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.
Journal of Psychopharmacology
September 22, 2025
Vítor Bruno, Martha López-canul, Brandon Richardson et al.
3 citations
Psilocybin, at a dose of 10 mg/kg administered every other day, does not produce conditioned place preference (CPP) in Sprague-Dawley rats, indicating a lack of rewarding or reinforcing effects under this regimen. During conditioning, psilocybin increased head twitching, wet-dog shaking, and defecation, while decreasing grooming, body licking, and rearing compared to vehicle. However, 48 hours after the final injection, no behavioral differences remained between groups. These findings suggest that psilocybin's acute behavioral effects are transient and that it does not induce reward-related learning in the CPP paradigm, though further research is needed to assess addiction liability across different protocols.
The International Journal of Neuropsychopharmacology
August 1, 2025
Valeria Bruno, Bruce Richardson, Martha López-canul et al.
In adult male rats, a high dose of psilocybin (10 mg/kg) did not produce rewarding effects in the conditioned place preference (CPP) paradigm, as there was no significant difference in time spent in the drug-paired compartment versus the vehicle-paired compartment. Psilocybin increased head-twitching, dog-shaking, and defecation while decreasing grooming, body licking, and rearing during conditioning sessions. These behavioral differences disappeared 48 hours after the last injection, indicating no long-term changes. The findings suggest psilocybin lacks rewarding properties and does not cause physical dependence, supporting its safety profile and therapeutic potential.