Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse

Meinhardt, Marcus W.; Güngör, Cansu; Skorodumov, Ivan; Mertens, Lea J.; Spanagel, Rainer

doi:10.1038/s41386-020-0694-z

Cited by 47 publications

(61 citation statements)

References 53 publications

(72 reference statements)

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“…[13–19] Additional studies assessing antidepressant-like and anxiolytic-like effects following treatment with 5-HT 2A R agonists in rodent behavioral tests like the Forced Swim Test (FST), Open Field Test (OFT), and Elevated Plus Maze (EPM) have also emerged more recently. [19–26] The observed results have sometimes been consistent with interpretations of antidepressant-like or anxiolytic-like activity, such as reductions in FST immobility time and increased open arm time in the EPM. However, there have also been results that are inconsistent with this interpretation, such as a lack of effect on FST in Flinders’ Sensitive Rats for up to a week after single or repeated psilocybin dosing.…”

Section: Introductionsupporting

confidence: 73%

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Jones

Zahid

Grady

et al. 2020

Preprint

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Psilocybin has shown positive preliminary signals in small-scale clinical trials for psychiatric disorders that exhibit maladaptive stress responses as a major component of their presentation. However, there are relatively few assessments of whether an acute administration of psilocybin exhibits reproducible effects in rodent models useful for the study of stress-associated psychiatric disorders. Here, we measured the responses of male C57BL/6J mice to this compound in a battery of relevant behavioral tests. These tests included the open-field test, forced swim test, sucrose preference test, and novelty suppressed feeding test. Furthermore, these tests were presented in either the absence or presence of chronic corticosterone administration, as a chemically induced model of ongoing stress burden. Our results indicate that the effects of psilocybin within these tests are dependent on the chronic hormonal stress burden of the mice: psilocybin alone promotes anxiolytic and hedonic responses, but promotes anxiogenic and anhedonic responses when pre-treated with chronic corticosterone. This identified interaction between stress hormone burden and psilocybin behavioral effects in mice suggests the possibility of further developing rodent behavioral models that can assess additional context-dependent effects of psychedelic administration that are deemed clinically-relevant, but are otherwise difficult to control for, in human studies.

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Section: Introductionsupporting

confidence: 73%

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Jones

Zahid

Grady

et al. 2020

Preprint

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“…Based on this criterion we identified ketamine and psilocybin doses (and plasma exposures) of 0.3-3 mg/kg (10-70 ng/ml) and 0.05-0.1 mg/kg (7-12 ng/ml [psilocin]) respectively for investigation. Preclinical studies explicitly examining low ("micro") doses of ketamine and psilocybin are beginning to appear in the literature (Horsley et al, 2018;Meinhardt et al, 2020), albeit without any demonstration of potential beneficial effects. One of the limitations to these studies is that antidepressant potential has been typically investigated using tests such as forced swim and elevated plus maze, which lack human equivalence.…”

Section: Discussionmentioning

confidence: 99%

“…With selfadministration of substances that are illegal in most jurisdictions, both the substance purity and its precise dose are impossible to determine, and without controlled trials, effects could be due to expectation and placebo response (Kuypers et al, 2019). Further, preclinical studies (Horsley et al, 2018;Meinhardt et al, 2020) have failed to show benefit of psilocybin and ketamine at doses designed to correspond to a human "microdose" experience.…”

Section: Introductionmentioning

confidence: 99%

Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property

Higgins¹,

Carroll²,

Brown³

et al. 2021

Front. Pharmacol.

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Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3–3 mg/kg [10–73 ng/ml]) and psilocybin/psilocin (0.05–0.1 mg/kg [7–12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1–3 mg/kg IP) and psilocybin (0.05–0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.

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“…We chose a hypothesis-driven focus on plasticity-related genes, instead of an exhaustive transcriptomic approach, allowing us to investigate a broad range of doses simultaneously, which was important for several reasons. First, the translationally relevant dose (in rodents) for the putative therapeutic effects of psilocybin is yet to be fully established (Hibicke and Nichols, 2020; Hibicke et al, 2020; Jefsen et al, 2019; Meinhardt et al, 2020). Second, species differences in the amino acid sequence of the 5-HT 2A receptor may complicate interspecies dose scaling.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

et al. 2020

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Background: Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. Methods: We examined the acute effects of a single administration of psilocybin (0.5–20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting. Results: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. Conclusion: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

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Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse

Cited by 47 publications

References 53 publications

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

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