Meditation, psychedelics, and brain connectivity: A randomized controlled resting-state fMRI study of N,N-dimethyltryptamine and harmine in a meditation retreat

Both meditation and psychedelics are widely studied for their therapeutic potential in mental health. Recent research suggests potential synergies between mindfulness practice and psychedelics, though empirical studies have primarily focused on psilocybin. This study investigates the distinct and combined effects of mindfulness practice and an ayahuasca-inspired formulation containing N,N-dimethyltryptamine (DMT) and harmine on brain functional connectivity (FC), with implications for advancing clinical interventions. In this double-blind, placebo-controlled pharmaco-functional magnetic resonance imaging (fMRI) study, 40 meditation practitioners participated in a 3-day meditation retreat. They were randomized to receive either placebo or buccal DMT–harmine (120 mg each) and underwent fMRI scans 2 days before and after administration. Neural changes were assessed using multiple connectivity metrics, including within- and between-network connectivity, network and global connectivity, and cortical gradient analyses. Within-group changes showed that meditators in the placebo group exhibited increased network segregation across several resting-state networks, while the DMT–harmine group showed increased FC within the visual network (VIS) and between VIS and attention networks. Between-group differences similarly showed increased FC between VIS and the salience network (SAL) in the DMT–harmine group compared with placebo post-retreat. No evidence of prolonged cortical gradient disruption, which is characteristic of acute psychedelic action, was observed. This suggests a return to typical brain organization shortly after the experience. These findings reveal distinct neural mechanisms underlying meditation and psychedelic-augmented meditation. While meditation alone reduced FC between networks, DMT–harmine increased within- and between-network connectivity. Given the potential of meditation and psychedelics for improving mental health, further exploration of their synergistic potential in clinical contexts is warranted. This study advances the understanding of how psychedelics and mindfulness practice shape brain function, offering insights into their complementary roles in emotional and psychological well-being.