MYCOLab Ai Logo - gold and army green

How to account for hallucinations in the interpretation of the antidepressant effects of psychedelics: a translational framework

Summary

Psychedelic drugs like LSD and psilocybin show promise in treating depression with effects lasting months after single doses. However, scientists debate whether the hallucinations and mystical experiences these drugs produce are necessary for their healing effects. This review proposes a framework to test whether lower doses without hallucinations might still provide antidepressant benefits, similar to how anesthesia-administered ketamine works without the patient’s awareness.

Background

Recent clinical trials demonstrate that psychedelics produce rapid and long-lasting antidepressant effects lasting up to several months after single administration. However, lack of appropriate placebo controls and incomplete understanding of the role of hallucinogenic and mystical experiences hampers interpretation of these therapeutic effects.

Objective

To develop a translational framework that establishes pharmacokinetic/pharmacodynamic relationships in rodents and humans for both hallucinogenic and therapeutic effects of psychedelics. The study aims to determine whether hallucinogenic experience is central to antidepressant effects by comparing ED50 values for therapeutic versus hallucinogenic effects.

Results

Analysis reveals that perceptual changes occur at lower doses than full mystical effects across psychedelics. The 5-HT2A receptor is essential for acute subjective effects as ketanserin pretreatment blocks effects in humans. Evidence suggests therapeutic effects may be independent from hallucinogenic experiences, similar to ketamine’s mechanisms.

Conclusion

The proposed translational framework utilizing PK/PD relationships and cognitive flexibility measures will help clarify the mechanism of action of psychedelics in depression and elucidate whether acute subjective/hallucinogenic experiences are necessary for therapeutic benefits.
  • Published in:Psychopharmacology,
  • Study Type:Narrative Review,
  • Source: PMID: 35348806
Scroll to Top