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The psychedelic-peptide paradox: a hormetic hypothesis

Summary

This review explores how psychedelic drugs like LSD and psilocybin work through the body’s natural stress-response systems, particularly two brain chemicals called oxytocin and vasopressin. It explains why psychedelics initially cause uncomfortable feelings like nausea and anxiety, but these are followed by improved mood, sociability, and emotional healing. The theory suggests that this initial ‘stress’ response triggers the body’s natural healing mechanisms, similar to how physical exercise makes you uncomfortable initially but builds strength over time.

Background

Psychedelics show paradoxical effects including initial anxiety and nausea followed by increased sociality and wellness. The neuropeptides vasopressin (VP) and oxytocin (OT) play central roles in stress responses and have overlapping effects with psychedelics. Current theories do not fully explain the temporal pattern of psychedelic effects.

Objective

This narrative review examines the hypothesis that vasopressin and oxytocin and their receptors have central roles in the behavioral and physiological consequences of psychedelic interventions. The review proposes a hormetic perspective to explain dose- and time-dependent psychedelic functions and their therapeutic potential.

Results

The review identifies that initial psychedelic effects involve VP-mediated anxiety and nausea, followed by OT-mediated stress buffering and neuroplasticity. Both VP and OT interact with serotonin systems and autonomic/immune functions. A hormetic model explains temporal sequencing of transient stressful responses followed by sustained beneficial effects.

Conclusion

Integrating VP-OT system dynamics with hormesis theory provides a novel framework for understanding psychedelic mechanisms and optimizing therapeutic use. This perspective suggests that initial discomfort may be necessary for subsequent benefits and highlights the importance of time-, dose-, and context-dependent effects in psychedelic therapy.
  • Published in:Comprehensive Psychoneuroendocrinology,
  • Study Type:Narrative Review,
  • Source: PMID: 40584160
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