LSD Works Via the 5-HT2A Receptor in Humans

Data analysis and gene expression maps confirm the role of the 5-HT2A receptor in the effects of LSD.

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In an October 2018 study published on eLIFE, researchers report on a study that identified the human brain receptors responsible for the effects of lysergic acid diethylamide (LSD).1 This was a double-blind, randomized, placebo-controlled, counterbalanced, cross-over study using 24 healthy human volunteers.

State of the Art Methods

The researchers studied the effects of LSD on brain receptors using a data-driven method called Global Brain Connectivity (GBC) and comparing it to cortical gene expression maps. The results showed LSD increased sensory-somatomotor thalamic connectivity and overall brain-wide connectivity. At the same time, LSD reduced associative connectivity. To summarize another way, LSD decreased connections in the brain that govern cognitive processes and increased activity in areas that are associated with sensory functions.

The GBC test also found the somatomotor network of the brain (which controls body movement) was associated with the subjective effects experienced by the volunteers. Volunteers who experienced increased connectivity in the somatomotor network area of the brain reported higher subjective effects like blissful state, disembodiment, and spiritual experience. The study authors noted that these results corroborate previous findings indicating the psychedelic state induced by LSD is closely associated with connectivity in the somatomotor network.

The other major finding of the study was that the whole-brain spatial effect patterns caused by LSD matched cortical gene expression maps for the 5-HT2A receptor in humans. This is the first time researchers have seen a match between gene expression patterns and in vivo pharmacological effects in humans. The researchers used the selective 5-HT2A receptor antagonist ketanserin to block the effects of LSD and confirm it was responsible for the effects, including the subjective effects.

This study builds on the pioneering work of researchers like Albert Hofmann. It adds to the knowledge base of the functional pathways of psychotropic substances like LSD and psilocybin.

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