Randomised, double-blind, placebo-controlled crossover fMRI study (n=25) testing single 100 µg oral LSD vs placebo and ketanserin (40 mg pretreatment) in healthy volunteers to probe 5-HT2A receptor contributions to self and personal meaning.
This randomised, double-blind, placebo-controlled, cross-over trial in 25 healthy volunteers assesses the effects of single-dose oral LSD (100 µg) on self-consciousness, perception and meaning-making using functional magnetic resonance imaging, psychometric and cognitive measures.
The study includes a ketanserin pretreatment condition (40 mg) to evaluate the contribution of the 5-HT2A receptor; sessions use matched placebo capsules and standardised washout, with outcomes including neuroimaging correlates and behavioural/psychometric assessments.
Randomised, double-blind, placebo-controlled crossover with placebo, LSD (100 µg) and ketanserin (40 mg) conditions.
Mannitol placebo capsule, per os
Single 100 µg LSD dose per session
Ketanserin 40 mg given as pretreatment (identical-appearing capsule)
In a double-blind, placebo-controlled cross-over study using spectral dynamic causal modelling of resting-state fMRI, the authors show that LSD alters effective connectivity within cortico–striato–thalamo–cortical circuits by increasing thalamus→posterior cingulate connectivity via serotonin 2A (5‑HT2A) receptor activation and decreasing ventral striatum→thalamus connectivity independently of 5‑HT2A. These results support the thalamic filter model of psychedelic action and advance mechanistic understanding relevant to therapeutic development.