as well as a continuous dialog within the workgroup about how different dilemmas should best be handled and boundaries drawn. The problem with, on the one hand, a medically oriented harm reduction work, and on the other hand, limitations in social workers’ medical competence or legitimacy, speaks for the importance of multi-professional teams in the work with PWUD. Since drug addiction usually includes biological, psychological, and social aspects, these teams should ideally consist of doctors/nurses, psychologists, and social workers. A scoping review of stakeholder preferences for supervised consumption site designs showed that both PWUD and stakeholders recommended these sites to be integrated within or near other social and health services and argued for a broad spectrum of services and staff with different competencies and backgrounds [ 47 ].

This is a first suggestion for the concept of HRSW. The concept needs to be discussed, developed, and adapted based on different contexts. HRSW can, as shown in this study, be particularly relevant for services targeting PWUD with a high vulnerability, but it could also be applied to social work more generally. This study has focused on professional social workers, but important HRSW is also carried out by non-professionals, by voluntary organizations, and by PWUD. HRSW can be a starting point or perspective in the work with PWUD or with people who engage in other risky behaviors, regardless of professional affiliation or background. Furthermore, social work with PWUD in Sweden can differ significantly from that carried out in other countries. Even Scania, the region in Sweden in which the study was conducted, differs in certain respects in relation to other regions in the country. The context-specific aspects are important to consider in the interpretation and possible generalizability of the results. Further research is needed on how social workers in harm reduction services in countries with different legislation, drug policies, or social work organization understand the concept of harm reduction and how they deal with the various dilemmas and challenges in everyday social work.

Social workers are key professionals in services for PWUD. We use the concept of Harm Reduction Social Work to show how social work with PWUD can have a primary focus on reducing harm and risks, while at the same time facilitate motivation, change and recovery. Social workers can contribute with a holistic perspective on clients’ resources and needs and bridge the gap between services focused on harm reduction on the one hand and abstinence on the other hand. Concepts such as harm reduction and recovery need to be discussed in social work education, and the suggested principles of HRSW can provide guidance in practical social work with PWUD.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to protection of informants’ privacy but are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank all the social workers who participated in the study. We would also like to thank colleagues at the Department of Social Work, Malmö University, for important input on the article manuscript.

Open access funding provided by Malmö University. This research received funding from Riksbankens Jubileumsfond, Grant Number: P18-0892:1.

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Department of Social Work, Malmö University, Nordenskiöldsgatan 1, 211 19, Malmö, Sweden

Torkel Richert & Johan Nordgren

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TR conceptualized the study, conducted the interviews, analyzed the data and wrote a first article manuscript. AS and JN reviewed and commented on the manuscript. All authors read and approved the final version of the manuscript. TR: Funding acquisition; Conceptualization; Data curation; Data analysis; Project administration; Writing—original draft; Writing—review & editing. AS: Funding acquisition, Writing—review & editing. JN: Funding acquisition, Writing—review & editing.

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Richert, T., Stallwitz, A. & Nordgren, J. Harm reduction social work with people who use drugs: a qualitative interview study with social workers in harm reduction services in Sweden. Harm Reduct J 20 , 146 (2023). https://doi.org/10.1186/s12954-023-00884-w

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A Conversation With …

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

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

By Matt Richtel

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

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

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

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

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

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

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

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

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

What do you credit for the change?

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

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

Does social media use among teens play a role?

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

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

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

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

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

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

But we don’t want to become complacent.

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

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

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

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

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

Anything else you want to add?

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

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

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

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

Why New CGRP Drugs Don’t Work for Everyone With Migraine

N ew migraine treatments have brought stunning relief to many people by blocking the action of calcitonin gene-related peptide (CGRP), a protein in the brain involved in the migraine process. But while many people have reported significant relief using the CGRP monoclonal antibodies (mAbs) and gepants, others have experienced little to no relief. 

If these CGRP-targeting treatments are so good, why don’t they work for everyone? The short version: Migraine disease is a complex neurological condition involving multiple genes and biological processes, and while CGRP is a major culprit in migraine, it’s not the only one. 

Here’s what you need to know about migraine disease , therapies that target CGRP, why they work for some people but not others, and how the CGRP story is helping scientists develop more new treatments aimed at other important targets in migraine.

Migraine Is More Than a ‘Bad Headache’ 

“One of the very big myths about migraine is that it's just a headache,” said Peter Goadsby, MD, professor-in-residence of neurology at the University of California, Los Angeles, and internationally respected migraine researcher. “That's completely wrong. Migraine is a disorder of the brain .” 

Migraine is a complex neurological condition affecting 1 in 7 people worldwide. The diagnosis includes a constellation of symptoms that span the entire body before, during, and after an attack. It’s one of the top disabling conditions worldwide .

Migraine is a spectrum disease  that impacts some people more than others. Those who have migraine symptoms 15 or more days per month have chronic migraine, while those who experience symptoms 14 or fewer days have episodic migraine.

What Should You Know About High-Altitude Headache?

The best over-the-counter migraine treatments for headache relief at home, how stress intensifies migraine (and how to avoid it), old-school migraine treatments were often ‘borrowed’ from other conditions.

Although migraine disease has no cure, it is treatable. Migraine treatments are typically categorized as acute, meaning you use them when you have an attack to reduce or eliminate symptoms, and preventive, meaning you use them on a regular schedule to reduce the number and severity of attacks. 

The only migraine preventives available before 2018 were medications created to treat other conditions, such as depression, high blood pressure, or epilepsy, that had demonstrated coincidental impact on migraine frequency and severity. While these medications work well for some patients, they are often ineffective for others and frequently discontinued because of intolerable side effects. 

Migraine-specific acute treatments called triptans have existed since the 1990s, but they increase the risk of heart attack and stroke in people with cardiovascular conditions, including high blood pressure. Migraine patients with those risks can’t use them safely.

How CGRP-Targeting Medications Changed the Game

After 30 years of intense development and regulatory review, the first CGRP monoclonal antibodies and gepants started to reach patients in 2018. By stopping the CGRP neuropeptide from connecting to its receptors in the migraine-sensitive brain, these new treatments block one of the major neurobiological events that cascade into the migraine process.

The treatments produced unexpectedly high numbers of “super responders,” people who get at least a 75 percent reduction in headache days.  

One of the great things about the CGRP, the monoclonals or the gepants, is that they tend to have very few side effects. So most people who get a response will get a response without paying a penalty. And those of the listeners who've paid the penalty of drugs in the past, say of propranolol, being tired or having nightmares … or of having amitriptyline, having dry mouth, sleepiness ... or of topiramate, having the pins and needles or having cognitive word-finding problems — you know what I'm talking about with paying a penalty. 

Migraine Treatments That Act on CGRP

The monoclonal antibodies that act on CGRP and are approved for migraine prevention in the United States include:

• erenumab (Aimovig)
• galcanezumab (Emgality)
• eptinezumab (Vyepti)
• fremanezumab (Ajovy)

The medications in the gepant category that act on CGRP and are approved for adults in the United States include:

• rimegepant (Nurtec ODT)  — approved for both prevention and acute treatment
• ubrogepant (Ubrelvy)  — approved for acute treatment
• atogepant (Qulipta)  — approved for prevention
• zavegepant (Zavzpret)  — approved for acute treatment

Unlike previous acute migraine medications, gepants don’t seem to contribute to medication overuse headache, which is a risk for anyone who uses acute treatments frequently. 

Rimegepant (Nurtec ODT) is approved for acute and preventive use based on the surprising finding that using it for acute treatment reduces attack frequency. This blurs the sharp line between acute and preventive therapies, suggesting that more focused target selection in the development of migraine therapies may change our understanding of migraine and lead to better patient outcomes.

Why CGRP-Targeting Treatments Don't Work for Everyone

Although these new treatments have produced remarkable results for some patients, the results aren’t universal. According to Goadsby, about half of the patients who try preventives targeting CGRP report only about a 50 percent reduction in headache days, and about 25 to 30 percent are nonresponders reporting little to no improvement. Why?

If migraine is more than one problem, we need more than one tool to fix it. “No one doing any DIY activity at home just has one thing, one screwdriver,” said Goadsby. “And migraine’s not a carpentry problem, but the principle being that you need enough tools to deal with the range of attacks.”

Upcoming Targets in the Migraine Research Pipeline

The next major development in migraine therapeutics may be a preventive treatment targeting PACAP , or pituitary adenylate cyclase-activating polypeptide. Like CGRP, PACAP is a peptide involved in the migraine process and overlaps in some areas with CGRP.

But PACAP is more prevalent than CGRP in the brain’s hypothalamus , which controls parts of the parasympathetic nervous system affecting heart rate, digestion, and other involuntary processes.

Unlike CGRP, PACAP is expressed heavily in the sphenopalatine ganglion , suggesting a different hot spot for migraine attacks. PACAP may stimulate the production of a specific kind of mast cell found on the meninges, the connective tissue surrounding the brain, which causes meningeal inflammation that triggers attacks. PACAP also appears to be far more important in prodrome or premonitory symptoms than CGRP. 

If CGRP is the major migraine troublemaker in some people’s brains, PACAP might be the major troublemaker in the brains of others. In late 2023, Danish biopharmaceutical company Lundbeck announced promising results of a phase 2 clinical trial of its humanized monoclonal antibody Lu AG09222.

• Opioid receptors that might mitigate pain without the risks of current opioid medications
• Neuropeptides related to CGRP
• Vasoactive intestinal peptide, or VIP
• Ion channels on cell membranes called transient receptor potential (TRP) channels
• Potassium channels on cell membranes that affect electrical activity between cells

New Tools Looking for Clues in Genetics

Researchers now have powerful tools to uncover more of migraine’s secrets. Experts have believed that most types of migraine are polygenetic conditions , meaning that there are multiple genes involved. 

Science isn’t just giving researchers more worthwhile targets for migraine research, but also helping them see previously undetected patterns that may lead to improved development projects and, ultimately, more effective treatments for more patients. 

Migraine Treatments to Try

There is no “one-size-fits-all” migraine treatment, says Elizabeth Leroux, MD, a neurologist and headache specialist at the Montreal Neurological Clinic in Canada. Options still exist though for people with migraine who haven’t had much luck with new treatments.

Neuromodulation devices, dietary approaches, mind-body techniques, localized nerve block procedures, and many more options can help get migraine attacks under control. Although it may take time, effort, and expense, there are tools you can try now to reduce your migraine burden. 

Dr. Leroux suggests that people with migraine try older medications that may be less well known. She also says that some people may get surprising benefits from strength training if they work with a physical therapist . 

“This is kind of a long-term approach,” she says. “I've learned that instead of spending a thousand bucks on an MRI, maybe you should invest in a physiotherapist who will teach you exercises that you will use for spine health  and what I call neck maintenance for the rest of your life, really.” 

Final Thoughts

The development of therapies targeting calcitonin gene-related peptide (CGRP) has led to an explosion of research into migraine-specific therapies and improved our understanding of migraine disease. But while treatments targeting CGRP have been game changers for many patients, others have had little to no therapeutic response. 

The variety of responses to migraine treatments targeting CGRP leads experts to believe that different substances in and around the brain play bigger roles in the migraine process than CGRP for some patients. To help more patients, researchers need to develop more treatments aimed at these other migraine-specific targets.

One of these targets is pituitary adenylate cyclase-activating polypeptide (PACAP). While CGRP appears to play a role in migraine in certain parts of the brain, PACAP may play a stronger role in others. PACAP seems to be especially important in the prodrome or premonitory phase of migraine attacks. 

Clinical trials suggest that a monoclonal antibody targeting PACAP may work safely to prevent migraine in people for whom CGRP mAbs were ineffective. A phase 2b clinical trial exploring Lundbeck’s PACAP-targeting mAb is expected to begin in mid-2024 in the United States, Japan, and Europe, with results expected in mid-2025. 

Researchers are exploring more potential therapeutic targets among several neuropeptides and other substances that may affect the migraine process. The development of the genomewide association study (GWAS) research tool has enabled researchers to discover more genes and gene combinations associated with migraine and conduct more specific research. 

While we're waiting for the next generation of novel migraine therapeutics, our improving understanding of migraine gives us more combinations of existing treatments (pharmaceutical and nonpharmaceutical) to reduce the burden of migraine. Although no one treatment or combination of treatments works for everyone, more research and more public awareness mean better odds for relief that works for you. 

If you have any tips or suggestions regarding new medications or what combination you've found success with, please share with the community at Tippi .