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Psilocybin And Inflammation: A New Frontier In Psychedelics?
Psychedelic compounds such as psilocybin may hold promise for the future treatment of inflammation-related diseases. Professor Charles Nichols, whose team discovered the potent anti-inflammatory effects of psychedelics, speaks to States of Mind to tell us more.
Psychedelics have gained increasing recognition in recent years as potential game-changers in the treatment of mental health conditions.
However, a growing body of research now suggests that psychedelic compounds such as psilocybin may also have profound effects on physical health — namely, inflammation and diseases driven by immune dysregulation.
States of Mind speaks with Professor Charles Nichols of the LSU School of Medicine about the current evidence and future direction of research.
Chance Encounters: Psilocybin For Inflammation
Nichols described the discovery as serendipitous. He and his team were not actively investigating the impact of psychedelics on inflammation when they found that the compounds can suppress inflammatory responses.
At the time, Nichols was developing a cell-based assay to measure outcomes such as cell growth, division, and toxicity. He had recruited a postdoctoral student to his lab who had been researching vascular inflammation and the cardiovascular aspects of 5-HT2A receptors in blood pressure regulation.
“He had expertise in this model of vascular inflammation, so we tried it,” explains Nichols.
“I really had no preconceived notions that we were going to see an anti-inflammatory effect, but we did.”
“Not only was it a very robust effect, but it was a very potent effect. At first, I didn’t really believe it, so I went and did it again. We looked at characterizing the effect, looked at some different drugs, and that resulted in our 2008 publication.”
The team’s landmark paper revealed that activating the serotonin 5-HT2A receptor, which psychedelics bind to, suppresses tumour necrosis factor alpha (TNF-alpha)-induced inflammation, a key driver of inflammatory and autoimmune diseases.
“At the time, there had been some reports about how some psychedelics had modulated the immune system, but nothing that showed that it was such a potent anti-inflammatory against TNF-alpha, specifically,” says Nichols.
“Since then, we have broadened that scope. The origin story is serendipitous: in the right place at the right time, and we did the right experiment and followed up on it.”
How Psychedelics May Interact With Inflammation And The Immune System
Nichols has spent 15 years investigating the potential mechanism of action by which psychedelics may mediate inflammatory pathways and responses. His research has spanned different inflammatory conditions, including asthma and rheumatoid arthritis.
Previous research has shown that typical serotonin receptor pathways like calcium signalling and beta-arrestin, which acts as a cellular “off-switch,” do not correlate with the anti-inflammatory effects observed with psychedelics.
As the 5-HT2A receptor belongs to the G protein-coupled receptor family, it can activate numerous intracellular pathways.
“It’s a pathway that we don’t know yet, and there are literally dozens of pathways that can couple to a G-protein coupled receptor, so it’s like trying to find a needle in a haystack,” Nichols says.
Nichols and his team are now studying structure, function, molecular dynamics, and ligand docking with a variety of psychedelic molecules to better understand which specific activation patterns lead to anti-inflammatory effects.
“It is also different between different psychedelics. For some psychedelics, we see better effectiveness in certain types of diseases and inflammation, and with other psychedelics in different types of diseases and inflammation.”
The team is now finishing up a study on the effects of three different psychedelics on rheumatoid arthritis. So far, Nichols says the model shows that psilocybin is not a very good anti-inflammatory for arthritis, but works well in the asthma model.
“Another drug which is very effective in the asthma model is 2C-B, but it is also very good in the arthritis model. So, it’s not just one anti-inflammatory mechanism,” he explains.
“I think that there are many proteins that are coupled to the receptor, so, depending on how that receptor is being activated, we can direct which inflammation we want to treat.”
Current Scientific Evidence And Therapeutic Potential
Although most evidence comes from animal models and indirect findings, early results suggest they could eventually offer new therapeutic approaches for inflammatory diseases, if they can be translated into humans.
In a 2022 article, Nichols highlights that the 5-HT2A receptor is widespread throughout the body — found in nearly “every tissue and cell type examined” — and that serotonin levels rise at sites of inflammation.
Nichols further proposes that, given the widespread nature of 5-HT2A, activation may reduce inflammatory signalling across the whole body, including the aortic arch and small intestine. His research also identified reductions in inflammatory cytokines.
He suggests that activation of 5-HT2A may represent a novel approach to develop therapeutics for inflammatory diseases such as atherosclerosis and inflammatory bowel disease.
“We’re now thinking of psychedelics not so much as an anti-inflammatory, but as a type of therapeutic that brings a system back to homeostasis and balance,” explains Nichols.
“They don’t really suppress the immune system like a corticosteroid.”
Nichols explains that when disease is present, it may reduce inflammation, but does not further lower biomarkers below baseline levels once inflammation is resolved.
“It’s really different from what you would normally think of as an anti-inflammatory, something that’s immunosuppressive,” says Nichols.
“In some sense, the drugs only work when you need them to work. If you’re not sick or unhealthy, they don’t do anything to your immune system and don’t have any negative effects that we’ve been able to see.”
Nichols and his team have also found that these anti-inflammatory effects can be seen at subperceptual doses, that is to say, microdoses.
Future Research
Further research will be needed to fully understand the safety and effectiveness of psychedelics such as psilocybin for inflammation.
Nichols has now co-founded a company that is investigating the anti-inflammatory effects of psychedelics, as well as developing and testing non-hallucinogenic compounds that target the same receptors as psychedelics for the same purpose.
“In our previous experiments, we looked at 25 different psychedelics and found that there was no correlation between the behavioral effects and the anti-inflammatory effects,” Nichols explains.
This suggests that the anti-inflammatory effects may be possible to achieve without the altered state induced by psychedelics.
One emerging area of interest is the anti-inflammatory effects of psilocybin on traumatic brain injury (TBI), which triggers neuroinflammatory responses in the brain.
A recent study supported by Heroic Hearts, a non-profit organization supporting veterans, suggested that psilocybin may improve mental health and cognitive function in veterans with TBI. The study hypothesizes that improvements may be partly due to psilocybin’s potential impact on neuroinflammation.
To test this theory, the research team has developed a new protocol in collaboration with the University of Colorado Boulder to measure inflammatory biomarkers in TBI from blood samples taken before and after a psychedelic retreat.
Nichols says the shift in perception that psychedelics are now being seen as promising treatments for diseases is “remarkable.”
“People are beginning to understand the anti-inflammatory effects and looking into that,” says Nichols.
“The burden of people with inflammation and inflammatory disorders is very high, and I think for people who are living with chronic inflammation, this could be really a new paradigm for their treatment.”
“I think, as we have success, other people will start studying this, and hopefully we can develop new and novel treatments.”
Expert Board Member
While most of us have heard about the potential of psychedelic therapy for mental health, a growing body of preclinical research suggests that psychedelic and non-hallucinogenic compounds acting on the same serotonin receptors may also be relevant for inflammatory and autoimmune diseases. In this interview, Professor Nichols discusses his team's work exploring the 5-HT2A receptor as a potential therapeutic target, with findings suggesting a uniquely homeostatic rather than immunosuppressive action. Human trials are yet to come, but this is a new direction worth watching.
