Differential drug responsiveness in addiction: Multivariate determinants across psychostimulants and opioids

Not all drug users are the same. To understand different profiles of patients that use addictive substances, research frameworks typically classify cases by drug class and severity of compulsive use. However, individuals exposed to the same psychostimulant or opioid under similar conditions vary markedly in motivation to obtain the drug, effort expenditure, sensitivity to punishment or constraint, relapse vulnerability, and transitions between drug classes. Psychostimulants and opioids engage overlapping but distinct neural systems within mesolimbic and cortico-striatal circuits, yet these differences are rarely examined within unified cross-drug frameworks.Cross-drug comparisons remain limited, with psychostimulant and opioid mechanisms often studied separately. Effort-based and cost-sensitive measures are underused as core phenotyping dimensions. Developmental stage, stress biology, and sex differences are typically examined in isolation rather than integrated into structured responsiveness models. Furthermore, classification models often employ experimenter-determined factors which may be subjective. Moreover, computational and multivariate approaches to identifying reproducible addiction clusters remain insufficiently developed.This Research Topic aims to redefine substance addiction by grouping individuals according to how they behaviorally and biologically respond to psychostimulants and opioids.It seeks to identify shared and drug-specific neural mechanisms, establish effort and constraint sensitivity as key markers of vulnerability, integrate developmental, stress-related, and sex-dependent influences into unified models, and apply quantitative approaches to validate biologically grounded addiction clusters that can guide prevention and treatment strategies.Subthemes include:• Addiction clusters defined by multidimensional responsiveness profiles rather than intake-based or substance-specific classifications.• Neurobehavioral mechanisms of differential responsiveness to psychostimulants and opioids, including dopamine and μ-opioid receptor signaling and reward-related synaptic plasticity.• Drug-class–specific adaptations in mesolimbic and cortico-striatal circuits shaping motivational value and cost-sensitive drug seeking.• Motivational responsiveness to increasing effort or constraint as a translatable marker of addiction cluster structure.• Environmental and stress-dependent modulation of drug responsiveness via glucocorticoid signaling, neuroimmune processes, and epigenetic regulation.• Developmental contributors to responsiveness profiles, including age-dependent circuit maturation.• Sex-interacting and sex-independent molecular mechanisms of responsiveness, including hormone-sensitive signaling and sex-biased gene expression.• Frontostriatal control and behavioral risk traits underlying variability in drug responsiveness across clusters.• Neural and behavioral mechanisms supporting transitions between psychostimulant and opioid use, including cross-sensitization and receptor regulation.• Molecular, circuit-level, and computational approaches to identifying and validating addiction clusters.• Responder-based stratification of addiction clusters to inform prevention and intervention strategies across drug classes. Topic editors: Martin Job, Sergios Charntikov Source: https://www.frontiersin.org/research-topics/79447/differential-drug-responsiveness-in-addiction-multivariate-determinants-across-psychostimulants-and-opioids