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

Neuropsychopharmacology volume 50, pages 1787–1794 (2025)Cite this article

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Abstract

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.

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Fig. 1: Study design and computational approach.
Fig. 2: Behavioral measures and analysis.
Fig. 3: Model performance for the prediction of HR ΔAUC and DEQ Feel ΔAUC.
Fig. 4: Predictive network anatomy and external validation.
Fig. 5: Leave-one-in network lesioning analysis.

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Data availability

Data will be shared for appropriate scientific use upon request. Code for the main analyses of the study can be found here: https://github.com/YaleYipLab/methamphetamine-response-cpm.

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Acknowledgements

The authors acknowledge the support of the University of Chicago Magnetic Resonance Imaging Research Center funded by S10OD018448, and the University of Chicago Research Computing Center.

Funding

MB was supported by a postdoctoral fellowship from the Yale Center for Brain and Mind Health. LR was supported by the National Science Foundation (DGE-2139841).

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Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Lester G. Rodriguez Santos, Marzieh Babaeianjelodar & Sarah W. Yip

  2. Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT, USA

    Lester G. Rodriguez Santos & Marzieh Babaeianjelodar

  3. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

    Hanna Molla & Harriet de Wit

  4. Child Study Center, Yale School of Medicine, New Haven, CT, USA

    Sarah W. Yip

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  1. Lester G. Rodriguez Santos
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Contributions

Data collection and study design were conducted by HDW in collaboration with HM. The overall analysis plan was created by HDW, HM, SWY and LR. Neuroimaging and statistical analyses were conducted by LR and MB. LR wrote the first draft of the manuscript, with feedback from all co-authors, and worked on subsequent drafts with SWY. All authors have approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Sarah W. Yip.

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Competing interests

HdW is on the Board of Directors of PharmAla Biotech, and on the Scientific Advisory Boards of Gilgamesh Pharmaceuticals and Mind Foundation. These roles are unrelated to this manuscript. HM declares no competing interests. The remaining authors have nothing to disclose.

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Rodriguez Santos, L.G., Molla, H., Babaeianjelodar, M. et al. Connectome-based encoding of subjective drug responses to acute oral methamphetamine. Neuropsychopharmacol. 50, 1787–1794 (2025). https://doi.org/10.1038/s41386-025-02215-y

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