LSD treatment improved performance in a novel object recognition task in rats and a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. Simulations using a neural network model of a cortico-hippocampal circuit, with baseline plasticity strength as a proxy for age and increased plasticity related to LSD dose, fit the experimental data well. The results suggest that LSD has nootropic effects.
A single dose of d-LSD, a potent serotonergic agonist, increased preference for novel objects in young and adult rats several days after treatment, but did not increase preference in old animals unless followed by a 6-day exposure to enriched environment, which rescued novelty preference to young levels. Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions with alterations of long-range synapses, and that better pattern separation within enriched environment explains its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.