The psychedelic-peptide paradox: a hormetic hypothesis

The purpose of this narrative review is to examine the hypothesis that two neuropeptides, vasopressin (VP) and oxytocin (OT) and their receptors have central roles in the behavioral and physiological consequences of psychedelic interventions. Transient consequences of psychedelics can include anxiety and in some cases sickness responses such as nausea and vomiting, which may involve VP and other components of the hypothalamic-pituitary-adrenal axis. Stressful experiences are often followed by a pulsatile release of OT. The effects of OT depend on interactions with VP and may be more apparent following stressful experiences including those associated with psychedelic drugs. Effects of both the VP-OT system and psychedelics also are mediated through interactions with the autonomic nervous system and the immune system, contributing to a process called “stress response hormesis.” The hypotheses arising from a hormetic perspective could guide novel approaches to understanding dose- and time-dependent psychedelic functions and to the treatment of emotional and physical disorders.