LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice

Abstract

There is a substantive clinical literature on classical hallucinogens, most commonly lysergic acid diethylamide (LSD) for the treatment of alcohol use disorder. However, there has been no published research on the effect of LSD on alcohol consumption in animals. This study evaluated the effect of LSD in mice using a two-bottle choice alcohol drinking paradigm. Adult male C57BL/6J mice were exposed to ethanol to develop preference and divided into three groups of equal ethanol consumption, and then treated with single intraperitoneal injection of saline or 25 or 50 μg/kg LSD and offered water and 20% ethanol. The respective LSD-treated groups were compared to the control group utilizing a multilevel model for repeated measures. In mice treated with 50 μg/kg LSD ethanol consumption was reduced relative to controls (p = 0.0035), as was ethanol preference (p = 0.0024), with a group mean reduction of ethanol consumption of 17.9% sustained over an interval of 46 days following LSD administration. No significant effects on ethanol consumption or preference were observed in mice treated with 25 μg/kg LSD. Neither total fluid intake nor locomotor activity in the LSD-treated groups differed significantly from controls. These results suggest that classical hallucinogens in the animal model merit further study as a potential approach to the identification of targets for drug discovery and investigation of the neurobiology of addiction.

Keywords: alcohol; hallucinogen; lysergic acid diethylamide; mouse; psychedelic; serotonin receptor agonists; substance-related and addictive disorders.

FIGURE 1

Ethanol consumption (A,B), ethanol preference (C,D), and total fluid consumption (E,F) in mice treated with single dosages of LSD of 25 (left column) or 50 (right column) μg/kg body weight, i.p. Data are presented as mean ± SEM (n = 8–10 per group). Horizontal axis indicates the number of days following the administration of LSD. The mice were divided into three groups of equal ethanol consumption based on the amount of ethanol consumed on the day before LSD administration (day 0). LSD dosages were administered on day 1 [“injection,” as indicated in the top row panels (A,B)]. In the group treated with 50 μg/kg LSD, MLM for repeated measures indicated significant reductions versus saline-treated controls in ethanol consumption (p = 0.0035) and preference (p = 0.0024). Differences from control were not significant for the group treated with 25 μg/kg. Total fluid intake did not differ significantly from controls in either LSD-treated group (E,F) (See “Results” in text).

FIGURE 2

Home cage ambulatory activity (beams broken X-Y) was measured for 24 h following the administration of LSD 50 μg/kg weight, i.p. to ethanol-naïve mice on day 1 immediately following LSD administration (A) and 8 days later (B). Data are presented as mean ± SEM (n = 8 per group). LSD administration did not significantly alter the ambulatory activity compared to saline treated mice on either day (See “Results” in text).