Connectome-based encoding of subjective drug responses to acute oral methamphetamine

Methamphetamine is a widely abused drug, and its chronic use is associated with significant negative physical and mental health consequences. Individual differences in subjective responses to acute methamphetamine have been previously linked to vulnerability for future misuse. However, the neural mechanisms underlying these individual differences remain poorly understood, particularly at the functional connectome level. Resting state functional connectivity data following an acute methamphetamine challenge was acquired from 83 healthy adults using a randomized, double-blind, placebo-controlled, cross-over study design (two sessions per participant; 165 total sessions) and used to generate brain-behavior predictive models of subjective response using five-fold cross-validation. Heart rate served as a control variable to assess the specificity of the predictive models to subjective versus physiological effects. External generalizability was tested using data from a separate sample of 22 healthy adults acquired using a similarly rigorous placebo-controlled design. Connectome-based predictive models successfully predicted individual differences in subjective response (rho(ρ)=0.25, p = 0.02) but not cardiovascular effects (ρ = 0.08, p = 0.199), as driven by individual differences in predominantly sensorimotor connections. Similar associations between connectivity within the identified network and subjective responses were observed in the external replication sample (ρ = 0.37, p = 0.044). These findings suggest that individual differences in subjective response to methamphetamine reflect distinct neural effects, particularly alterations of motor/sensory network function. These associations are specific to subjective responses and thus cannot easily be accounted for by pharmacokinetic factors. Together these findings suggests that individual differences in the functional connectome encode for differences in subjective methamphetamine effects that may contribute to differences in susceptibility for escalation in use.