Nootropic effects of LSD: Behavioral, molecular and computational evidence

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Ornelas, Isis M. ; Cini, Felipe A. ; Wiessner, Isabel ; Marcos, Encarni ; Araujo, Draulio B. ; Goto-Silva, Livia ; Nascimento, Juliana ; Silva, Sergio R. B. ; Costa, Marcelo N. ; Falchi, Marcelo ; Olivieri, Rodolfo ; Palhano-Fontes, Fernanda ; Sequerra, Eduardo ; Martins-de-Souza, Daniel ; Feilding, Amanda ; Renno-Costa, Cesar ; Tofoli, Luis Fernando ; Rehen, Stevens K. ; Ribeiro, Sidarta

• Document type: Journal article
• Source: Experimental Neurology; v. 356, p. 14-pg., 2022-07-12.

Abstract

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 per-formance 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 plas-ticity, 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. (AU)

• FAPESP's process: 14/10068-4 - Multi-User Equipment approved in grant 13/08711-3: mass spectrometer waters SYNAPT G2-Si HDMS + nanoACQUITY UPLC
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 17/25588-1 - From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07699-0 - Research, Innovation and Dissemination Center for Neuromathematics - NeuroMat
• Grantee: Oswaldo Baffa Filho
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/00098-7 - Multi-User Equipment approved in grant 2017/25588-1: cromatógrafo Acquity UPLC I-Class
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Multi-user Equipment Program