Does LSD treatment change working memory brain function in major depression?

Two LSD doses, one working memory task

The study asked whether LSD treatment changes the brain activity that supports working memory in people with major depressive disorder (MDD). It is a secondary analysis of a randomized, double-blind, parallel-group trial: 43 patients (21 low-dose, 22 high-dose) received two oral LSD sessions four weeks apart, either 25 µg twice or 100 µg then 200 µg. Functional MRI was collected during an n-back working memory task before treatment and about one week after the second session.

The n-back task asks participants to respond when the current stimulus matches one shown earlier (1-back) or two earlier (2-back), with a simpler 0-back condition as the low-load reference. The imaging contrast of interest was 2-back plus 1-back versus 0-back, so the measured signal reflects the extra brain response recruited as working memory load rises. The key statistical test was a treatment × time interaction, which asks whether the change from baseline to follow-up differed between the high-dose and low-dose groups.

Using a low dose as the comparator rather than an inert placebo is central to reading the result. The authors note that this active comparator prevents them from separating treatment effects from test-retest or practice effects that come with repeating the same task. The interaction design partly accounts for such treatment-independent change, but it cannot supply a true placebo baseline.

High-dose LSD raised, rather than lowered, task responses

The authors hypothesized that high-dose LSD would reduce blood oxygen level-dependent (BOLD) responses during the working memory task. The one-tailed test for a decrease was not significant; the two-tailed test showed a significant treatment × time interaction (β = 0.257, 95% CI [0.075, 0.439], p = 0.007) across task-activated regions. Working memory-related responses rose from baseline to follow-up in the high-dose group and fell in the low-dose group.

Region-specific analyses showed the same direction in the dorsolateral prefrontal cortex (β = 0.251, p corrected = 0.007), parietal cortex (β = 0.286, p corrected = 0.023), striatum (β = 0.227, p corrected = 0.024), and thalamus (β = 0.269, p corrected = 0.006). The insula showed a similar but non-significant estimate (β = 0.199, p corrected = 0.114). A separate analysis using an independent working memory mask reproduced the main interaction (β = 0.338, p = 0.003, uncorrected).

These regions were defined from baseline task activation in this sample rather than imported from prior studies, which the authors present as a strength because it ties the regions to the patients actually scanned. The direction of the effect matters for interpretation: the authors read the increase as more consistent with a model in which depressed patients under-recruit working memory regions, but they could not test that directly because no healthy comparison group was scanned.

Brain response tracked performance, not symptom change

Across both scans and both groups, stronger working memory-related brain responses were associated with better task performance. The standardized coefficients were β = 0.21 (95% CI [0.01, 0.40], p corrected = 0.03) for d-prime, a sensitivity measure that accounts for response bias, and β = 0.55 (95% CI [0.01, 1.1], p corrected = 0.04) for accuracy. The authors describe this positive correlation as suggesting a potential LSD-induced boost in neural function.

Depression severity told a different story. Baseline IDS-C scores were not significantly associated with baseline BOLD responses in any region, and change in IDS-C was not significantly associated with change in BOLD response at follow-up. In the same 43-patient subset, high-dose LSD did reduce depressive symptoms more than low-dose treatment (β = −9.776, 95% CI [−17.402, −2.150], p = 0.013) two weeks after the last session.

So the treatment changed both mood and task-related brain activity, but the two changes did not move together across patients. The authors interpret this as evidence that depressive symptoms and cognitive brain function in MDD may rest on distinct neurobiological mechanisms. That is their interpretation of an absent correlation, not a demonstrated causal separation.

Perceptual alterations, not positive mood, matched the signal

The study also explored whether the acute psychedelic experience predicted the imaging change. Across patients, change in working memory-related brain responses correlated above r > 0.3 with several 5D-ASC subscales: audio-visual synesthesia, elementary imagery, changed meaning of percepts, complex imagery, and disembodiment. Most of these belong to the visionary restructuralization dimension, which measures perceptual alterations.

The authors contrast this with the acute positive experiences, such as oceanic boundlessness and mystical-type experiences, that prior work has linked to therapeutic improvement. They note that working memory-related brain function was not associated with those positive experiences, which they read as further support for separate mechanisms behind perceptual, cognitive, and mood outcomes. These are exploratory correlations, and the paper reports them as such rather than as confirmed predictors.

A logging fault trimmed the behavioral data

Task performance was not measured cleanly. After data collection the authors found that MRI trigger pulses, which mark the start of each brain volume, had been logged as button responses. When a trial required a press and a trigger pulse was recorded, it was impossible to tell whether the participant had responded, so those ambiguous trials were excluded. On average this removed 25% of trials (range 7–37%, median 26%), and accuracy was computed only over the unaffected trials.

This matters for the performance correlations: d-prime and accuracy were derived from a reduced trial set, and the authors also note the task may not have been sensitive enough to resolve individual differences in working memory. The performance–brain association is therefore supportive context for the imaging result, not an independent cognitive outcome measured without complication.

Baseline imbalance and timing limit the comparison

The low-dose group started with higher working memory-related brain function and lower symptom severity than the high-dose group. The authors acknowledge that this baseline difference raises the possibility of regression to the mean, and that randomization cannot guarantee perfect matching in a trial of this size. The treatment × time interaction accounts for baseline differences, but it does not eliminate this concern.

Follow-up scans occurred 6 ± 6 days after the second session (median 5, range 1–31), and an exploratory check found no significant effect of the treatment-to-scan interval on the results. Imaging was an optional component, so not every patient contributed both scans: 42 baseline and 34 follow-up scans from 43 participants entered the analysis. The absence of a healthy reference group also means the study cannot establish whether these patients differed from healthy individuals at baseline.

Cognitive and mood effects may need separate tracking

The paper's most decision-relevant point is a dissociation rather than a single effect size. High-dose LSD raised working memory-related brain responses and reduced depressive symptoms relative to low-dose treatment, yet the brain change correlated with task performance and perceptual alterations, not with symptom improvement. For readers weighing psychedelic treatment, that means cognitive brain function is a separate outcome that mood scales will not capture.

The authors frame the result as the first task-based fMRI evidence that LSD treatment modulates cognitive brain function in MDD, and they call for future studies with a healthy reference group and both a control condition and cognitive performance measures. Until such comparisons exist, the finding should be read as a dose-dependent change in task-related brain activity within this trial, not as proof of cognitive improvement or of a mechanism linking LSD to mood.

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