Psychedelics as anti-inflammatory agents

This review (2018) examines the cellular pathways through which psychedelics act as anti-inflammatory agents by means of selectively blocking the expression of pro-inflammatory mediators and thereby modulating histone modifications and epigenetic signaling. It is thus hypothesized that psychedelics may be of therapeutic value to a wide range of inflammatory disorders in humans.

Abstract

“Review: Serotonin (5-hydroxytryptamine, 5-HT)_2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT_2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT_2A receptor in the inflammatory response, as well as highlight studies using the 5-HT_2A agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT_2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.“

Authors: Thomas W. Flanagan & Charles D. Nichols

Summary

Serotonin (5-HT)2A receptor agonists have recently emerged as promising treatment options for a variety of disorders, including anxiety, depression, obsessive-compulsive disorder and addiction. They also have potential as anti-inflammatory agents.

Introduction

The term psychedelic was coined in 1957 by Humphrey Osmond to describe a class of hallucinogenic drugs that activate serotonin 5-HT2A receptors. Recent clinical studies using known psychedelic compounds have contributed to a greater appreciation of their potential as therapeutic medications. These studies have found that psilocybin significantly improves well-being and life satisfaction, while concurrently reducing anxiety and depression in patients with a life-threatening cancer diagnosis.

Inflammation plays a significant role in the pathophysiology underlying psychiatric disorders like depression and addiction, for example.

Serotonin, an immune modulator, is associated with memory impairment and neuropsychiatric disorders in the developing brain, and with elevated levels of anxiety and depression in multiple sclerosis patients. Psychedelics may be acting as anti-inflammatory agents by reducing neuroinflammation and preventing the brain from returning to an inflamed pathological state.

Serotonin and inflammation

Inflammation is an endogenous repair/host defense mechanism that promotes healing after a physical, chemical, thermal, or biological insult. It is comprised of innate and adaptive components that work together to combat noxious stimuli and establish pathogen profiles.

Innate immune cells release cytokines that regulate the immune system. The adaptive immune system is activated when the innate immune system is unable to effectively eliminate the infectious agents, and produces antibodies that bind to ‘non-self’ antigens on pathogens and target them for efficient destruction.

Serotonin is heavily involved in inflammation and the inflammatory response and is seen as primarily pro-inflammatory. Depletion of serotonin reduces inflammation in a number of different animal disease models and is associated with a lower expression of proinflammatory cytokines in blood samples taken from healthy volunteers.

Serotonin and the 5-HT2A receptor

Serotonin receptors are prevalent throughout the body and regulate several processes, including learning and memory, sleep/wake cycles, appetite, sexual behaviour, pain, motor activity, and aspects of autonomic function. Dysregulation of the serotoninergic system has been implicated in several diseases and disorders, including anxiety and depression.

The serotonin receptor family is comprised of seven different receptor families, and there are 14 distinct subtypes in mammals. The 5-HT2A receptor is the most widely expressed mammalian serotonin receptor throughout the brain and body, and has been implicated in disorders like schizophrenia. The 5-HT2A receptor is believed to modulate aspects of vasoconstriction and cardiomyocyte proliferation within the vasculature and in other tissues like renal cells, lymphocytes, fibroblasts, and hepatic cells.

5-HT2A receptors and the immune system

The 5-HT2A receptor has been detected in many immune related tissues, including spleen, thymus, and circulating lymphocytes. It is also expressed in human peripheral blood mononuclear cells, eosinophils, and T cells. Early attempts to identify the role of the 5-HT2A receptor in the immune response produced contradictory results. However, one study found that blockade of the 5-HT2A receptor could modestly down-regulate inflammation and eosinophil infiltration in a mouse model of allergic asthma. Activating 5-HT2 receptors with (R)-DOI partially blocked LPS and TNF-a stimulated nitrite accumulation in rat C6 glioma cells, and decreased spleen and peripheral blood CD8() T cells counts with cytotoxic/suppressor function. Ketanserin blocks this effect.

Anti-inflammatory effects of 5-HT2A receptor activation with psychedelics

While studying the effects of psychedelics on inflammation, Yu et al. (2008) discovered that activation of 5-HT2A receptors with psychedelics produces a potent anti-inflammatory effect. 5-HT2A receptor activation may be a viable therapeutic strategy for persistent and chronic inflammation.

In vivo experiments using (R)-DOI showed that it blocked the effects of TNF-a in several tissues, including the aortic arch, intestine, and blood. The 5-HT2A receptor selective antagonist M100109 was used as a control to demonstrate that the anti-inflammatory effects were indeed mediated by selective activation of 5-HT2A receptors.

The anti-inflammatory effects of (R)-DOI and other psychedelics may be partially explained by functional selectivity, where serotonin stabilizes the 5-HT2A receptor in a conformation that recruits pro-inflammatory signalling pathways, whereas psychedelics stabilize the receptor in a slightly different conformation that recruits anti-inflammatory signalling pathways.

5-HT2A receptors and asthma

Asthma is an inflammatory disorder characterized by airflow obstruction, airway hyperresponsiveness (AHR), mucus over-production, and bronchial inflammation. 5-HT2A receptors are expressed at elevated levels in numerous immune related cell types that contribute to the pathophysiology of inflammation and asthma.

Multiple models of murine allergic airways disease exist, including exposure to chicken egg albumin [OVA] or house dust mite antigen followed by analysis of airway structural remodelling and lung function, inflammatory cell infiltration, mucus production, and inflammatory mediator expression. (R)-DOI treatment prevents the development of asthma at doses as low as 0.01 mg/kg.

Current asthma therapies include b2-adrenergic receptor agonists and glucocorticoids, but (R)-DOI and/or other psychedelics may represent a new class of disease-modifying, steroid sparing, small molecule therapeutics for the treatment of asthma.

Conclusion

Psychedelics block the inflammation produced by TNF-a in cell and animal models of inflammation. It is plausible that psychedelics modify histone modifications and epigenetic signalling for their therapeutic effects, including the regulation of the expression of anti-inflammatory genes.

Psychedelics may affect inflammation in several ways. These include changing the expression of several inflammatory mediators and modulating the differentiation of immune-related cells to more anti-inflammatory phenotypes.