Assessing the Psychedelic "After-Glow" in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities

Abstract

Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures.

Methods: Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose.

Results: Magnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the "nonjudging" subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later.

Conclusions: These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca.

Keywords: ayahuasca; human; magnetic resonance imaging; mindfulness; psychedelic after-effects.

Figure 1.

Location of the ¹H-MRS voxels (top) and a representative spectrum (bottom). The top panel shows sagittal views of voxel placement over the anterior cingulate (left), posterior cingulate (center), and cerebellum (right). The dimensions of the respective voxels were: 25 x 25 x 25 mm³ in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) and 20 x 40 x 20 mm³ in the cerebellum.

Figure 2.

Seed-to-voxel connectivity maps between the posterior cingulate cortex (PCC) seed (green circle) at MNI coordinates x = 0, y = -56, z = 28, and the rest of the brain. The top panels show statistically significant positive (hot colors) and negative (cold colors) correlations in the pre-ayahuasca and post-acute assessments. The bottom panels show the results of the second-level random effects analysis (post-acute vs. pre-intake). Only significant increases in connectivity were found, located in 2 main clusters: the anterior cingulate cortex (ACC) (left brain map) and the visual cortex (right brain map). In all statistical maps results are shown corrected for multiple comparisons at the cluster level (FWE < 0.05, z > 2.5, 20 contiguous voxels).

Figure 3.

Statistical map showing the results of the second-level analysis (post- vs. pre-intake) of changes in connectivity between the dorsal anterior cingulate (dACC) seed (green circle) at MNI coordinates x = 5, y = 14, z = 42, and the rest of the brain. As shown in the top panel a significant increase in connectivity was found with voxels in the precuneus/posterior cingulate cortex. As shown in the bottom panel, significant decreases (cold colors) were found with voxels located in the cuneus (visual association cortex: BA 18 and 19). Results are shown corrected for multiple comparisons at the cluster level (FWE < 0.05, z > 2.5, 20 contiguous voxels).

Figure 4.

Statistical maps showing the results of the second-level analysis (post- vs. pre-intake) of changes in connectivity between the superior rostral anterior cingulate (srACC) seed (green circle) at MNI coordinates x = 0, y = 15, z = 30, and the rest of the brain. As shown in the top panel, decreases in connectivity (cold colors) were found with voxels located in the cuneus (visual cortex: BA 18 and 19). Increases in connectivity were found with 3 separate clusters (bottom panel): (a) the right medial temporal lobe (left brain map); (b) the precuneus and posterior cingulate cortex (center brain map); and (c) the left angular gyrus and left parietal lobule (right brain map). Results are shown corrected for multiple comparisons at the cluster level (FWE < 0.05, z > 2.5, 20 contiguous voxels).

Figure 5.

The graph bars shows mean scores on mindfulness measures that showed statistically significant post- vs. pre-ayahuasca intake changes. Data from n = 16 participants at the pre- and post-acute assessments, and from n = 14 participants at follow-up 2 months later. FFMQ, Five Facets Mindfulness Questionnaire; EQ, Experiences Questionnaire; MINDSENS, Mindsens composite index; SC, Self-Compassion Questionnaire. The error bars denote 1 standard error of mean. Significant differences in the statistical comparison (post-acute or follow-up vs. pre-intake) are denoted as *P<.05 after FDR correction. ^#Significance lost after FDR correction. Scores on nonsignificant subscales are provided in the supplementary information file.

Figure 6.

Scatter plots showing significant correlations between difference scores at the post-acute and follow-up assessments (relative to baseline values) for the FFMQ nonjudging subscale and changes in neuroimaging measures (post-acute minus pre-intake). The top panels show the correlations with changes (Δ) in Glx (glutamate+glutamine) concentrations (millimolar) in the posterior cingulate cortex (PCC) voxel as measured using MRS. The middle panels show the correlations with changes in functional connectivity (Δ in z values) between the superior rostral anterior cingulate (srACC) seed and the precuneus/PCC cluster. The lower panels show the correlations with changes in functional connectivity (Δ in z values) between the srACC seed and the right medial temporal lobe (MTL) cluster. The left column shows correlations with FFMQ nonjudging difference scores in the post-acute assessment and the right column shows correlations with difference scores at follow-up. R and P values are reported in the main text.