Psilocybin and LSD Have No Long-Lasting Effects in an Animal Model of Alcohol Relapse

Psychedelic compounds such as psilocybin and LSD have recently regained interest as potential treatments for a range of psychiatric disorders, including alcohol use disorder (AUD). Despite growing clinical enthusiasm and some preliminary human data suggesting beneficial effects on drinking behaviour, there is comparatively little preclinical work testing whether these drugs produce enduring anti-relapse effects. The authors note that animal models offer a way to isolate pure pharmacological effects from the psychotherapeutic context and expectancy that accompany human trials. This study set out to test whether psilocybin and LSD reduce relapse-like drinking in the alcohol deprivation effect (ADE) model in rats. Two main hypotheses were examined: that a clinically relevant high-dose psychedelic intervention given acutely can produce long-lasting reductions in relapse behaviour, and that chronic intermittent microdosing might similarly reduce relapse. Male and female Wistar rats were included to explore sex differences in treatment effects.

Ninety-one two-month-old male and female Wistar rats from the authors' colony were used. Animals were singly housed under a 12 h light/dark cycle with food and water ad libitum; room temperature and humidity were controlled. Body weights were recorded weekly and all procedures were approved by institutional and regional animal care authorities. Drug details are provided in the Supplementary Information. Relapse-like drinking was modelled using a long-term voluntary alcohol consumption procedure with repeated deprivation phases (the ADE model). After a 2-week habituation, rats had continuous access to 5%, 10% and 20% ethanol solutions plus water for eight weeks. Deprivation periods were then introduced (first after 8 weeks) and repeated in an irregular schedule over a total procedure duration of nine months. Reintroduction of alcohol after each deprivation typically elicits a transient increase in voluntary alcohol intake (the ADE), which the authors used as the primary behavioural endpoint. Baseline alcohol intake was measured for one week before deprivation and groups were balanced so mean baseline total alcohol intake was similar across treatment conditions. Three experiments tested different administration schemes. Experiment 1 used a repeated subchronic dosing schedule: five intraperitoneal (i.p.) injections of either vehicle or psilocybin (1 mg/kg) across three days, with the first injection the night before reintroduction and the second injection occurring ~9 a.m. when alcohol bottles were returned. Ethanol intake (g/kg/day), water intake (ml/kg/day) and home-cage locomotor activity (infrared sensor sampling every second) were recorded daily for one week and then for three further weeks to probe persistence. Experiment 2 adapted a clinically translatable prophylactic schedule: two i.p. injections given 7 days apart during abstinence, with the second injection administered ~15 h before alcohol reintroduction. Groups received psilocybin twice (2.5 mg/kg or 10 mg/kg) or LSD twice (0.08 mg/kg or 0.32 mg/kg). Food/water intake, locomotion and body weight were monitored as in experiment 1. Experiment 3 tested chronic intermittent microdosing: psilocybin 0.1 mg/kg (defined by the authors as a sub‑hallucinogenic microdose in rats) or vehicle was given i.p. twice weekly for four weeks (eight injections total); alcohol was reintroduced 16 h after the last dose and the same intake and locomotion measures were collected. Statistical analysis used two-way repeated measures analysis of covariance (ANCOVA) with treatment as the between-subject factor and day/week as the within-subject factor. Male and female data were pooled and sex was included as a covariate; because baseline intake differed by sex the baseline alcohol, water and locomotion variables were mean-centred within each sex group. Post-hoc Student Newman Keuls tests were applied when ANCOVA indicated significant effects. Outcome variables during post-treatment days were expressed as percentage relative to baseline.

Experiment 1 (psilocybin 1 mg/kg, five-dose schedule): Baseline alcohol intake differed by sex, with females consuming more than males (baseline means reported as vehicle males 4.17 ± 0.31 g/kg/day, psilocybin males 4.02 ± 0.33; vehicle females 5.65 ± 0.59, psilocybin females 5.69 ± 0.35). The vehicle-treated group displayed the expected ADE (an increase in alcohol consumption after deprivation). Psilocybin treatment reduced the expression of the ADE on the initial post-deprivation measurements: ANCOVA showed a significant day effect [F(5,165)=2.59, p < 0.027] and a significant treatment group × day interaction [F(5,165)=3.89, p < 0.002], indicating lower alcohol intake in the psilocybin group during the acute relapse window. Sex as a covariate was not significant [F(1,33)=0.84, p = 0.36]. Water intake did not differ between psilocybin and vehicle groups, suggesting the effect was selective for ethanol. Home-cage locomotor activity fell across the first three days of ADE in all groups, consistent with alcohol intoxication; overall there was no significant treatment × day interaction for activity [F(8,152)=0.67, p = 0.71], although a subgroup analysis found a 2-hour reduction in locomotion after psilocybin in males only. Experiment 2 (two high doses, psilocybin 2.5 or 10 mg/kg; LSD 0.08 or 0.32 mg/kg, given twice 7 days apart): All treated groups exhibited a clear ADE after deprivation. ANCOVA confirmed a strong day effect for both psilocybin [F(5,275)=14.42, p < 0.0001] and LSD [F(5,250)=11.18, p < 0.0001], but there was no evidence that either psilocybin or LSD at the tested doses altered the magnitude of the ADE; treatment effects were not significant. Measurements of total fluid intake and locomotion likewise showed no differences between treatment and control groups. Experiment 3 (psilocybin microdose 0.1 mg/kg, eight injections over 4 weeks): Reintroduction of alcohol produced the expected ADE in all groups. ANCOVA showed a significant day effect [F(5,165)=5.64, p < 0.0001], but no difference between microdosed and vehicle-treated rats on the ADE. Total fluid intake and locomotion did not differ across groups. Overall, only the subchronic five-dose psilocybin regimen produced a short-lasting reduction in relapse-like drinking; neither clinically modelled high-dose pretreatment nor chronic microdosing yielded long-lasting anti-relapse effects in this ADE model.

Meinhardt and colleagues report that neither clinically translatable high‑dose pretreatment nor a chronic microdosing regimen of psilocybin or LSD produced long-lasting reductions in relapse-like drinking in the ADE rat model. The only positive finding was a short-lived attenuation of the ADE after a standard subchronic five-dose psilocybin schedule; the authors emphasise that this regimen is not a translatable prophylactic strategy for relapse prevention in humans. Animal models, the investigators note, permit testing of pure pharmacological effects without psychotherapeutic support or expectancy influences that occur in human trials. The discussion places the results in the context of prior work. The authors acknowledge a discrepancy with an earlier preclinical report by Alper et al. that found a sustained ethanol consumption reduction after a single low LSD dose; they indicate they are unable to explain the differing outcomes, noting dose and species/model differences as possible factors. Mechanistic speculation is presented cautiously: the acute anti-relapse effect of psilocybin might relate to transient increases in mesocortical dopamine and serotonin signalling, whereas lasting relapse prevention would likely require engagement of neuronal plasticity pathways. LSD has been linked to immediate early gene induction such as Egr2 in prefrontal cortex, but the authors note that Egr2 is downregulated in alcohol-dependent rats, which could conceivably blunt LSD's capacity to induce durable plasticity in this model. These mechanistic ideas are explicitly described as speculative and in need of direct testing. Key limitations acknowledged include the restricted generalisability from the ADE model to the human clinical situation, because animal models cannot reproduce the psychological and contextual elements of psychedelic-assisted psychotherapy. The authors therefore caution against extrapolating their negative preclinical findings to humans and call for additional preclinical work using other AUD models (for example post-dependent models or alcohol-preferring lines), alternative dosing schedules, and molecular investigations. They also highlight that the positive, preliminary clinical findings for psilocybin in AUD may involve biological effects beyond the subjective psychedelic experience, but this requires further study.