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

This rodent study (n=81) investigates the efficacy of psilocybin and LSD (microdose, sub-chronic dose, high-dose) to mitigate relapse behavior in an alcohol-deprived rat model of addiction. Contrary to the previous hypothesis, psilocybin and LSD had no long-lasting effects on relapse after alcohol deprivation, but the subchronic dose exerted a short-lasting effect.

Abstract

“Introduction: For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run.

Methods: Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model.

Results: In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention.

Discussion: In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.”

Authors: Marcus W. Meinhardt, Cansu Güngör, Ivan Skorodumov, Lea J. Mertens & Rainer Spanagel

Summary

Psychedelic drugs are one of the hottest topics in psychiatry with lots of hope, but so far little research especially in animal models of psychiatric disorders has been conducted. Here we used a well-established animal model of alcohol relapse to test the hypothesis whether psychedelic drugs will exhibit long-lasting anti-relapse properties in alcohol use disorder individuals.

AUD is a major problem for affected patients and society due to its immense economic costs. AUD is highly prevalent, physically and psychologically disabling, and often occurs comorbid to other psychopathologies and somatic conditions.

Currently, there are few effective pharmacological treatments for alcohol use disorder (AUD). However, a proof-of-concept clinical trial using psilocybin in AUD showed some preliminary efficacy in decreasing drinking behavior in weeks 5 – 12 relative to baseline and relative to weeks 1 – 4 (i.e., before the first psilocybin dose).

While preliminary results of clinical trials on psilocybin and LSD are promising, well-controlled studies are lacking. Understanding the mechanisms underlying the putative anti-relapse effects is essential to optimize safety and efficacy.

The present study aimed to investigate the effects of LSD and psilocybin on a rat model of alcohol relapse, namely the alcohol deprivation effect (ADE) model. The ADE model involves compulsive drinking, wanting (craving), and loss of control in a relapse situation.

Several human studies showed that psychedelics can produce long-lasting changes in mood and behavior. The current study tested the hypothesis that a high dose psychedelic intervention will reduce relapse behavior in the ADE model.

MATERIALS AND METHODS Animals

Ninety-one 2-month-old male and female Wistar rats were used in the experiment. They were housed individually in standard rat cages under a 12 h artificial light/dark cycle.

To model relapse-like drinking in rats, the ADE model was applied. After 8 weeks of continuous alcohol availability, the first deprivation period was introduced, followed by 3 and 4 more deprivation periods in a random manner.

Rats were divided into three groups and their alcohol intake was measured for 1 week. Then the alcohol bottles were removed and the animals had free access to food and water.

We performed three experiments with different drug administration schemes to test the effects of psychedelics on alcohol dependence. These experiments were a repeated dosing scheme, two high dose applications 1 week apart, and a 4-week microdosing regime with two doses a week.

After a period of abstinence, rats were given five intraperitoneal injections, followed by four applications in 12 h intervals of either vehicle or a moderate dose of psilocybin. The occurrence of an ADE was determined, and the treatment was continued for three more weeks. In addition, locomotor activity was monitored by an infrared sensor placed above each cage. The data was downloaded into a personal computer and processed with Microsoft Excel.

We administered psilocybin or LSD twice (7 days apart) during the deprivation period to rats to investigate their effect on alcohol dependence. The occurrence of an alcohol dependence episode was determined the morning after the second injection. Total ethanol and water intake were measured daily for the subsequent week, and body weight was recorded 24 h before each of the two injections.

In recent rodent literature, intermittent microdosing of the psychedelic tryptamine N, N-dimethyltryptamine has been shown to have beneficial effects on mood and anxiety. However, there is no well-established definition of a “microdose” in humans.

We administered eight injections of vehicle or psilocybin (0.1 mg/kg) to male and female rats within a 4-week deprivation period. The rats’ body weight and locomotor activity were measured weekly during this period.

Data derived from home-cage drinking and locomotor activity were analyzed using a two-way repeated measures Analysis of Covariance (ANCOVA), with treatment as the between-subject factor and day/week as the within-subject factor. Sex was added as a covariate.

RESULTS

In the first experiment, psilocybin was used to treat alcohol relapse. Female rats consumed significantly more alcohol than male rats, and the effect of psilocybin was observed in both alcohol and locomotion outcome variables. The vehicle-treated group showed the expected increase in alcohol consumption, indicating occurrence of an ADE. Psilocybin treatment reduced the expression of ADE, and water intake was not different in psilocybin-treated animals compared with controls during treatment days. A general reduction in home-cage activity was observed in all animal groups during the first three days of the ADE experiment, which was likely caused by alcohol intoxication. Psilocybin did not affect home-cage activity in male rats.

We administered twice (seven days apart) two different high doses of psilocybin or LSD to rats during abstinence and investigated the effect of such a pre-/prophylactic treatment on ADE. No difference was found between groups for either psilocybin or LSD treatment.

Rats received eight injections of psilocybin i.p., two per week, during a 4-week abstinence period. All groups showed a significant increase in alcohol consumption, but no difference of psilocybin treatment compared to vehicle on ADE was observed.

DISCUSSION

We applied three different treatment schedules with psychedelics to the ADE rat model to investigate the effect of psilocybin and LSD on relapse-like drinking. However, psilocybin had no long-lasting effects on the ADE in rats, neither in the repeated subchronic dosing scheme nor in the chronic microdosing regime.

Animal models allow for testing of the pure pharmacological effects of psychedelic drugs. However, we could not see any effect on ethanol consumption in rats after a single hallucinogenic dose of LSD and no effect on mood and anxiety.

Previous studies have shown that targeting the serotonergic system may be beneficial for relapse prevention. Psilocybin has been shown to activate 5-HT2A receptors in the medial prefrontal cortex and increase dopamine levels in the mesocortex, which may explain the observed short-lasting effect on ADE.

LSD has been shown to induce early gene expression within the prefrontal cortex, which is critical for long-term, activity-dependent adaptive responses of neurons. However, this gene is downregulated in alcohol-dependent rats, which could explain the lacking effect observed in experiment 2.

Despite negative results with psychedelic pretreatment, a positive finding with acute psilocybin treatment suggests that the efficacy of psilocybin for the treatment of alcohol misuse may also involve a biologically mediated effect and is not solely due to the therapeutic effects of the subjective psychedelic experience.