Psychedelics as potent anti-inflammatory therapeutics

This review (2022) by the renowned Charles Nichols synthesizes our knowledge of psychedelics as anti-inflammatory therapeutics. Though most evidence is in cells (in vitro) and rodents (in vivo), all evidence points towards anti-inflammatory effects, with much of this happening at sub-perceptual (non-hallucinogenic) doses.

Abstract

“Psychedelics have seen a resurgence of interest from both the scientific and lay community in recent years. Psychedelics are known for their ability to produce profound perceptual alterations, ego dissolution, and separation from reality in humans. Virtually all research into psychedelics and their mechanism of action has focused on examining effects in the brain, and on consciousness. Remarkably, we have discovered that psychedelics are also potent anti-inflammatories and immunomodulators in peripheral tissues. In this review, the discovery of this phenomenon, and the development of psychedelics as potential therapeutics for human inflammatory disease is presented. We believe that certain psychedelics represent a new class of small molecule, highly bioavailable, anti-inflammatory that is steroid sparing and efficacious at sub-behavioral levels that can be used to treat and prevent a variety of inflammatory-related diseases and conditions.”

Author: Charles D. Nichols

Summary

Psychedelics are known for their ability to produce profound perceptual alterations, ego dissolution, and separation from reality in humans. However, recent research has discovered that psychedelics are also potent anti-inflammatories and immunomodulators in peripheral tissues.

Psychedelics were popular in the 1960’s due to their effects on the brain. They can produce peak ego-dissolution experiences and subjective effects of feeling at one with the universe. Psychedelics were labeled as dangerous with no medical value, but scientists were still studying them. They discovered that they had potent anti-inflammatory activity in the periphery, and that serotonin receptors were widely expressed in nearly every tissue and cell type examined.

Serotonin levels are high in inflammation and can exacerbate the inflammation when applied within a model of inflammation. The 5-HT2A receptor is the primary receptor mediating pro-inflammatory effects of serotonin. Research on 5-HT2A receptors has focused on studying agonists for their psychoactive effects. We found that (R)-2,5-dimethoxy-4-iodoamphetamine ((R)-DOI) can have anti-inflammatory activity in peripheral tissues, and that this effect is mediated through 5-HT2A receptor activation.

We tested several psychedelics for anti-inflammatory effects, and found that some were more potent than others. These results suggested that certain psychedelics represented a new and potent anti-inflammatory therapeutic class, with therapeutic efficacy at sub-behavioral levels. We administered (R)-DOI 30 minutes prior to treatment with TNF- and collected tissues 5 hours later. We measured significant reductions to complete suppression of TNF-mediated inflammation in several tissues.

(R)-DOI had significant anti-inflammatory effects in the small intestine at doses far below the known behavioral threshold, demonstrating potent sub-behavioral anti-inflammatory efficacy in a whole animal. In a mouse model of cardiovascular and metabolic disease, (R)-DOI suppressed several proinflammatory biomarkers, and did not cause any abnormal behaviors. This was an important finding because it indicated that psychedelics were not acting as a broad-spectrum immunosuppressive like a Journal Pre-proof.

Psychedelics potently suppressed several key proinflammatory biomarkers, but several were not affected at all. In addition, the (R)-DOI treatment group had significantly less total cholesterol in circulation, and glucose homeostasis was normalized, suggesting that psychedelics at low doses could also have beneficial effects to treat metabolic disease and diabetes. We have used standard and new paradigms for generating allergic asthma in rodents, including initial sensitization to an allergen, chicken egg white protein ovalbumin.

Injecting OVA into the animal (i.p.) once each on Day 0 and 7 or 14 to generate an IgE immune response and exposing it to nebulized OVA for 20 minutes on three consecutive days at least 14 days after the final OVA sensitization results in difficulty breathing. In acute prophylactic studies, we have used rats to study the effects of psychedelics on the lungs. We have found that (R)-DOI is effective in completely preventing pulmonary inflammation, mucus overproduction, and normalized Journal Pre-proof.

The effects of (R)-DOI on breathing mechanics were due to prevention of Th2 cell recruitment to the lungs, and prevention of eosinophila. However, the effects were not broad immunosuppressants, and only subsets of key proinflammatory molecules were blocked in expression. We examined 25 different psychedelics to block the effects of OVA exposure in rats. The primary outcome measure was whole body plethysmography (WBP), which is an excellent proxy measure for pulmonary inflammation.

We found that the efficacy of psychedelics to prevent inflammation was not correlated with calcium mobilization or -arestin2 recruitment at the 5-HT2A receptor, or behavioral potency. We generated new chemical entities maintaining anti-inflammatory potency and efficacy with reduced behavioral effects.

(R)-DOI was administered six hours prior to WBP testing to rescue pre-existing inflammation in the lungs. It had significant and specific anti-inflammatory effects on T-cells within the lung. In another system, we induced chronic asthma-like symptoms in mice. Treatment with (R)-DOI (nose only) was able to rescue chronic inflammation, mucus overproduction, and airway hyperresponsiveness, and to normalize collagen deposition and pulmonary fibrosis.

Psychedelics have been shown to potently prevent and ameliorate several types of inflammation in several cell and tissue types across several species, suggesting that they are a broad-based phenomenon. Further, psychedelics may have therapeutic utility in treating aspects of metabolic disease.

Bonson KR, Flanagan TW, Billac GB, Landry AN, et al (2021) investigated the effects of psychedelics on inflammation and cholesterol levels in a rat model of asthma, and Halberstadt AL, Chatha M, Klein AK, et al (2020) investigated the effects of psychedelics on inflammation and structural remodeling in a chronic mouse asthma model.

Shajib MS, Khan WI (2015), Urban JD, Clarke WP, von Zastrow M, et al (2007), Wu H, Denna TH, Storkersen JN, Gerriets VA (2019) and others have studied the role of serotonin in inflammation and immunity.