The effects of tryptamine psychedelics in the brain: a meta-analysis of functional and review of molecular imaging studies

Castelhano and colleagues frame tryptamine hallucinogens (for example LSD, psilocybin, DMT, ayahuasca) as both experimental models for psychosis and as candidate therapeutics for psychiatric disorders. Earlier work has emphasised their agonist action at serotonin receptors, particularly 5-HT2A, and has reported altered perceptual, cognitive and affective states as well as changes in large-scale brain networks such as the default mode network (DMN). However, the authors note uncertainty about which brain systems show reliable changes across studies, and whether those functional effects map onto the regional distribution of serotonin receptor subtypes (notably 5-HT2A and 5-HT1A).

The investigators performed a quantitative coordinate-based meta-analysis of functional neuroimaging studies and a narrative review of available molecular PET studies. They searched PubMed in September 2020 using terms for LSD, lysergic compounds, psilocybin, ayahuasca and dimethyltryptamine combined with imaging keywords (fMRI, BOLD, PET). From 78 initially identified records the final selection included 16 fMRI studies and four PET studies; the fMRI sample totalled 323 participants and the PET studies 57 participants. All included fMRI studies imaged the whole brain, reported coordinate-based results in a standard space, used fMRI or PET methods, enrolled healthy subjects, and had sample size N ≥ 8. It is noted that MRI studies included placebo controls and the reported contrasts are drug versus placebo comparisons.

Foci from the eligible fMRI papers were manually extracted, converted to MNI space (Brett transform) and entered into activation likelihood estimation (ALE) meta-analyses. The study team ran three ALE analyses: one pooling all fMRI experiments, one restricted to BOLD amplitude changes, and one using connectivity results. Statistical inference used 1,000 permutations, threshold p < 0.001 and a minimum cluster size of 200 mm3; resulting maps were converted to Z scores for display and anatomical labels were assigned with the Talairach Daemon. The pooled ALE identified eleven clusters of concordant activation or connectivity change across studies, chiefly located in frontal, parietal and limbic regions. Putamen and anterior cingulate cortex showed highly significant alterations (reported p < 0.00001). Separate analyses of BOLD amplitude changes revealed reliable deactivations concentrated in the right hemisphere, notably the amygdala, temporal gyrus and fusiform gyrus (p < 0.0004; Zmin 3.38). Connectivity-based ALE showed a left-hemisphere distributed network of altered connections that included the cingulate cortex (Brodmann areas 31 and 32; p < 0.000013; Z = 4.22) and inferior temporal gyrus in occipital regions (p < 0.00002; Z = 4.10). Only four PET studies met the imaging inclusion criteria, so molecular data were synthesised narratively rather than meta-analytically. Two FDG studies suggested frontal and temporal hypermetabolism after psilocybin, consistent with some fMRI findings. One study using the 5-HT2A agonist radioligand (11C)Cimbi-36 reported reduced 5-HT2A occupancy following psilocybin, supporting involvement of that receptor subtype. Additional molecular evidence indicated that psilocybin reduced [11C]raclopride binding potential in the caudate and putamen, implying dopaminergic (D2) system engagement in addition to serotonergic effects. The authors note that regions identified in fMRI commonly bear substantial densities of both 5-HT1A and 5-HT2A receptors, suggesting multi-receptor contributions to the observed functional changes. The narrative synthesis of task and behaviour-related findings highlights consistent psychological effects across substances: alterations in emotion, perception, cognition, visual imagery and selfhood. Key functional themes emerging from the meta-analysis and review include (1) amygdala deactivation—particularly right-sided—associated with reduced reactivity to negative stimuli and transient mood elevation; (2) deactivation of salience network nodes (for example dorsal anterior cingulate), with implications for salience attribution and models of psychosis; (3) modulation of theory-of-mind and social-cognition regions such as supramarginal gyrus, medial prefrontal cortex, precuneus and posterior cingulate, linked to phenomena like ego dissolution and altered social processing; (4) strong engagement of visual and imagery-related cortices (visual BA19, fusiform BA37), consistent with 5-HT2A-mediated increases in visual cortex excitability and complex hallucinatory imagery; and (5) decreased DMN integrity (notably PCC/precuneus) in several studies, although some reports describe increased DMN activity, indicating heterogeneity across paradigms and substances. Finally, the review emphasises that molecular imaging evidence is still sparse, limiting firm conclusions about receptor-specific mechanisms; available PET data suggest involvement of 5-HT2A and 5-HT1A receptors and secondary effects on dopaminergic signalling.

The investigators interpret their findings as indicating robust neuromodulatory effects of tryptamine psychedelics in networks supporting mental imagery, social cognition and affective regulation. Amygdala deactivation is proposed as a candidate mechanism for the reported acute reductions in negative emotion processing and mood changes; the authors suggest this may underlie therapeutic effects in disorders characterised by excessive amygdala reactivity, such as PTSD and anxiety disorders. Reduced integrity of the salience network and DMN is discussed in the context of altered top‑down control and increased excitability of sensory and appraisal areas, a pattern the authors relate to subjective phenomena such as ego dissolution, increased introspection and the emergence of novel associations. Castelhano and colleagues advise caution in assigning effects exclusively to 5-HT2A receptors. They underline that many implicated regions express both 5-HT2A and 5-HT1A receptors and that molecular imaging indicates engagement of other transmitter systems (for example dopaminergic D2 signalling). Accordingly, the authors argue for a multi-receptor, network-level perspective on psychedelic action rather than a single-receptor explanation. Regarding clinical implications, the paper notes growing but preliminary clinical evidence of safety and efficacy of psychedelics in a range of psychiatric conditions (post-traumatic stress disorder, treatment-resistant depression, substance use disorders, obsessive–compulsive disorder, end‑of‑life anxiety, and social anxiety in autism). Subjective reports from trials include enhanced connection, insight and shifts in self‑perspective; nevertheless, the researchers stress that rigorous mechanistic work—ideally integrating PET and fMRI—remains necessary to clarify therapeutic mechanisms and risks. The authors acknowledge several limitations: the meta-analysis included studies with relatively small and heterogeneous samples (individual studies ranged from 10–38 participants; median 20), unequal gender distributions, and a minority of studies without control groups (noting that most MRI studies did include placebo comparisons). Heterogeneity of substances, dosages and experimental paradigms is highlighted as a further constraint, as is the limited number of PET studies that precluded a quantitative molecular meta-analysis. These caveats temper the strength of mechanistic inferences and point to the need for larger, more standardised pharmacoimaging studies.