Preliminary evidence of links between ayahuasca use and the corpus callosum

Ayahuasca is a traditional Amazonian botanical brew containing β-carbolines (from Banisteriopsis caapi) and N,N-Dimethyltryptamine (DMT, from Psychotria viridis). When combined, reversible MAO-A inhibitors in the β-carbolines permit orally ingested DMT to reach the central nervous system, producing potent psychoactive effects. Emerging preclinical and clinical work suggests ayahuasca and its alkaloids may influence neurobiological processes relevant to neurodegeneration and motor function, including sigma-1 and serotonin receptor activity, adult neurogenesis, and anti-inflammatory effects. Given these findings and prior links between the corpus callosum and various movement and neurodegenerative disorders, the corpus callosum is a plausible target for investigation in normative samples. De Berardis and colleagues set out to examine whether long-term ayahuasca use is associated with differences in midsagittal corpus callosum thickness. The study compared callosal thickness point-wise across 100 equidistant nodes between 22 ayahuasca users and 22 matched controls, and explored correlations between callosal thickness and the number of past ayahuasca sessions. The authors hypothesised thicker callosal regions in users versus controls and expected effects in the isthmus, a region linked to motor fibres.

This cross-sectional, secondary analysis used structural MRI data from 22 ayahuasca users recruited from a Santo Daime church in Spain and 22 matched controls. The groups were matched on sex (6 men, 16 women in each group), age (means ~41 years), years of education (~13 years), fluid intelligence (WAIS-III) and verbal intelligence (Spanish New Adult Reading Test); no between-group differences were reported for employment, marital status, tobacco or alcohol use. Inclusion criteria for the ayahuasca group required frequent use in the past 2 years, abstinence from ayahuasca and other drugs in the 2 weeks prior to scanning (verified by urine toxicology), limited lifetime cannabis and other drug use, and no current or past psychiatric or neurological disorders. The extracted text references a more detailed original study for full recruitment and testing procedures. Structural images were acquired on a 3 Tesla scanner using a T1-weighted MPRAGE protocol with 1 mm isotropic resolution. Images were preprocessed in SPM12 and the CAT12 toolbox with corrections for field inhomogeneity and rigid-body spatial alignment. The midsagittal corpus callosum was manually outlined for each participant; these outlines were resampled into 100 equidistant nodes for the upper and lower boundaries. A midline curve was computed as the two-dimensional average of corresponding boundary nodes, and callosal thickness at each of the 100 nodes was calculated as the perpendicular distances from the upper and lower boundaries to the midline. Total intracranial volume (TIV) was computed as the sum of native-space gray matter, white matter and cerebrospinal fluid volumes and included as a nuisance covariate. Statistical analyses employed mass-univariate general linear models implemented in Matlab. Point-wise callosal distances were the dependent variables; group (ayahuasca versus control) was the primary independent variable, with age and TIV entered as covariates of no interest. Within the ayahuasca group a separate point-wise correlation analysis examined associations between thickness and the self-reported number of past ayahuasca sessions, again controlling for age and TIV. Given a priori hypotheses, one-tailed t-tests were used at p ≤ 0.05 to generate uncorrected significance and effect-size maps. Multiple-comparison correction was implemented using a Monte Carlo permutation approach with 10,000 permutations to test whether observed clusters survived correction.

Point-wise comparisons revealed a thicker corpus callosum in the ayahuasca group relative to controls within the isthmus. At the significance maximum of this isthmus cluster, mean midsagittal thickness was 5.47 ± 0.71 mm in the ayahuasca group versus 4.78 ± 1.01 mm in controls (p = 0.006; Cohen's d = 0.85). Within the ayahuasca group, the average reported number of past ayahuasca sessions was 123 (range 30–352). A point-wise positive correlation between callosal thickness and number of sessions was observed in the rostral body, with a peak correlation r = 0.45 and p = 0.026, a medium effect size. Crucially, none of the reported group differences or correlations survived correction for multiple comparisons using the Monte Carlo permutation procedure. No region showed greater thickness in the control group compared with ayahuasca users, and no callosal region was negatively associated with ayahuasca use, even at uncorrected significance thresholds.

De Berardis and colleagues interpret the observed thicker isthmus in ayahuasca users and the positive association between sessions and rostral body thickness as preliminary, exploratory evidence linking long-term ayahuasca use to callosal anatomy. They note that both the isthmus and rostral body have been implicated in motor function, so the anatomical findings are congruent with hypotheses about ayahuasca's potential relevance for motor and neurodegenerative conditions. Mechanistically, the authors suggest that greater callosal thickness could reflect more axons, larger axon calibre, increased myelination, or a combination, which in turn might indicate greater interhemispheric connectivity or faster conduction velocities. The investigators caution that the findings are tentative: the cross-sectional design precludes causal inference and it remains possible that pre-existing anatomical differences account for the group effects. They also acknowledge the absence of dose information per session, meaning dose-dependent relationships could not be examined, and emphasise that none of the uncorrected effects survived multiple-comparison correction. Another limitation is the study population; participants were healthy adults rather than patients with movement or neurodegenerative disorders, so therapeutic implications are speculative. The authors therefore call for replication in larger samples, longitudinal designs to test causality, collection of motor and behavioural measures, and assessment of dosing, before considering clinical translation.

Research on ayahuasca has largely targeted mental health, while its potential relevance for movement and neurodegenerative disorders is less explored. Because the corpus callosum is implicated in several such conditions, this study examined midsagittal callosal thickness in ayahuasca users versus matched controls and found preliminary evidence of thicker callosal regions associated with ayahuasca use. Given the cross-sectional design, lack of dose information and that effects did not survive correction for multiple comparisons, causal claims are not possible. The authors recommend longitudinal replication in larger normative samples, followed by clinical studies if robust effects are established.