This project investigates the effects of two CNS drugs, benzodiazepines (BZDs) and psilocybin, on neuropsychiatric and cognitive symptoms in Alzheimer’s disease (AD).

Benzodiazepines impair memory via GABA-A modulation, while psilocybin enhances synaptic plasticity; both may influence neuropsychiatric and cognitive symptoms in Alzheimer’s disease, yet clinical mechanisms remain unclear.

We conducted a structured review (2010–2025) of studies on BZD use and cognition in community-dwelling adults, extracting data on study design, dementia incidence, cognitive outcomes, and confounder control.

In parallel, we examined alprazolam’s effects on memory circuits in male and female mice using contextual fear conditioning and postmortem analysis of hippocampal activity (ArcCreERT2 x EYFP tagging, c-Fos staining).

To assess psilocybin as a BZD alternative, APP^NLGF^ mice received a single dose one week before behavioral or electrophysiology testing to evaluate synaptic function.

A review of BZD use and cognition revealed mixed findings: while some large-scale studies linked long-term, high-dose, or long-acting BZDs to cognitive decline and dementia, others found no association. Despite this, BZDs remain widely prescribed, including in AD.

We found that alprazolam impaired contextual fear memory in both sexes. In females, it increased dorsal CA1 encoding, elevated dorsal CA3 engram overlap, and reduced ventral CA1 retrieval activity—effects not observed in males, indicating sex-specific hippocampal disruption.

A single psilocybin dose at 6 months improved exploratory behavior in female controls and AD mice, reduced anxiety in control males, and rescued or enhanced fear memory in AD and aged males. Electrophysiology showed reduced hippocampal hyperexcitability in psilocybin-treated AD mice, suggesting enhanced synaptic and network stability.

Benzodiazepines may impair memory via sex-specific hippocampal disruptions, raising concerns for use in AD. In contrast, psilocybin improved behavior and synaptic stability in AD models, supporting its potential as a novel treatment for cognitive and neuropsychiatric symptoms.