Persistent Cancer Cells: The Deadly Survivors.

Persistent cancer cells are the discrete and usually undetected cells that survive cancer drug treatment and constitute a major cause of treatment failure. These cells are characterized by their slow proliferation, highly flexible energy consumption, adaptation to their microenvironment, and phenotypic plasticity. Mechanisms that underlie their persistence offer highly coveted and sought-after therapeutic targets, and include diverse epigenetic, transcriptional, and translational regulatory processes, as well as complex cell-cell interactions. Although the successful clinical targeting of persistent cancer cells remains to be realized, immense progress has been made in understanding their persistence, yielding promising preclinical results.

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese.

BACKGROUND: Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. METHODS: A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. RESULTS: Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. CONCLUSIONS: These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Microglia-mediated calcium-permeable AMPAR accumulation in the nucleus accumbens drives hyperlocomotion during cocaine withdrawal.

During withdrawal from cocaine, calcium permeable-AMPA receptors (CP-AMPAR) progressively accumulate in nucleus accumbens (NAc) synapses, a phenomenon linked to behavioral sensitization and drug-seeking. Recently, it has been suggested that neuroimmune alterations might promote aberrant changes in synaptic plasticity, thus contributing to substance abuse-related behaviors. Here, we investigated the role of microglia in NAc neuroadaptations after withdrawal from cocaine-induced conditioned place preference (CPP). We depleted microglia using PLX5622-supplemented diet during cocaine withdrawal, and after the place preference test, we measured dendritic spine density and the presence of CP-AMPAR in the NAc shell. Microglia depletion prevented cocaine-induced changes in dendritic spines and CP-AMPAR accumulation. Furthermore, microglia depletion prevented conditioned hyperlocomotion without affecting drug-context associative memory. Microglia displayed fewer number of branches, resulting in a reduced arborization area and microglia control domain at late withdrawal. Our results suggest that microglia are necessary for the synaptic adaptations in NAc synapses during cocaine withdrawal and therefore represent a promising therapeutic target for relapse prevention.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

The Dark Triad and aggression among drug abstainers: a moderated mediation model of self-control and physical exercise.

BACKGROUND: Drug addiction is a significant public health concern, and aggression is common among people with drug addiction. Despite mounting evidence showing that the Dark Triad is a risk factor for aggression, the mediating and moderating mechanisms underlying this relationship are less known. This study tested the mediation effect of self-control in the association between the Dark Triad and aggression and whether this mediation was moderated by physical exercise. METHODS: A cross-sectional study was conducted in two compulsory drug rehabilitation centers in Nanning, China. A convenience sample of 564 drug abstainers completed a questionnaire to assess their Dark Triad, self-control, aggression, and physical exercise levels. Mediation and moderation analyses were carried out in SPSS macro-PROCESS. RESULTS: Self-control partially mediated the positive association between the Dark Triad and aggression. Physical exercise moderated the indirect effect of the Dark Triad on aggression via self-control, with the effect decreasing with the increase in physical exercise levels. CONCLUSIONS: This study offers fresh insights into the underlying mediating and moderating mechanisms between the Dark Triad and aggression. The findings provide important practical implications for future intervention and prevention programs to address aggression among drug abstainers, which may be realized through strengthening self-control and physical exercise.

Early life adversity: Epigenetic regulation underlying drug addiction susceptibility.

Drug addiction is a leading cause of disability worldwide, with more than 70,000 Americans dying from drug overdose in 2019 alone. While only a small percentage of chronic drug users escalate to drug addiction, little is understood on the precise mechanisms of this susceptibility. Early life adversity is causally relevant to adult psychiatric disease and may contribute to the risk of addiction. Here we review recent pre-clinical evidence showing that early life exposure to stress and/or drugs regulates changes in behavior, gene expression, and the epigenome that persist into adulthood. We summarize the major findings and gaps in the preclinical literature, highlighting studies that demonstrate the often profound differences between female and male subjects.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

Oral self-administration of pregabalin in a mouse model and the resulting drug addiction features.

Prescription drug abuse is an issue that is rapidly growing globally. Pregabalin, an anticonvulsant, analgesic, and anxiolytic medication, is effective in the management of multiple neurological disorders; however, there is increasing concern regarding its widespread illicit use. It has been previously reported in mice that pregabalin can induce conditioned place preference. In this current investigation, the potential of pregabalin to elicit free-choice drinking in a mouse model of drug addiction, and its effect on recognition and withdrawal behaviors after forced abstinence, were studied. Twenty-two male BALB/c mice were randomly divided into three groups (n = 7-8/group); control, pregabalin-30, and pregabalin-60. The study had three phases: habituation (days 1-5) with free water access, free-choice drinking (days 6-13) with pregabalin groups receiving one water and one pregabalin bottle, and forced abstinence (days 14-21) with free water access. On day 13, the first open field test was conducted, followed by the Novel Object Recognition Test. On day 21, the second open field test was performed, followed by the Tail Suspension Test and Forced Swimming Test. Pregabalin elicited voluntary drinking in the higher-dose group, concurrently causing a decline in recognition memory performance in the novel object recognition test. Moreover, pregabalin induced withdrawal behavior after a period of forced abstinence in the forced swimming and tail suspension tests. This is the first report to establish an animal model of free-choice pregabalin drinking that may be used for further molecular studies and targeted therapy for pregabalin addiction.

[The characteristics of prevention of drug addiction and narcotism in municipal formation of city of Novorossiysk].

The drug addiction is one of most serious deviant behavior seriously harming both addict person and one's relationship. The drug using is considered as deviant because means using substances from non-legal turn-over or applied in non-medical purposes. Then follows degradation of health of person and one's positioning into physical and mental dependence on them. With time, personal dependence on drugs becomes stronger. The addicted person looses possibility to experience joy from natural stimuli and more difficulties in controlling drug using appear. Persons using drugs frequently commit crimes to have money to maintain one's dependence. Therefore, issues of prevention narcotism and struggle with drug addiction are fundamental ones for whole system of prevention in Novorossiysk. The article presents analysis of implemented activities and adopted measures of struggle with drug addiction in population of Novorossiysk.

[The analysis of main causes of increasing of cost of social aftermath of drug addiction in the region according to results of repeated evaluation].

The article presents an attempt to evaluate what factors could contribute into significant changes of both amount and structure of social cost of drug consumption in the region. The analysis, based on preserved basic principles of assessment, was applied to processes that occurred in both state and non-state spheres. The purpose of the study was to analyze main causes of dynamics of social cost of drug consumption during re-assessment. MATERIALS AND METHODS: The social cost of drug consumption in the Samara Oblast was re-assessed in 2017-2020 (first assessment was implemented in 2007-2010). The main causes of increasing of social cost of drug consumption were analyzed on the basis of the study results. RESULTS: In Samara Oblast, due to financial and structural changes in state and non-state spheres, occurred increasing of social cost of drug consumption from 18.0 billion to 25.4 billion rubles per year. At that, percentage of social cost of drug consumption in the gross domestic product decreased from 2.9% to 1.6%. In general structure of expenses greatest changes affected percentage of social aftermath of drug addiction (increase from 17.8% to 26.1%) and expenses of drug consumers (decrease from 69.7% to 62.3%). CONCLUSIONS: The increase of absolute values of financial expenditures of the Oblast related to drug consumption conditioned by financial and structural changes in society, is accompanied by decreasing of percentage of ocial cost of drug consumption in value of gross domestic product. The main cause of its dynamics is significant increasing of gross regional product.

Proteomic Analysis Reveals the Neurotoxic Effects of Chronic Methamphetamine Self-Administration-Induced Cognitive Impairments and the Role of Melatonin-Enhanced Restorative Process during Methamphetamine Withdrawal.

Cognitive flexibility is a crucial ability in humans that can be affected by chronic methamphetamine (METH) addiction. The present study aimed to elucidate the mechanisms underlying cognitive impairment in mice chronically administered METH via an oral self-administration method. Further, the effect of melatonin treatment on recovery of METH-induced cognitive impairment was also investigated. Cognitive performance of the mice was assessed using an attentional set shift task (ASST), and possible underlying neurotoxic mechanisms were investigated by proteomic and western blot analysis of the prefrontal cortex (PFC). The results showed that mice-administered METH for 21 consecutive days exhibited poor cognitive performance compared to controls. Cognitive deficit in mice partly recovered after METH withdrawal. In addition, mice treated with melatonin during METH withdrawal showed a higher cognitive recovery than vehicle-treated METH withdrawal mice. Proteomic and western blot analysis revealed that METH self-administration increased neurotoxic markers, including disruption to the regulation of mitochondrial function, mitophagy, and decreased synaptic plasticity. Treatment with melatonin during withdrawal restored METH-induced mitochondria and synaptic impairments. These findings suggest that METH-induced neurotoxicity partly depends on mitochondrial dysfunction leading to autophagy-dependent cell death and that the recovery of neurological impairments may be enhanced by melatonin treatment during the withdrawal period.

A systematic review of the local field potential adaptations during conditioned place preference task in preclinical studies.

Addiction is a global concern with a high relapse rate and without effective therapeutic options. Developing new effective therapeutic strategies is impossible without discovering the disease's neurobiological basis. The present systematic review aimed to comprehensively recognize and discuss the role of local field potentials from brain areas essential in forming and storing context-drug/food associations following the conditioned place preference (CPP) paradigm as a popular animal model of reward and addiction. Qualified studies were incorporated by a broad search of four databases, including Web of Science, Medline/PubMed, Embase, and ScienceDirect, in July 2022, and they were evaluated via appropriate methodological quality assessment tools. The current study found that drug-seeking behavior in different stages of the CPP paradigm is accompanied by alterations in neural oscillatory activity and adaptations in connectivity among various areas such as the hippocampus, nucleus accumbens, basolateral amygdala, and prelimbic area, intensely engaged in reward-related behaviors. These findings need to be extended by more future advanced studies to finally recognize the altered oscillatory activity patterns of large groups of cells in regions involved in reward-context associations to improve clinical strategies such as neuromodulation approaches to modify the abnormal electrical activity of these critical brain regions and their connections for treating addiction and preventing drug/food relapse in abstinent patients. DEFINITIONS: Power is the amount of energy in a frequency band and is the squared amplitude of the oscillation. Cross-frequency coupling refers to a statistical relationship between activities in two different frequency bands. Phase-amplitude coupling is perhaps the most commonly used method of computing cross-frequency coupling. Phase-amplitude coupling involves testing for a relationship between the phase of one frequency band and the power of another, typically relatively higher, frequency band. Thus, within phase-amplitude coupling, you refer to the "frequency for phase" and the "frequency for power." Spectral coherence has been frequently used to detect and quantify coupling between oscillatory signals of two or more brain areas. Spectral coherence estimates the linear phase-consistency between two frequency-decomposed signals over time windows (or trials).

DNA replication stress and mitotic catastrophe mediate sotorasib addiction in KRASG12C-mutant cancer.

BACKGROUND: Sotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration for treating KRASG12C-mutant non-small-cell lung cancer (NSCLC). Clinical trials on the therapeutic use of sotorasib for cancer have reported promising results. However, KRASG12C-mutant cancers can acquire resistance to sotorasib after treatment. We incidentally discovered that sotorasib-resistant (SR) cancer cells are addicted to this inhibitor. In this study, we investigated the mechanisms underlying sotorasib addiction. METHODS: Sotorasib-resistant cells were established using KRASG12C-mutant pancreatic cancer and NSCLC cell lines. Cell viability in the presence or absence of sotorasib and in combination with multiple inhibitors was assessed through proliferation assay and annexin V/propidium iodide (PI) flow cytometry assays. The mechanisms underlying drug addiction were elucidated through 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, immunofluorescence staining, time-lapse microscopy, and comet assay. Furthermore, a subcutaneous xenograft model was used to demonstrate sotorasib addiction in vivo. RESULTS: In the absence of sotorasib, the sotorasib-resistant cells underwent p21Waf1/Cip1-mediated cell cycle arrest and caspase-dependent apoptosis. Sotorasib withdrawal resulted in robust activation of mitogen-activated protein kinase (MAPK) pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo. CONCLUSIONS: We elucidated the mechanisms underlying the sotorasib addiction of cancer cells. Sotorasib addiction appears to be mediated through MAPK pathway hyperactivity, DNA damage, replication stress, and mitotic catastrophe. Moreover, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer.

The gut microbiota alone and in combination with a social stimulus regulates cocaine reward in the mouse.

The gut microbiota is a key factor in the maintenance of physiological homeostasis and immunity. Correlational studies have demonstrated that alterations in microbiota composition have been associated with addiction. Moreover, animal studies have confirmed a link between reward and social processes, which may be shaped by the gut microbiota thus influencing neurodevelopment and the programming of social behaviors across diverse animal species. However, whether there is an interaction between the microbiota and social reward processes in the context of drug reward remains unclear. To this end, we explored the influence of gut microbiota in regulating behaviourally conditioned responses to different rewards (cocaine and social interactions). Depletion of the intestinal microbiota resulted in differential reward responses to both drug and social stimuli with an attenuation of the former and enhancement of the latter independent of concomitant immune changes. Moreover, the combination of depleting the gut microbiota in the presence of a positive social stimulus attenuates cocaine reward. Together these data suggest that the two-pronged approach of targeting the microbiota and enhancing social behaviour could constitute a valuable component in reducing harm in drug use by altering the salient effects of cocaine.

Understanding the habenula: A major node in circuits regulating emotion and motivation.

Over the last decade, the understanding of the habenula has rapidly advanced from being an understudied brain area with the Latin name 'habena" meaning "little rein", to being considered a "major rein" in the control of key monoaminergic brain centers. This ancient brain structure is a strategic node in the information flow from fronto-limbic brain areas to brainstem nuclei. As such, it plays a crucial role in regulating emotional, motivational, and cognitive behaviors and has been implicated in several neuropsychiatric disorders, including depression and addiction. This review will summarize recent findings on the medial (MHb) and lateral (LHb) habenula, their topographical projections, cell types, and functions. Additionally, we will discuss contemporary efforts that have uncovered novel molecular pathways and synaptic mechanisms with a focus on MHb-Interpeduncular nucleus (IPN) synapses. Finally, we will explore the potential interplay between the habenula's cholinergic and non-cholinergic components in coordinating related emotional and motivational behaviors, raising the possibility that these two pathways work together to provide balanced roles in reward prediction and aversion, rather than functioning independently.

Integrative Approaches of DNA Methylation Patterns According to Age, Sex and Longitudinal Changes.

Background: In humans, age-related DNA methylation has been studied in blood, tissues, buccal swabs, and fibroblasts, and changes in DNA methylation patterns according to age and sex have been detected. To date, approximately 137,000 samples have been analyzed from 14,000 studies, and the information has been uploaded to the NCBI GEO database. Methods: A correlation between age and methylation level and longitudinal changes in methylation levels was revealed in both sexes. Here, 20 public datasets derived from whole blood were analyzed using the Illumina BeadChip. Batch effects with respect to the time differences were correlated. The overall change in the pattern was provided as the inverse of the coefficient of variation (COV). Results: Of the 20 datasets, nine were from a longitudinal study. All data had age and sex as common variables. Comprehensive details of age-, sex-, and longitudinal change-based DNA methylation levels in the whole blood sample were elucidated in this study. ELOVL2 and FHL2 showed the maximum correlation between age and DNA methylation. The methylation patterns of genes related to mental health differed according to age. Age-correlated genes have been associated with malformations (anteverted nostril, craniofacial abnormalities, and depressed nasal bridge) and drug addiction (drug habituation and smoking). Conclusion: Based on 20 public DNA methylation datasets, methylation levels according to age and longitudinal changes by sex were identified and visualized using an integrated approach. The results highlight the molecular mechanisms underlying the association of sex and biological age with changes in DNA methylation, and the importance of optimal genomic information management.

Disrupted functional connectivity of the brain reward system in substance use problems: A meta-analysis of functional neuroimaging studies.

Extensive literature suggests that the brain reward system is crucial in understanding the neurobiology of substance use disorders. However, evidence of reliable deficits in functional connectivity across studies on substance use problems remains limited. Therefore, a voxel-wise seed-based meta-analysis using brain regions of the reward system as seeds of interest was conducted on 96 studies representing 5757 subjects with substance use problems. The ventromedial prefrontal cortex exhibited hyperconnectivity with the ventral striatum and hypoconnectivity with the amygdala and hippocampus. The executive striatum showed hyperconnectivity with the motor thalamus and dorsolateral prefrontal cortex and hypoconnectivity with the anterior cingulate cortex and anterior insula. Finally, the limbic striatum was found to be hyperconnected to the orbitofrontal cortex and hypoconnected to the precuneus compared with healthy subjects. The current study provided meta-analytical evidence of deficient functional connectivity between brain regions of the reward system and cortico-striato-thalamocortical loops in addiction. These results are consistent with deficits in motivation and habit formation occurring in addiction, and they highlight alterations in brain regions involved in socio-emotional processing and attention salience.

Machine learning with neuroimaging biomarkers: Application in the diagnosis and prediction of drug addiction.

Drug abuse is a serious problem worldwide. Owing to intermittent intake of certain substances and the early inconspicuous clinical symptoms, this brings huge challenges for timely diagnosing addiction status and preventing substance use disorders (SUDs). As a non-invasive technique, neuroimaging can capture neurobiological signatures of abnormality in multiple brain regions caused by drug consumption in each clinical stage, like parenchymal morphology alteration as well as aberrant functional activity and connectivity of cerebral areas, making it realizable to diagnosis, prediction and even preemptive therapy of addiction. Machine learning (ML) algorithms primarily used for classification have been extensively applied in analysing medical imaging datasets. Significant neurobiological characteristics employed and revealed by classifiers were used to diagnose addictive states and predict initiation and vulnerability to drug usage, treatment abstinence, relapse and resilience of addicts and the risk of SUD. In this review, we summarize application of ML methods in neuroimaging focusing on addicts' diagnosis of clinical status and risk prediction and elucidate the discriminative neurobiological features from brain electrophysiological, morphological and functional perspectives that contribute most to the classifier, finally highlighting the auxiliary role of ML in addiction treatment.

Algorithms to Identify Nonmedical Opioid Use.

The rise in nonmedical opioid overdoses over the last two decades necessitates improved detection technologies. Manual opioid screening exams can exhibit excellent sensitivity for identifying the risk of opioid misuse but can be time-consuming. Algorithms can help doctors identify at-risk people. In the past, electronic health record (EHR)-based neural networks outperformed Drug Abuse Manual Screenings in sparse studies; however, recent data shows that it may perform as well or less than manual screenings. Herein, a discussion of several different manual screenings and recommendations is contained, along with suggestions for practice. A multi-algorithm approach using EHR yielded strong predictive values of opioid use disorder (OUD) over a large sample size. A POR (Proove Opiate Risk) algorithm provided a high sensitivity for categorizing the risk of opioid abuse within a small sample size. All established screening methods and algorithms reflected high sensitivity and positive predictive values. Neural networks based on EHR also showed significant effectiveness when corroborated with Drug Abuse Manual Screenings. This review highlights the potential of algorithms for reducing provider costs and improving the quality of care by identifying nonmedical opioid use (NMOU) and OUD. These tools can be combined with traditional clinical interviewing, and neural networks can be further refined while expanding EHR.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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.