A Single Dose of a Psychedelic Drug Repairs Prefrontal Cortex Synaptic Physiology in a Mouse Model of Prenatal Alcohol Exposure

This study investigated whether a single dose of the psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) could reverse brain abnormalities caused by prenatal alcohol exposure (PAE) in mice. DOI is a 5-HT2A receptor agonist commonly used in preclinical psychedelic research; it is not used clinically in humans.

Prenatal alcohol exposure can produce lifelong cognitive impairments associated with fetal alcohol spectrum disorders (FASD). There are currently no approved medications that directly reverse the underlying cortical dysfunction.

This study suggests that psychedelic-inspired compounds might eventually become candidates for repairing disrupted neural circuits rather than simply treating symptoms.

Abstract

Background: Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorders (FASDs), which are characterized by neural circuit and behavioral dysfunction due to impaired brain development. At the neural and behavioral levels, PAE is associated with disrupted cortical synaptic transmission and lifelong impairments in learning and cognitive control. Despite the prevalence of FASDs (affecting up to one in 20 school-aged children in the United States) and the associated personal, familial, and societal costs, there are currently no treatments to reverse neural circuit dysfunction.

Methods: Using whole-cell patch-clamp electrophysiology, we investigated intrinsic excitability and synaptic activity in prefrontal cortex (PFC) pyramidal neurons from adolescent mice prenatally exposed to ethanol (6.6%) and later given a single injection of either saline or 25CN-NBOH, a psychedelic neuroplastogen.

Results: We found that PAE reduced intrinsic excitability and synaptic drive in PFC pyramidal neurons. 25CN-NBOH treatment partially rescued intrinsic excitability deficits and restored synaptic drive.

Conclusions: Psychedelic neuroplastogens may show promise as potential therapeutics for synaptic deficits associated with PAE and should be further explored in preclinical models.

Ekins TG, Deng T, Ahmed OJ. A Single Dose of a Psychedelic Drug Repairs Prefrontal Cortex Synaptic Physiology in a Mouse Model of Prenatal Alcohol Exposure. Brain Behav. 2026 Apr;16(4):e71406. doi: 10.1002/brb3.71406. PMID: 42007539; PMCID: PMC13093898. Read Paper

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