859. From Neurons to Behavior: Preclinical Insights into LSD’s Anxiolytic Mechanisms
The International Journal of Neuropsychopharmacology September 1, 2026 DOI: 10.1093/ijnp/pyag040.514 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male mice and rats |
| Intervention | LSD |
| Dose | 5–60 μg/kg acute; 30 μg/kg/day for 7 days repeated; 20 μg/kg and 200 μg/kg in rats |
| Duration | 7 days repeated administration; electrophysiology 10–20 minutes post-injection |
| Measures | anxiety-like behavior, cortical spine density, dorsal raphe 5-HT neuron firing, 8-OH-DPAT sensitivity, microiontophoresis of 5-HT1A and AMPA responses, electrocorticography (ECoG) power in theta, beta, gamma, and alpha bands, Lempel-Ziv complexity (LZC), Higuchi fractal dimension (HFD) |
| Topics | LSD |
| Key points | Repeated LSD (30 μg/kg/day for 7 days) prevented stress-induced anxiety-like behavior and preserved cortical spine density in mice, while acute LSD suppressed dorsal raphe 5-HT neuron firing and repeated LSD restored it. The authors propose that repeated LSD may counteract stress-induced anxiety by enhancing cortical synaptic plasticity and serotonergic neurotransmission, possibly via presynaptic 5-HT1A desensitization and potentiation of post-synaptic 5-HT1A and AMPA receptors. |
Abstract
Abstract Background Lysergic acid diethylamide (LSD), a serotonergic psychedelic, has gained renewed interest for its potential anxiolytic effects in clinical trials. However, the neurobiological mechanisms underlying these effects remain poorly understood. Aims & Objectives The goal of this study is to understand the mechanism of action of LSD in animal models by using in vivo electrophysiology and behavioral paradigms.
Method: Using a combination of behavioral paradigms in male mice (n=10-12) subjected to chronic restraint stress we assessed the effects of acute and chronic LSD (5–60 μg/kg). In vivo electrophysiology, microiontophoresis, and morphological analysis (n=4-6) were used to understand its mechanism of action. Electrocorticography (RCoG) and in vivo electrophysiology was also carried out in rats (n=6) to understand the electrophysiological signatures of LSD. Data was analyzed using one- or two-way ANOVA ( p<0.05).
Results: Acute intraperitoneal LSD (5–60 μg/kg) had no effect on anxiety-like behavior in non-stressed mice. Repeated administration of LSD (30 μg/kg/day for 7 days) prevented stress-induced anxiety-like behavior and preserved cortical spine density. Notably, while acute LSD suppressed the firing of dorsal raphe nucleus (DRN) 5-HT neurons, repeated LSD restored their activity following stress and reduced their inhibitory sensitivity to the 5-HT₁A receptor agonist 8-OH-DPAT. At the level of the mPFC, microiontophoresis data indicated that the LSD potentiates 5-HT1A post-synaptic and AMPA receptors responses. Electrocorticography (ECoG) reports that LSD at the single dose of 20 μg/kg, there were no effects in the signal. However, at the dose of 200 μg /kg, LSD decreased total power from 10 – 20 minutes post-injection, with a rapid reduction of the absolute cortical power in theta, beta, and gamma bands, and relative power in the alpha band, reflecting cortical desynchronization and reduced arousal. No changes in signal complexity (LZC) or fractal properties (HFD), suggesting stable global dynamics despite power suppression. Discussion & Conclusions These findings suggest that while acute LSD, at high doses decreases decreased theta, beta, and gamma power and 5-HT firing activity, after repeated LSD may counteract stress-induced anxiety by enhancing cortical synaptic plasticity and serotonergic neurotransmission, potentially via 5-HT₁A receptor desensitization at the presynaptic level and potentiation of the 5-HT1A post-synaptic receptors and AMPA receptors. This mechanism may underlie the therapeutic actions of serotonergic psychedelics in stress-related disorders.