Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology

Abstract

Serotonergic psychedelics induce altered states of consciousness and have shown potential for treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are not fully understood. Here, we provide a novel, synergistic understanding of psychedelics arising from systematic reviews and meta-analyses of three hierarchical levels of analysis: (1) subjective experience (phenomenology), (2) 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, in general, psychedelics significantly strengthen between-network functional connectivity (FC) while significantly diminishing within-network FC. Pharmacologically, LSD induces significantly more inositol phosphate formation at the 5-HT_2A receptor than DMT and psilocin, yet there are no significant between-drug differences in the selectivity of psychedelics for the 5-HT_2A, 5-HT_2C, or D₂ receptors, relative to the 5-HT_1A receptor. Our meta-analyses link DMT, LSD, and psilocybin to specific neural fingerprints at each level of analysis. The results show a highly non-linear relationship between these fingerprints. Overall, our analysis highlighted the high heterogeneity and risk of bias in the literature. This suggests an urgent need for standardising experimental procedures and analysis techniques, as well as for more research on the emergence between different levels of psychedelic effects.

Fig. 1. Meta-analysis of the 5-Dimensional Altered States of Consciousness (5D-ASC) data reveals few significant differences between psychedelics, but many more significant differences within psychedelics.

The 5D-ASC is one of the most common scales for assessing the subjective effects of psychedelics. It measures altered states of consciousness along five different dimensions: oceanic boundlessness (OB; a feeling of interconnectedness), anxious ego dissolution (AED), visionary restructuralisation (VR; the quality and intensity of visual hallucinations), auditory alterations (AA), and reduction of vigilance (RV). Our literature search identified 23 studies that reported 5D-ASC data. We performed a multilevel random-effects meta-analysis in order to account for the lack of statistical independence between measurements of different dimensions within the same group of participants. Within-study and between-study heterogeneity were estimated with the restricted maximum likelihood procedure. Using a Correlated and Hierarchical Effects model to account for within-study correlations in sampling error, we analysed the effect of dose and drug (DMT, LSD, or psilocybin) on pooled 5D-ASC scores. DMT was administered intravenously in phenomenological studies, whereas LSD and psilocybin were administered orally. Thus, DMT has different pharmacokinetics from LSD and psilocybin, which impacts the subjective experience, so we only compared significant between-drug differences for LSD and psilocybin. We only compared the two drugs for similar doses, assuming that 0.1 mg LSD = 20 mg psilocybin (Ley et al. [14]). (a–c, left column) Between-drug comparisons of pooled 5D-ASC scores for LSD and psilocybin. LSD almost always ranked higher than psilocybin, but differences only reached significance in the VR dimension for high and medium doses and in the OB dimension for medium dose. (a–c, right column) Within-drug comparisons for LSD and psilocybin. VR and OB received significantly higher scores than AED and AA, for both LSD and psilocybin. (d, e) Within-drug comparisons for DMT. At low doses, OB and VR ranked significantly higher than AED. Only one study measured ASC scores for the AA and RV dimensions on DMT, so we did not perform a meta-analysis on these dimensions for DMT. Numerical data for the above figure are given in Table S1. We also conducted a meta-analysis of the 11-dimensional ASC scale, which is also widely used in the literature; the results are displayed in Fig. S3 and Table S2. * p < 0.05, ** p < 0.01, *** p  < 0.001.

Fig. 2. Phenomenology profiles of the psychedelics demonstrate broad similarity between the neural correlates of their subjective effects.

We identified 14 studies that measured correlations between ASC ratings and fMRI activity or pairwise connectivity, including three studies on ketamine. We determined the Yeo network that contained each brain region that exhibited a significant correlation, and then we averaged across the correlations associated with each Yeo network, resulting in the mean correlation between each Yeo network and each ASC scale. The phenomenology profiles were defined by a weighted combination of the mean correlations for each ASC scale, in which the weights were the pooled ASC ratings of high doses of each psychedelic for the corresponding scale. Because the pooled ASC ratings are similar across psychedelics, the phenomenology profiles are very alike one another as well. However, the lack of data on the neural correlates of the ASC ratings limits our confidence in the validity of these profiles.

Fig. 3. Meta-analysis of the functional connectivity (FC) data indicates that psychedelics potently increase between-network FC.

To perform a meta-analysis on the FC data, we determined the Yeo networks that contained each pair of functionally connected regions of interest (ROIs) in the literature and then performed a weighted sum of the number of significant connections between Yeo networks. We included n = 12 studies in this meta-analysis, after excluding studies that did not measure pairwise FC and secondary analyses of identical datasets. a The aggregate FC matrix shows the overall connectivity between pairs of Yeo networks. b Several connections were deemed to be insignificant relative to a null distribution that was formed from an independent resting-state fMRI dataset collected by the Human Connectome Project. c A rendering of (b) on the surface of the brain, created with the BrainNet Viewer [141].

Fig. 4. Functional connectivity (FC) profiles show unique FC patterns for each psychedelic.

Out of the n = 12 studies that we examined in our quantitative FC meta-analysis, n = 3 were studies on ayahuasca/DMT (ayahuasca: n = 2; DMT: n = 1), n = 3 on LSD, and n = 6 on psilocybin. Each FC profile contains the total FC of each network, which was obtained by taking the sum of the rows of the corresponding aggregate FC matrices (Fig. S5). (The units of the profiles are arbitrary.) The psychedelics display distinct FC profiles; for instance, LSD strongly elevates the total FC of the limbic network, whereas FC between the limbic network and all other networks was insignificant for ayahuasca/DMT and psilocybin (hence there is no point on the limbic network for the respective spider plots).

Fig. 5. Pharmacology meta-analysis reveals that there are no significant differences in selectivity between psychedelics relative to 5-HT_1A and that LSD induces significantly higher relative activity at the inositol phosphate (IP) formation pathway.

For both the selectivity and relative activity data, we created random-effects models that modelled between-study variance. a Selectivity is the ratio between the binding affinity (measured as K_i) for a receptor of interest and the affinity for a reference receptor. We measured selectivity for three different receptors – 5-HT_2A, 5-HT_2C, and D₂ – relative to 5-HT_1A. Our literature search identified n = 14 studies on selectivity, including n = 6 studies on DMT, n = 9 studies on LSD, and n = 5 studies on psilocin. We did not find any significant between-drug differences in selectivity for any of the three receptors. b Relative activity is a measure of the cellular signalling that is elicited when a drug binds to a receptor. It is calculated here as ∆log(E_max/EC₅₀), where E_max is the maximal effect of the drug relative to a reference ligand and EC₅₀ is the concentration needed to elicit 50% of the maximal effect [142]. We found n = 18 studies on functional activity, including n = 6 studies on DMT, n = 13 studies on LSD, and n = 6 studies on psilocin. We measured relative activity at three different signalling pathways: calcium mobilisation, IP formation, and β-arrestin2 recruitment. IP formation was the only pathway that exhibited any significant between-drug differences; LSD elicited significantly higher activity than both DMT and psilocin. * p < 0.05, ** p  < 0.01, *** p  < 0.001.

Fig. 6. Pharmacology profiles primarily reveal the distribution of 5-HT_2A receptors in the Yeo networks, as well as the (insignificantly) higher selectivity of psilocin for the 5-HT_2A receptor compared to DMT and LSD.

Based on an available PET atlas of the 5-HT_2A and D₂ receptors [66], we created the pharmacology profile of each psychedelic. The profiles show the expression of those two receptors in the Yeo networks, weighted by the selectivity of the corresponding psychedelics for those receptors. Because the selectivity for 5-HT_2A is two orders of magnitude higher than the selectivity for D₂, the profiles are dominated by 5-HT_2A receptor expression. Since psilocin has the most selectivity for 5-HT_2A (relative to 5-HT_1A), followed by LSD then DMT, psilocin’s pharmacology profile is the “largest.”.

Fig. 7. Our multi-level analysis of psychedelic effects highlights the nonlinear relationship between their pharmacology, neuroimaging, and phenomenology.

The effects of psychedelics form a tripartite hierarchy, consisting of subjective experience (a, phenomenology), functional connectivity (b, neuroimaging), and their selective affinity for receptors (c, pharmacology). Here, we show the neural correlates of each level of the hierarchy in the seven Yeo networks. In brief, each profile was derived from (a) neural correlates of the subjective dimensions of the ASC scale, (b) summing the aggregate FC between each network and other networks, and (c) the distribution of each receptor, weighted by each psychedelic’s selectivity for that receptor. Clearly, there is a very weak correspondence between the different levels of the hierarchy, revealing the highly non-linear relationship between phenomenology, neuroimaging, and pharmacology. Note: we analysed data on both DMT and ayahuasca in our FC meta-analysis, but only on DMT for the other meta-analyses. We examined data on psilocin in our pharmacology meta-analysis and on psilocybin in both of the other meta-analyses.