Modulation of spatial learning and memory by cannabinoid-estrogen interaction in an AD-like cognitive impairment: The role of cannabinoid receptors and BDNF protein.

Mirshekar M.; Nadi F.; Fanaei H.; Chahkandi M. · IBRO neuroscience reports · 2026

**Background & Methods** This preclinical study investigated marijuana extract effects on cognitive impairment in ovariectomized (OVX) rats with Alzheimer's disease-like pathology induced by intra-hippocampal amyloid-beta (Aβ25-35) administration. Animals received marijuana extract (60 mg/kg/day, containing 8.5% Δ9-THC) alone or combined with 17β-estradiol for 28 days, with spatial learning and memory assessed via Morris water maze and hippocampal CB1/CB2 receptor expression and BDNF protein levels measured as molecular markers. **Key Findings** • Chronic marijuana extract administration improved Aβ25-35-induced deficits in spatial learning and memory performance in the Morris water maze task. • Behavioral improvements were accompanied by alterations in hippocampal CB1 receptor expression and elevated BDNF protein levels, suggesting cannabinoid signaling involvement in neuroprotection. • Co-administration of estradiol did not produce synergistic cognitive benefits, indicating complex and non-additive interactions between cannabinoid and estrogen-related signaling pathways rather than complementary effects. **Dosage & Administration** Marijuana extract: 60 mg/kg/day orally (corresponding to approximately 5.1 mg/kg/day Δ9-THC); 17β-estradiol: 1 mg/kg administered every 4 days; treatment duration: 28 days. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical review-type study with significant limitations. The marijuana extract was not fully phytochemically characterized beyond HPLC quantification of THC, limiting understanding of other active compounds' contributions. Mechanistic analyses were correlational rather than causal, preventing definitive conclusions about CB1/CB2 or BDNF involvement. The OVX rat model approximates post-menopausal female vulnerability but has limited translational relevance to human AD pathophysiology. The study lacks safety/adverse effect reporting and long-term outcome data. The authors acknowledge these limitations and recommend cautious interpretation pending further mechanistic clarification and translational studies before clinical application.

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