Proceedings of the National Academy of Sciences
January 25, 2021
Danilo de Gregorio, Jelena Popić, Justine P. Enns et al.
137 citations
Repeated doses of LSD (30 μg/kg daily for 7 days) increase social behavior in male mice without producing antidepressant or anxiety-reducing effects. The prosocial effect requires the integrity of mTORC1 in excitatory glutamatergic neurons of the medial prefrontal cortex (mPFC), as shown by optogenetic inhibition and conditional knockout experiments. LSD potentiates AMPA and 5-HT2A synaptic responses in the mPFC and increases phosphorylation of Akt and mTOR, but does not affect NMDA or 5-HT1A responses. In mice lacking Raptor in GABAergic neurons, LSD still promotes social behavior. The findings suggest that 5-HT2A/AMPA/mTORC1 signaling in mPFC excitatory neurons mediates LSD's prosocial effects, offering a potential target for treating social deficits in autism and social anxiety.
Neuropsychopharmacology
March 17, 2022
Danilo de Gregorio, Antonio Inserra, Justine P. Enns et al.
89 citations
Lysergic acid diethylamide (LSD) is a serotonergic psychedelic being studied for potential anxiety and depression treatments, but its brain mechanisms are unclear. In male mice exposed to chronic restraint stress, acute LSD at doses of 5, 15, 30, and 60 μg/kg did not reduce anxiety or depression in non-stressed mice. However, daily 30 µg/kg LSD for 7 days prevented stress-induced anxiety-like behavior and the stress-induced loss of cortical dendritic spines. Repeated LSD increased the baseline firing rate of serotonin neurons in the dorsal raphe nucleus, which had been lowered by stress, and reduced the neurons' inhibitory response to a 5-HT1A receptor agonist. These effects suggest that repeated LSD prevents stress-induced anxiety by enhancing serotonin transmission and cortical spine density, possibly through desensitization of 5-HT1A receptors.
Frontiers in Pharmacology
January 27, 2022
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
44 citations
Psychedelic compounds such as LSD, psilocybin, and DMT show empathogenic and prosocial effects, suggesting potential therapeutic benefit for behavioral traits in autism spectrum disorder (ASD), including reduced social behavior and co-occurring anxiety and depression. The review examines dysregulated neurobiological systems in ASD—synaptic function, serotonergic signaling, prefrontal cortex activity, and thalamocortical signaling—that may underlie or limit these effects. Clinical studies from the 1960s and 70s using psychedelics in children with ASD reported positive outcomes like enhanced mood and social behavior, but also adverse effects including increased aggression, dissociation, and psychosis. Further studies are needed to weigh benefits against risks and determine if the 5-HT 2A receptor could be a target for social-behavioral disorders.
European Psychiatry
April 1, 2021
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
5 citations
Repeated low doses of lysergic acid diethylamide (LSD) increase social behavior in male mice. This pro-social effect is mediated by the medial prefrontal cortex (mPFC), specifically through the 5-HT2A and AMPA receptors. Blocking either receptor in the mPFC prevented LSD's behavioral effects. LSD also potentiated the excitatory responses of mPFC neurons to agonists of these receptors. The findings suggest a mechanism by which LSD promotes sociability, relevant to understanding its potential therapeutic use for conditions involving social dysfunction, such as autism spectrum disorder and social anxiety disorder.