Intranasal Administration of Disulfiram in Rats Produces Rapid and Potent Anxiolytic-Like Effects Without Adverse Alcohol-Related Interactions.

Background: The U.S. Food and Drug Administration has approved disulfiram (DSF) as a treatment for alcoholism. DSF shows strong anxiolytic-like effects in mice without the side effects commonly associated with benzodiazepines. However, when combined with alcohol, oral administration exhibits side effects, such as headache and decreased body temperature, limiting its clinical use. We aimed to evaluate the effects of intranasal DSF administration. Methods: Male Wistar/ST rats were used. For intranasal formulation, DSF was encapsulated by 2-hydroxypropyl-β-cyclodextrin to form an inclusion complex. The DSF formulation exhibited a uniform particle size. The elevated plus maze (EPM) test was used to examine the anxiety-reducing effects of DSF. Ethanol (2000 mg/kg, p.o.) was administered 48 h after DSF. The body temperature was measured 2 h after ethanol administration. Subsequently, we collected blood and measured the blood acetaldehyde levels. Results: Intranasal DSF administration (1.5 mg/rat) significantly increased the time spent in the open arms of the EPM within 20 min of administration. Oral DSF administration of DSF (1000 mg/kg) significantly increased the time spent in the open arms of the EPM 30 min after administration. In contrast to the oral administration, the intranasal DSF administration did not reduce body temperature or increase the blood acetaldehyde levels. Conclusions: The intranasal DSF administration exhibited rapid and potent anxiolytic-like effects at lower doses than oral administration, without triggering the alcohol interactions observed upon oral administration. Hence, the intranasal DSF formulation may have potential clinical applications as a novel anxiolytic agent. Trial Registration: Japan Registry of Clinical Trials (jRCT): jRCTs031180183.