A temporary increase in stress hormones appears to play a key role in reducing anxiety-like behavior in mice treated with the hallucinogen psilocybin. The survey results are ACS Pharmacology and Translational Scienceprovides new insights into the underlying mechanisms that may be involved in psilocybin-assisted psychotherapy.
Psilocybin is a naturally occurring psychedelic compound found in certain types of mushrooms, also known as “magic mushrooms.” When you ingest psilocybin, it is converted into the active form of psilocin in your body. Psilocin primarily interacts with serotonin receptors in the brain, specifically the serotonin 2A receptor subtype. This interaction leads to changes in perception, mood, and consciousness, resulting in a psychedelic experience.
Psilocybin-assisted psychotherapy is a therapeutic approach in which controlled doses of psilocybin are administered to an individual under the guidance of a trained therapist. Treatment sessions typically include psychological preparation, administration of psilocybin in a supportive environment, and post-session integration. Therapists help individuals navigate psychedelic experiences, providing emotional support and guidance to explore and address underlying psychological issues and challenges.
This form of psychotherapy has gained attention in recent years because of its potential to treat a variety of mental health conditions, including substance use disorders, end-of-life anxiety, major depressive disorder, and treatment-resistant depression. However, there is still much to learn about the mechanisms involved in this therapeutic process.
The authors of the new study aimed to better understand the role of stress-related hormones in psilocybin’s effects. There is evidence to suggest a correlation between acute cortisol release, anxiety, and treatment outcome with psilocybin. However, it is unclear whether cortisol release is a necessary component of psilocybin’s anxiolytic (anxiety-reducing) effects.
“Psychedelic drugs like psilocybin are increasingly being studied in human clinical trials as a means to support non-drug talk therapy approaches to diseases such as depression, anxiety, addiction, and post-traumatic stress disorder. ” said the study authors. Cody J. Wenther, assistant professor and director of the Psychotropic Drug Research Program at the University of Wisconsin-Madison. “As these compounds move closer and closer to review for clinical use by the FDA, a better understanding of how they work at the biological level will help maximize safety and minimize risk. This is extremely important in designing protocols to reduce this.”
To better understand the molecular effects of psilocybin independent of psychological support, researchers turned to animal models to understand the biological and This allowed us to investigate the pharmacological aspects.
The researchers administered psilocybin to male C57Bl6/J mice and examined various behavioral parameters. They also used mass spectrometry to measure the concentrations of psilocybin and its active metabolite, psilocin, in the plasma of the mice. The study included tests such as the open field test (OFT), head twitch response, and novel suppressed feeding (NSF) assay.
The research revealed several important findings. First, mice given a specific dose of psilocybin (3 milligrams per kilogram of body weight) exhibited behavior similar to the effects of anxiolytics (substances known to reduce anxiety). This effect was noticeable 4 hours after administration to mice. Psilocybin also increases the number of head twitch reactions, indicating its hallucinogenic activity.
One of the key findings of this study was that corticosterone, a hormone associated with the stress response, plays a pivotal role in mediating the behavioral effects of psilocybin. When mice were administered psilocybin, plasma corticosterone levels rapidly increased.
This hormone appears to be closely associated with the behavioral changes observed in mice after psilocybin administration. In other words, the behavioral effects of psilocybin, such as changes in anxiety-like behavior, appear to be influenced by the release of corticosterone.
To further confirm this relationship, the researchers used a substance called mifepristone, which is known to block or antagonize receptors for corticosterone. Treating mice with mifepristone before administering psilocybin effectively prevented behavioral changes typically associated with psilocybin administration.
Furthermore, when psilocybin was administered to mice that already had chronically elevated plasma corticosterone levels, the long-term anxiolytic effects of psilocybin were abolished. In other words, when corticosterone levels were consistently high, the anxiety-reducing effects of psilocybin did not emerge.
“Psilocybin, along with the changes in perception of reality it causes, causes the release of stress-related hormones,” Wenther told PsyPost. “We found that in mice, this increase in stress-related hormones actually supported reduced anxiety, with effects lasting up to a week. Importantly, this means that increased levels of these hormones “We only saw it when the levels returned to normal. When the levels remained high for a week, we saw the opposite effect: an increase in long-term anxiety.”
Interestingly, the researchers also found that alternative interventions that caused increases in plasma corticosterone could induce similar post-acute anxiolytic effects. Lisuride, a compound with similar serotonin 2A agonist activity as psilocybin but without obvious sensory-altering effects, also induces anxiolytic-like effects in NSF assays, and glucocorticoid release alone may cause these effects. It shows that there is.
“We were surprised that the anxiety-reducing effects were not significantly altered by blocking serotonin 2A receptors, which are one of the main ways psilocybin causes perceptual changes,” Wenther said. Ta. “This indicates that activation of systemic hormonal responses is complementary and may not be an entirely serotonin-dependent pathway through which psychedelics can support behavioral changes.”
The results of this study raise the question of glucosuria, whether induced by psilocybin or other stressors, as a potential confounding factor in interpreting both acute and post-acute effects of psilocybin on anxiety-like behavior in mice. This highlights the importance of considering the role of corticoid release.
But as with all research, the new study comes with some caveats. This study provides insight into the basic mechanisms underlying psilocybin’s effects, but it remains to be seen how these findings relate to human experience.
“These experiments were done on mice, not humans,” Wenther said. “This helps us understand what biological components of a response are important, without people’s common preconceived notions and expectations about psychedelics, but it also helps us understand what biological components of the response are important. It really limits our ability to understand how psilocybin interacts with the effects of psilocybin. To that end, we continue to work with people to potentially influence the magnitude and duration of therapeutic responses. Changes in cortisol over time as a factor need to be further investigated.”
Wenther added that Nathan Jones, a graduate student in his lab, played a key role in this research and is the first author of this publication.
the study, “Transient elevation of plasma glucocorticoids supports psilocybin-induced anxiolysis in mice” is written by Nathan T. Jones, Zalmeen Zahid, Sean M. Grady, Ziyad W. Sultan, Jen Jen, John Radzidlo, Matthew I. Banks, and Cody J. Wenther.
