d-Lysergic acid diethylamide has major potential as a cognitive enhancer

Felipe Augusto Cini, Isis Ornelas, Encarni Marcos, Livia Goto-Silva, Juliana Nascimento, Sergio Ruschi, José Salerno, Karina Karmirian, Marcelo Costa, Eduardo Sequerra, Dráulio de Araújo, Luis Fernando Tófoli, César Rennó-Costa, Daniel Martins-de-Souza, Amanda Feilding, Stevens Rehen, Sidarta Ribeiro

BioRxiv, 6 december 2019.

Doi : 10.1101/866814

 

Abstract

Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d- LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE). 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 longrange synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.

 

Introduction

Normal aging is associated with a decline in cognitive abilities, such as learning capacity, processing speed, working memory, and executive functions (1, 2). Cognitive aging is thought to reflect decreased synaptogenesis in elderly individuals (3). In the 1960s and 1970s, psychedelic substances that are agonists of serotonin receptors were extensively used in psychotherapy because of their potential to cause long-lasting psychological changes (4-7). Decades of prohibitive regulation prevented research on the cognitive benefits of serotonergic agonists, but in the past years psychedelic research is undergoing a
major renaissance (8-11), particularly in psychiatric conditions. Agonists of serotonin receptors have been shown to have foremost utility for the treatment of depression (12, 13) and terminal anxiety (14-16). The use of serotonergic psychedelics is associated with decreased psychological suffering and lower suicide rates (17). These substances have also been shown to induce neural plasticity and synaptogenesis both in vitro and in vivo (18-20), and are therefore likely to enhance learning capacity. Indeed, psychedelics have been shown to enhance memory consolidation when administered after fear learning or novel object exploration (21, 22). In the former, a single dose immediately after learning enhanced memory consolidation in adult mice, while treatment immediately before learning facilitated the extinction of fear memory (21). In the latter, chronic treatment of adult rats with d-LSD for 11 days improved learning in animals deprived of olfaction by bulbectomy, but no effects were observed in
sham controls (22). The lesion increases hippocampal 5-HT2A levels, and d-LSD down-regulated these to normal levels, with no effects in sham animals. The main interpretation proposed for these findings was that the post-learning activation of 5-HT2A receptors improves memory consolidation, and promotes positive mood changes. Neither study investigated the effects of d-LSD treatment several days before the learning task. Thus, we hypothesized that d-LSD treatment before a given learning task would increase synaptogenesis, creating a rich synaptic landscape that should favor the encoding of new memories.

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