LSD alters brain network connectivity. In a double-blind, randomized, crossover study, 20 healthy participants received 100 μg LSD or placebo, and resting-state brain activity was measured with fMRI. LSD decreased functional connectivity within visual, sensorimotor, auditory, and default mode networks, while increasing connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These hub changes resemble patterns seen in psychosis and may relate to therapeutic effects of hallucinogens.
The intense and distinctive subjective effects of psychedelics complicate tests of the efficacy and mechanisms of action of psychedelic-assisted treatments for mental-health conditions. Estimates of treatment efficacy are confounded under functional unblinding, and uncertainty surrounds whether subjective or neurobiological effects are causal mechanisms. Methodological solutions include improved active placebo conditions, expectancy-focused recruitment and consent procedures, better measurement of expectancies and blinding, and rigorous statistical modeling. Strategies to disentangle subjective and neurobiological effects include administering psychedelics under general anesthesia, developing non-psychoactive analogues, leveraging Mendelian randomization, and studying microdosing. Combining multiple innovative methods may offer the most robust insights.