The Hierarchy of Psychedelic Effects: Three Systematic Reviews and Meta-Analyses

• Published in: bioRxiv
• Main Authors: Shinozuka, Kenneth, Jerotic, Katarina, Pedro Am Mediano, Zhao, Alex T, Preller, Katrin H, Carhart-Harris, Robin L, Kringelbach, Morten L
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 26.12.2023
• Subjects: Addictions; Consciousness; Inositol phosphate; Lysergide; Medical imaging; Mental disorders; Neural networks; Neuroimaging; Phenomenology; Psilocybin; Psychedelic drugs; Serotonin S1 receptors; Serotonin S2 receptors
• DOI: 10.1101/2023.10.06.561183

Serotonergic psychedelics induce altered states of consciousness and have shown potential in treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are currently not fully understood. Here, we provide three systematic reviews and meta-analyses of three hierarchical levels relevant to the effects of psychedelics, i.e., 1) subjective experience (phenomenology), 2) whole-brain neuroimaging and 3) molecular pharmacology. Phenomenologically, medium and high doses of LSD yield significantly higher ratings of visionary restructuralisation than psilocybin on the 5-dimensional Altered States of Consciousness Scale. Our neuroimaging results reveal that psychedelics significantly strengthen between-network functional connectivity (FC) while diminishing within-network FC. Pharmacologically, we found no significant between-drug differences in the selectivity of psychedelics for the 5-HT2A, 5-HT2C, or D2 receptors, relative to the 5-HT1A receptor, but we did observe that LSD induces significantly more inositol phosphate formation at the 5-HT2A receptor than DMT and psilocin. Our meta-analyses link each of the classic psychedelics - DMT, LSD, and psilocybin - to specific neural fingerprints at each level of the tripartite hierarchy. The results show a highly non-linear relationship between these fingerprints. Overall, the results point to the need for standardising experimental procedures and analysis techniques, as well as for more research on the emergence between different levels of psychedelic effects. Future work could use our tripartite hierarchy framework to investigate the dose-dependent effects of different psychedelics in the same participants.Competing Interest StatementThe authors have declared no competing interest.Footnotes* I corrected the phenomenology analysis to adjust for different dose levels, and I also modified the pharmacology analysis so that I analysed relative rather than absolute affinity and activity values.