Researcher Charles Nichols Studies the Impact of Psychedelic Substances on Inflammation

This article accompanies “Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation,” and details the company’s research on how psychedelic medicines could improve immunity. 

A long time researcher of psychedelic substances is on the forefront of investigating how these materials may be used to reduce inflammation and support the immune system. 

These investigations may provide new opportunities for scientists to develop more effective treatments for diseases impacted by inflammation such as Alzheimer’s disease and cancer. 

Charles Nichols, a professor of pharmacology of the Louisiana State University Health Sciences Center, is examining how the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine, also known as DOI, affects immune function. 

The psychedelic effects of DOI have been compared to LSD, but unlike that material, it is not a Schedule 1 substance in the U.S. 

First synthesized by the esteemed psychedelic chemist Alexander Shulgin and documented in his book PiHKAL: A Chemical Love Story, a radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of Nichol’s father, David E. Nichols.

Charles Nichlols and his research team found that by triggering the serotonin receptor 5-HT2A, DOI affects the tumor necrosis factor, a cell signaling protein or cytokine that regulates the immune cells. 

Tumor necrosis factor, also known as TNF-alpha, is involved in systemic inflammation which is implicated in Alzheimer’s disease, cancer and other ailments. 

Other substances that trigger the 5-HT2A serotonin receptor, including TCB-2 and LSD, have also been found to inhibit TNF-alpha, with DOI being the most active. 

Nichols notes that psychedelic substances that impact serotonin receptors appear to work differently from existing treatments for inflammation. He says that presently available anti-inflammatories take three different forms: NSAIDs like ibuprofen or aspirin, corticosteroids like hydrocortisone, and biologic anti-inflammatories like antibodies. 

Nichols says these drugs all have harmful side-effects that may even be fatal, and don’t treat all diseases.

“Psychedelics do not act through any of these mechanisms, but instead very potently prevent inflammation through blockade of specific cellular inflammatory pathways contributing to disease,”says Nichols. “They are not immunosuppressant in nature, and as such are predicted to have less adverse side-effects.” 

In addition to triggering serotonin receptors and affecting TNF-alpha, Nicols says that DOI also affects the activity of nuclear factor-κB (NF-κB), a protein that controls cytokine and other inflammatory responses. 

“There are profound effects to both prevent and treat pre-existing symptoms of asthma, and vascular inflammation associated with cardiovascular disease that we have published, and are currently working on additional disease models,” says Nichols of his work with NF-κB.  

“These are complex inflammatory diseases involving more than TNF-alpha, so we believe that the anti-inflammatory effects are multifaceted and affect multiple pathways in several different tissue types.”

Cautious Investigations for a Range of Possible Treatments

Nichols is now the chair of the scientific advisory board for Eleusis Ltd., a London-based life sciences company founded in 2013. Eleusis is sponsoring Nichols’ research into a new substance called ELE-02 which is part of the ELE series of compounds. 

Part of the chemical class of substituted phenethylamines, which includes LSD, the ELE compounds also bind to serotonin receptors and trigger an anti-inflammatory response without a psychoactive effect. The ELE compounds are currently being investigated by Eleusis as a possible treatment for eye inflammation.  

Does research into the anti-inflammatory properties of psychedelic substances have the potential to develop treatments for diseases like COVID-19? Nichols cautions that there is presently insufficient information to determine if this might be true. 

“We have found that psychedelics are not immunosuppressants, and only target subsets of pathways that together are able to treat disease pathology,” says Nichols. 

“We have found that psychedelics are not therapeutic for inflammation associated with several disease models. Therefore, the therapeutic potential for psychedelics for a particular inflammatory-related condition will have to be evaluated on a disease-by-disease basis.”

Investigating DMT 

Nichols says that investigations into N,N-Dimethyltryptamine, also known as DMT, also shows promise for new treatments. He says that studies show that DMT interacts with the sigma-1 receptor which impacts both the central nervous system and immune cells. Triggering this receptor has significant impacts on immunity and inflammation, says Nichols. 

Attila Szabo, a National Institutes of Health Distinguished Investigator, studies DMT and its derivative, 5-MeO-DMT, both naturally-occurring in the body. He examines how these substances interact with the sigma-1 receptor when stimulated by E. Coli or influenza. 

Szabo found that these interactions reduced levels of inflammatory cytokines, while increasing levels of anti-inflammatory proteins. They also reduce activity of T-cells, which regulate inflammation.

Szabo notes that since the endogenous levels of these tryptamines, or those produced inside the body, are quite low in mammals, more research is needed to verify the physiological significance of these findings and how they can be applied to fight disease. 

“One of the possible mechanisms is that the levels of endogenous tryptamines can be massively upregulated [increased] at the site of infection or inflammation due to local cellular stress responses,” says Szabo. These molecules may achieve concentrations sufficiently high enough to be able to influence immune or inflammatory responses.”

Like Szabo, Nichols is cautious about the need for more research. “I think the jury is still out on sigma-1 receptors,” says Nichols. “[Existing investigations with DMT] have not been translated, to my knowledge, to any relevant animal models of human inflammatory disease for validation. Certainly more research needs to be performed in this area to better define the potential.”  

Impact of Mood and Emotions on Immunity

The psychoactive effects of psychedelics may also be relevant to immunity. Psychedelics produce altered states that can affect a person’s mood, emotional, or spiritual health in complex ways.

“It has been well known for years that the environment and experiences of an individual can influence the immune system,” says Nichols. “The immune system is highly complex, and its activity can be modulated by the brain, the gut, the food we eat, etc.”

Nichols points to the hypothalamic–pituitary–adrenal axis or HPA axis, which is a neuroendocrine system. It controls our reactions to stress and regulates many functions including mood, emotion, and the immune system. Studies have shown that MDMA and psilocybin can help alleviate disorders like PTSD, depression and anxiety, which are associated with dysfunction in the HPA axis.

According to Nichols, clinical studies investigating MDMA and psilocybin could also look at their impact on inflammation. 

“It’s quite conceivable that MDMA and psilocybin-mediated reductions in stress and anxiety, and normalization of HPA axis function, would result in a strengthened immune system,” says Nichols. “Clinical studies using MDMA and psilocybin that incorporate the measurement of inflammatory biomarkers may address this.”