The Hierarchy of Psychedelic Effects: Three Systematic Reviews and Meta-Analyses
Poster No:
2478
Submission Type:
Abstract Submission
Authors:
Kenneth Shinozuka1
Institutions:
1University of Oxford, Oxford, Oxfordshire
First Author:
Introduction:
Serotonergic psychedelics, including dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin, induce altered states of consciousness. 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) their subjective experience (phenomenology), 2) whole-brain neuroimaging and 3) molecular pharmacology.
Methods:
Phenomenology:
We performed a meta-analysis on studies that measured the subjective experience of psychedelics through the Altered States of Consciousness (ASC) questionnaire. We conducted a three-level meta-analysis in order to account for statistical dependencies arising from the fact that ASC studies measured multiple subjective dimensions in the same group of participants. This three-level analysis models both the within-study heterogeneity and the between-study heterogeneity.
Neuroimaging:
To perform a meta-analysis on studies of FC, we essentially "re-parcellated" all of the data into the same parcellation: the seven resting-state Yeo networks. We conducted what amounted to a "vote-counting" meta-analysis. If a pair of ROIs became more connected under psychedelics, then a "vote" was cast in favour of the two Yeo networks that comprised this pair. To compute the significance of our results, we compared our results to a surrogate dataset formed from Human Connectome Project data.
Pharmacology:
We performed two meta-analyses of the pharmacology literature. The first was conducted on the selectivity of binding affinities, measured as the ratio between the affinity (Ki) for a given receptor and the affinity for a reference receptor, which we chose to be the 5-HT1A receptor. For the selectivity meta-analysis, we limited our literature search to four receptors – 5-HT1A, 5-HT2A, 5-HT2C, and D2 – expressed in human cells or cortical slices.
The second meta-analysis was performed on relative functional activity, measured as ∆log(Emax/EC50), where ∆ refers to the difference between this quantity for the psychedelic of interest and that of a reference ligand (e.g. serotonin). We examined three types of GPCR-mediated functional activity at the 5-HT2A receptor: calcium mobilisation and inositol phosphate formation, which capture Gq-protein signalling, and beta-arrestin-2 recruitment.
For both the selectivity and relative activity meta-analyses, we constructed random-effects models, which model between-study heterogeneity.
We performed a meta-analysis on studies that measured the subjective experience of psychedelics through the Altered States of Consciousness (ASC) questionnaire. We conducted a three-level meta-analysis in order to account for statistical dependencies arising from the fact that ASC studies measured multiple subjective dimensions in the same group of participants. This three-level analysis models both the within-study heterogeneity and the between-study heterogeneity.
Neuroimaging:
To perform a meta-analysis on studies of FC, we essentially "re-parcellated" all of the data into the same parcellation: the seven resting-state Yeo networks. We conducted what amounted to a "vote-counting" meta-analysis. If a pair of ROIs became more connected under psychedelics, then a "vote" was cast in favour of the two Yeo networks that comprised this pair. To compute the significance of our results, we compared our results to a surrogate dataset formed from Human Connectome Project data.
Pharmacology:
We performed two meta-analyses of the pharmacology literature. The first was conducted on the selectivity of binding affinities, measured as the ratio between the affinity (Ki) for a given receptor and the affinity for a reference receptor, which we chose to be the 5-HT1A receptor. For the selectivity meta-analysis, we limited our literature search to four receptors – 5-HT1A, 5-HT2A, 5-HT2C, and D2 – expressed in human cells or cortical slices.
The second meta-analysis was performed on relative functional activity, measured as ∆log(Emax/EC50), where ∆ refers to the difference between this quantity for the psychedelic of interest and that of a reference ligand (e.g. serotonin). We examined three types of GPCR-mediated functional activity at the 5-HT2A receptor: calcium mobilisation and inositol phosphate formation, which capture Gq-protein signalling, and beta-arrestin-2 recruitment.
For both the selectivity and relative activity meta-analyses, we constructed random-effects models, which model between-study heterogeneity.
Results:
Phenomenology:
At medium doses, 5D-ASC scores were significantly greater for LSD than psilocybin in the oceanic boundlessness dimension (OB; p = 0.0283), which corresponds to feelings of interconnectedness, and the visionary restructuralisation dimension (VR; p = 0.0468), which measures the quality and intensity of visual hallucinations. We also observed significant differences between LSD and psilocybin in the VR dimension (p = 0.0417) at high doses.
Neuroimaging:
All psychedelics significantly strengthened between-network connectivity. Within-network connectivity decreased in all networks except for the frontoparietal network. However, all reductions in within-network FC were deemed insignificant.
Pharmacology:
There were no significant differences between psychedelics in their selective affinity for the 5-HT2A, 5-HT2C, or D2 receptor, relative to the 5-HT1A receptor. There were also no significant differences in relative functional activity at the calcium mobilisation, inositol phosphate formation, or β-arrestin-2 recruitment pathways.
At medium doses, 5D-ASC scores were significantly greater for LSD than psilocybin in the oceanic boundlessness dimension (OB; p = 0.0283), which corresponds to feelings of interconnectedness, and the visionary restructuralisation dimension (VR; p = 0.0468), which measures the quality and intensity of visual hallucinations. We also observed significant differences between LSD and psilocybin in the VR dimension (p = 0.0417) at high doses.
Neuroimaging:
All psychedelics significantly strengthened between-network connectivity. Within-network connectivity decreased in all networks except for the frontoparietal network. However, all reductions in within-network FC were deemed insignificant.
Pharmacology:
There were no significant differences between psychedelics in their selective affinity for the 5-HT2A, 5-HT2C, or D2 receptor, relative to the 5-HT1A receptor. There were also no significant differences in relative functional activity at the calcium mobilisation, inositol phosphate formation, or β-arrestin-2 recruitment pathways.
Conclusions:
We found that the phenomenology, neuroimaging, and pharmacology of psychedelics exhibit a weak one-to-one correspondence with one another, which is not surprising given their highly non-linear relationships. We encourage future research to develop tools for modelling these relationships in order to improve our scientific understanding of psychedelics.
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Perception, Attention and Motor Behavior:
Consciousness and Awareness 1
Perception: Multisensory and Crossmodal
Perception: Visual
Perception and Attention Other 2
Keywords:
Consciousness
FUNCTIONAL MRI
Meta- Analysis
Perception
Seretonin
1|2Indicates the priority used for review
·Results of the phenomenology meta-analysis.
·Results of the undirected functional connectivity meta-analysis.
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