Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

This rat-model study (Flinders Sensitive Line – depressed rats) found no anti-depressant effects when given psilocybin (or psilocin). This study shows that a rat-model study may not be a good model for studying depression and psychedelics/psilocybin.

Abstract

“Objective: Psilocybin is a serotonin receptor agonist with therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.

Methods: Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment
paradigms, and timing of the tests in relation to the drug administration.

Results: Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected.

Conclusion: Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.”

Authors: Oskar Jefsen, Kristoffer Højgaard, Sofie L. Christiansen, Betina Elfving, David J. Nutt, Gregers Wegener & Heidi K. Mülle

Summary

Psilocybin, a serotonin receptor agonist, showed no antidepressant-like effect in the Flinders Sensitive Line rat model of depression. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

Introduction

Depression is a major public health concern that affects hundreds of millions of people and poses a large burden on the society. Ketamine could be a new, more effective way to treat depression. Psilocybin, a psychedelic serotonin receptor agonist found in ‘magic mushrooms’, has shown promising therapeutic potential for treatment-resistant depression, end-of-life anxiety, and addiction.

A single acute versus chronic treatment of serotonin receptor 2A agonism with fluoxetine showed a rapid-acting (1 week) and long-lasting (3 months) antidepressant effect in patients with treatment-resistant depression.

The underlying mechanisms of psilocybin’s antidepressant effects are largely unknown, but studies in animals may reveal novel molecular targets to pursue in preclinical research.

In the present study, we used a rat model of depression to show that psilocybin and psilocin can decrease immobility in the forced swim test, corresponding to an antidepressant-like effect.

Study design

Four consecutive experiments were conducted with FSL and FRL rats. The antidepressant-like effect was evaluated as the decrease in immobility time between the FSL group treated with psilocin or psilocybin and the FSL group treated with saline.

Animals

We housed eight male Flinders Line rats in pairs at 22 C on a 12-h light/dark cycle, and assessed their welfare daily. We used a sample size of eight animals per group and assumed an effect size of 1.6 and a standard deviation of 12.5%.

Drugs

Psilocin or psilocybin was dissolved in 0.9% sterile saline solution, acidified with hydrochloric acid, and subsequently adjusted to pH = 5 – 6. Psilocin is 1.4 times more potent per milligram than psilocybin.

Treatments

Saline, psilocin, or psilocybin was injected intraperitoneally at a volume of 1 ml, in the animals’ home cage, and 3 h after injection, behavioural testing was conducted to ensure that any effects were due to persistent changes and not to the acute effects of the drug.

Open field test

The open field test was conducted in a sound-proof and dimly-lit room, and animals were left in the middle of a square black plastic box for 5 min.

Forced swim test

Rats were subjected to a modified FST, with no pre-swim session, and their activity was video-recorded for later scoring. Immobility, swimming, and struggling behaviour were assessed, and the averages were calculated and reported in seconds.

Statistical analysis

The unit of analysis was a single animal. ANOVA was conducted to determine the effects of strain and treatment, and Tukey’s multiple comparisons tests were used to determine significance.

Open field test

In four separate experiments, psilocin and psilocybin were tested for their effects on locomotor activity. No statistically significant effects were found in any of the experiments, suggesting that the drugs did not have any stimulant or depressant effects on locomotor activity.

Forced swim test

The FST was used to assess antidepressant-like effects of either psilocin or psilocybin in four separate experiments. Psilocin and psilocybin did not exert an antidepressant-like effect in the FSL rats.

Discussion

This study found that psilocin and psilocybin did not exert an antidepressant-like effect in FSL rats, when evaluated using the FST and OFT.

According to the published literature, psilocin and psilocybin have not been investigated in an animal model of depression. However, some studies have reported antidepressant-like effects of DMT and Ayahuasca in the rodent FST.

Our results suggest that the FST is an inappropriate test for replicating the antidepressant effect of psilocybin, and that the FSL rat is an inappropriate model for replicating depression. The FSL rat has been shown to respond to traditional antidepressants using the no pre-swim FST setup, and also showed inherent depressive-like behaviour, without the pre-swim session.

Rats lacking 5-HT2A receptors have decreased expression in the frontal cortex and hippocampus, which may render them inappropriate for studying psilocybin and psilocin.

Psilocybin’s antidepressant effect in humans is not directly translatable to animal models of depression, because the human 5-HT2A receptor has a 15-fold higher affinity for psilocin than the rat 5-HT2A receptor, and because the human brain is different from the rat brain.

In human studies with psilocybin, psychotherapy was always accompanied by the administration of drugs. Higher cognitive abilities might be necessary for achieving a positive effect with psychedelics, but we currently do not know whether this is the case in rats.

The present studies have some limitations, such as having only measured a single behavioral outcome in the FSL rats, and having used a high (10 mg/kg) dose, which is higher than those commonly reported in the published literature.

We consider our results to carry a low risk of bias, because animals were randomly assigned to experimental groups, allocation was concealed, and the outcome assessor was blinded.

We found no antidepressant-like effect of psilocin or psilocybin in the FSL rats using the FST, but suggest testing psilocybin in other behavioural tests.