Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called ‘peak experiences’, characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extant changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). We derived measures of SNS and PNS activity from the electrocardiogram data of 17 participants (11 males, 6 females, mean age = 33.8 y, SD = 8.3) while they received either DMT or placebo. Results show that the joint influence of SNS and PNS (‘sympatho-vagal coactivation’) over cardiac activity was robustly correlated with participants ratings of ‘Spiritual Experience’ and ‘Insightfulness’ during the DMT experience, while also being related to improved wellbeing scores two weeks after the session. In addition, we found that the state of balance between the two ANS branches (‘sympatho-vagal balance’) before DMT injection predicted scores of ‘Insightfulness’ during the DMT experience. These findings demonstrate the important involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic-therapy.Significance statementPsychedelics can give rise to intense positive subjective experiences - aligned with Maslow’s notion of ‘peak experiences’ - that can have a positive and enduring impact on mental health. Understanding how these experiences relate to peripheral physiology before and during the acute effects of psychedelics is an important object of enquiry, as it may help advance the therapeutic use of these compounds. In this study, we demonstrate that specific peripheral states computed from heart rate activity recordings predicted and correlated with acute peak experiences and increases in wellbeing. These findings have implications for the relationship between peripheral physiology and altered states of consciousness. Moreover, they highlight a putative marker of physiological ‘readiness’ prior the psychedelic experience that could predict therapeutically relevant mechanisms that might be modified to improve mental health outcomes in psychedelic-therapy.