Nootropic effects of LSD: Behavioral, molecular and computational evidence

Isis M Ornelas, Felipe A Cini, Isabel Wießner, Encarni Marcos, Dráulio de Araújo, Livia Goto-Silva, Juliana Nascimento, Sergio R B Silva, Marcelo N Costa, Marcelo Falchi , Rodolfo Olivieri, Fernanda Palhano-Fontes, Eduardo Sequerra, Daniel Martins-de-Souza, Amanda Feilding, César Rennó-Costa, Luis Fernando Tófoli, Stevens K Rehen, Sidarta Ribeiro. 

The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in 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. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.

Full Paper