Dissociable effects of LSD and MDMA on striato-cortical connectivity in healthy subjects

Psychedelics such as lysergic acid diethylamide (LSD) and the entactogen MDMA are receiving renewed interest for potential psychiatric applications, but the neural mechanisms that might underlie therapeutic effects remain incompletely understood. Previous neuroimaging work has largely focused on cortical resting-state networks or on subcortical regions such as the thalamus, and has shown that classic psychedelics tend to increase global functional connectivity and reduce modularity. However, the striatum—a set of subcortical nuclei central to reward, motivation and many cortico‑striatal loops implicated in addiction, mood disorders and PTSD—has been relatively under-investigated despite its relevance to these conditions. Ertl and colleagues therefore set out to examine acute drug-induced changes in striatal functional connectivity using resting-state fMRI. The study re-analysed existing datasets from acute LSD and MDMA challenge studies, testing connectivity for three striatal subdivisions (associative, limbic and sensorimotor) both within their canonical networks and across the whole brain, to determine whether LSD and MDMA produce dissociable effects on striato-cortical coupling that might relate to their distinct phenomenology and putative therapeutic actions.

The analyses are re-analyses of previously published LSD and MDMA challenge studies; the extracted text refers readers to the original publications for full protocol details. For LSD, the design was a balanced randomised single-blind study in which participants attended two scanning days at least two weeks apart and received 75 µg LSD or placebo administered intravenously. Resting-state scanning included two rs-fMRI runs per session (at ~70 and ~90 minutes post-dose) separated by a music task, and participants were acclimatised in a mock scanner prior to real scanning. For MDMA, the design was a double-blind, placebo-controlled, within-subject randomised trial with two sessions seven days apart; MDMA was given orally as 100 mg MDMA‑HCl and placebo as 100 mg vitamin C in identical capsules. Functional MRI preprocessing and analysis were performed with FSL 6.0 following common pipelines: spatial smoothing (6 mm FWHM), high-pass temporal filtering (100 s), motion correction (MCFLIRT), and non-linear registration to MNI152. White matter and CSF segmentations were extracted and included as nuisance regressors alongside an extended set of 24 head-motion regressors (translations, rotations, derivatives and quadratic terms). Data were inspected for motion and scans with mean framewise displacement >1 mm or maximum displacement >3 mm led to participant exclusion. Two participants were excluded from the LSD analysis for excessive motion and one for a separate artefact; three participants were excluded from the MDMA analysis for excessive motion. Paired t tests comparing mean framewise displacement between drug and placebo conditions indicated significant differences for both LSD and MDMA sessions. Seed‑voxel (seed‑to‑voxel) connectivity analyses targeted three striatal seeds—associative, limbic and sensorimotor—based on an established parcellation. Group mean networks were first derived across all subjects and sessions to validate the seeds; those networks were thresholded at 50% of maximum Z and binarised to create within‑network masks. Mean connectivity parameter estimates were extracted from these masks and compared between drug and placebo using paired t tests to assess within‑network changes. Whole‑brain seed‑to‑voxel contrasts used within‑subject models and higher-level group analyses employed FSL's FLAME‑1 with cluster‑level thresholding (Z = 2.3, p < 0.05) to identify regions showing relative increases or decreases in connectivity under drug versus placebo.

Validation analyses reproduced expected striatal networks: the associative striatum with frontal regions, the limbic striatum with medial temporal lobe areas, and the sensorimotor striatum with motor cortex. Using the 50% thresholded network masks, no significant drug‑related changes were observed in within‑network connectivity for any of the three striatal seeds with either LSD or MDMA. In contrast, seed‑to‑voxel whole‑brain analyses revealed multiple significant changes in striato‑cortical connectivity outside the canonical striatal networks for both drugs. Under acute LSD, the associative striatum showed increased connectivity with a large cluster that included visual cortex, bilateral sensorimotor cortex and medial frontal regions; decreased connectivity was observed with the tail of the left putamen extending into the thalamus. The limbic striatum increased connectivity with the left orbitofrontal cortex and inferior occipital/lingual regions, while showing decreased connectivity with a region extending from inferior parietal into superior lateral occipital cortex. The sensorimotor striatum exhibited increased connectivity with bilateral parahippocampal and temporal cortical areas and with a precuneus/intracalcarine cluster, and decreased connectivity around the rostral anterior cingulate and left inferior frontal gyrus. Acute MDMA also altered connectivity for all three striatal seeds. The associative striatum increased connectivity with sensorimotor cortex and lingual gyrus and decreased connectivity with the cerebellum. The limbic striatum showed increased coupling with sensorimotor and higher visual areas (lingual and intracalcarine cortex) but reduced connectivity with the thalamus, amygdala and hippocampus. Finally, the sensorimotor striatum demonstrated reduced connectivity with the inferior frontal gyrus and cerebellum under MDMA. The authors note that head‑motion differed between drug and placebo sessions, which remains a potential confound despite rigorous correction and exclusions.

Ertl and colleagues interpret the pattern of findings as indicating that neither LSD nor MDMA produces strong changes in striatal within‑network connectivity, but both drugs markedly alter striatal coupling with regions outside canonical striatal networks. They frame these results as consistent with prior reports that classic psychedelics reduce network modularity and increase between‑network integration, allowing brain regions and networks to communicate in atypical ways. The discussion highlights dissociable features of the two drugs. Under LSD, the associative striatum exhibited the largest increases in connectivity with visual cortex (lingual gyrus), sensorimotor areas and frontal poles; the authors link increased associative striatum–visual cortex coupling to the prominent visual phenomenology of LSD and suggest associative striatal–frontal changes may relate to alterations in cognitive integration. Limbic striatal changes under LSD were comparatively modest, which the authors note is consonant with the non‑addictive profile of classic psychedelics. Sensorimotor striatal increases with parahippocampal regions are discussed in relation to spatial memory and altered bodily awareness, while reduced connectivity with the left inferior frontal gyrus is proposed to reflect diminished inhibitory control and a subjective sense of disembodiment. For MDMA, the authors emphasise reduced connectivity between the limbic striatum and the amygdala and hippocampus, alongside increased coupling with sensorimotor and visual cortices. They suggest attenuation of amygdala connectivity may underlie MDMA's therapeutic effects in PTSD by reducing fear responses and facilitating emotional processing. Decreased cerebellar connectivity—particularly involving the vermis—was interpreted in relation to motor and oculomotor changes reported with MDMA. Clinically, the authors propose that LSD's associative striatum–frontal increases might be relevant to treating disorders involving maladaptive reward or cognitive control (for example, aspects of addiction), and that MDMA's limbic–amygdala attenuation could mechanistically support PTSD interventions. The authors acknowledge several limitations stated in the extracted text: the analyses are secondary re‑analyses of existing datasets with relatively small sample sizes for fMRI research, there were significant differences in head motion between drug and placebo sessions that cannot be entirely ruled out as confounders, and the sex distribution across studies was unbalanced. They recommend replication with larger, more balanced samples and note the need for improved methodological rigour in future MDMA research. The authors conclude that the dissociable striato‑cortical effects of LSD and MDMA reported here expand understanding of how these compounds alter brain networks and may inform targeted therapeutic applications.

The study concludes that acute LSD and MDMA produce distinct alterations in striatal connectivity beyond standard striatal networks. MDMA selectively reduced connectivity between the limbic striatum and the amygdala, a finding the authors link to a potential mechanism for facilitating PTSD treatment. LSD increased connectivity between the associative striatum and frontal and visual cortices, which the authors suggest may relate to effects on sensory integration, cognition and potential utility in disorders involving maladaptive reward processing. The authors emphasise that these findings add to the mechanistic literature on psychedelic medicines but call for replication in larger, better‑balanced samples given the methodological limitations noted.