Autoimmune Disorders | +30 articles

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Psychedelic treatment approaches to Autoimmune Disorders*

by Joel Ng, MA | Psychedelic Science Review | 11 Dec 2020

There is much research into psychedelic treatment of mental disorders, but psychedelics might be effective in treating autoimmune disorders as well.

After being banned in the United States in 1970, psychedelic compounds have recently made their way back into the attention sphere of the mainstream medical community for their efficacy in treating mental illnesses such as PTSD, depression, and anxiety. Current research into psychedelic drugs primarily focuses on their potential in treating mental illnesses, however, there exists some evidence for their potential in treating another field of illnesses called autoimmune disorders. In this article, the potential link between autoimmune disorders and mental illnesses will be explored, along with possible biochemical pathways that might explain psychedelic’s efficacy in treating both types of conditions.

What are Autoimmune Disorders?

Autoimmunity is when the body’s immune system malfunctions and attacks healthy tissue. The link between autoimmune disorders and mental disorders has received increasing attention in the past twenty years. Being diagnosed with an autoimmune condition increases one’s chances of being diagnosed with a mood disorder. Research into how these two disorders are related has revealed several potential pathways, ranging from chronic inflammation, dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis), disruptions in the gut microbiome, and chronic stress and trauma. Examining these potential causes, there are many points in which psychedelics might be acting on to explain their treatment efficacy.

Psychedelic Pharmacology

Classic psychedelics exhibit agonistic activity at various serotonin (5-HT) receptors, with the most commonly shared feature being 5-HT2A receptor agonist binding. The table below details some common psychedelics and the receptor subtypes they are known to bind to.
​

Psychedelic​	5-HT Subtype Affinity​	Other Receptor Affinity​
LSD​	1A, 1B, 1D, 1E, 2A, 2B, 2C, 5A, 6, and 7​	Dopaminergic receptors subtypes D1 and D2​
Psilocin​	1A, 1D, 2A, 2C​	Adrenergic alpha A and B, dopamine D3, histamine H1​
DMT​	1A, 1B, 1D, 2A, 2B, 2C, 5A, 6 and 7​	Glutamate receptors, dopamine, acetylcholine, and the opioid-like receptor Sig1R​

Other psychedelic compounds like ketamine affect N-Methyl-D-aspartate (NMDA) receptors as well, which research shows might affect autoimmune disorders via its effect on glutamate pathways.

Inflammation and Immune Modulation

Research has shown that chronic inflammation plays a key role in autoimmune disorders. Dysregulated inflammation is present in many autoimmune disorders, such as Lupus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren’s Syndrome. Correspondingly, there has been much research into the 5HT system and its inflammation and immune regulation properties. Sig1R, another receptor that psychedelics like DMT effect, also modulates inflammatory and immune responses. Via their effect on the 5HT system and Sig1R system, psychedelics might have anti-inflammatory properties that could explain their potential in treating autoimmune disorders.

Trauma and Stress

Another pathway where mental disorders and autoimmune disorders might be linked lies in stressful and traumatic childhood events. Adverse childhood experiences (ACEs) are strongly correlated with autoimmune disorders in later life. Research into the effect that psychological stress has on the immune system reveals that psychological stress can compromise the immune system function as well. This leads to disorders such as food sensitivity, HPA axis dysregulation, and leaky gut syndrome, all of which are strongly correlated with autoimmune disorders. This research hints at how psychedelic treatment of trauma-related illnesses might also improve physiological ailments related to trauma.

Glutamate and Brain-Derived Neurotrophic Factor

Glutamate excitotoxicity involves overactive glutamate receptors in the brain. Chronic excitation of glutamate receptors can contribute to oxidative stress, causing brain damage. Glutamate excitotoxicity is related to depression, addiction, and other neurodegenerative diseases. Examining ketamine’s effect on NMDA glutamate receptors, it is possible that ketamine’s effect on depression might be related to glutamate regulation. Agonists of the Sig1R receptor subtype have also shown to be neuroprotective glutamate excitotoxicity. Also, DMT has been shown to have potent neuroprotective effects via the Sig1R.

Psychedelics might increase levels of brain-derived neurotrophic factor (BDNF) gene expression, which facilitates neurogenesis. Low BDNF expression has been linked to depression, anxiety, schizophrenia, and neurodegenerative diseases. This pathway is related to 5-HT2A receptor agonist activity of classic psychedelics – in an experiment, administration of a 5-HT2A antagonist reduced the neuroplastic effects of classic psychedelics LSD, DMT, and DOI. It is feasible that the BDNF-upregulating qualities of psychedelics could reduce the inflammatory effects of glutamate excitotoxicity in autoimmune disease.

Gut Microbiome Dysregulation

The gut microbiome refers to the microorganisms present in the gastrointestinal tract (GIT). The gut microbiome produces many neurotransmitters in the body, including dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid (GABA). Chronic infections with bacteria, fungi, and viruses are common in those with autoimmune disorders. Microbiome bacterial populations appear to play a significant role in a number of immune responses, and influence the presence of autoimmune disorders.

Psychedelic plants like ayahuasca and peyote have been shown to exhibit anti-microbial properties, which may explain how psychedelics can effectively treat autoimmune conditions. Also, experiments that introduced serotonin to the gut microbiome indicate the presence of a bidirectional signalling system between the host serotonin system and the gut microbiome. This highlights the potential for psychedelic serotonin analogues psilocybin, DMT, and 5-MeO-DMT interacting with bacterial receptors.

Lastly, the psychological benefits of psychedelics may indirectly alter microbial communities in the GIT via induced changes in vagal nerve tone and stress response. Several studies examining the effects of chronic stress and PTSD on microbiome pattern associations found a link between stress and microbiome health. The psychological and neurological benefits from a psychedelic experience may cause biochemical cascades in the HPA axis and the nervous system, which may influence the ecology of microbial populations.

Conclusion

Autoimmune disorders involve a malfunction of the body’s immune system, causing it to attack the body it is meant to protect. While the causes of autoimmune diseases are varied, several pathways have been proposed involving neurotransmitter dysfunction, gut microbiome dysfunction, and an assortment of other dysregulations present in the nervous system’s biochemistry.

There appears to be an immensely complex biochemical network involving the peripheral nervous system, the gut microbiome, and the immune system. This helps explain psychedelics’ well-known efficacy in treating mental illnesses and also highlights the potential for psychedelics to treat autoimmune disorders.

Further research into the potential biochemical pathways that connect these areas of the body may provide more effective psychedelic treatment programs for mental illnesses. Also, these studies lay the groundwork for using psychedelics for treating of a whole other class of disorders involving the immune system.

*From the article here :

It Takes Guts: Psychedelic Treatment Approaches to Autoimmune Disorders

There is much research into psychedelic treatment of mental disorders, but psychedelics might be effective in treating autoimmune disorders as well.

psychedelicreview.com

 

[mr peabody]

Rheumatoid arthritis is an autoimmune condition causing concern around the world.

Global spread of autoimmune disease blamed on western diet

Rheumatoid arthritis is one of the autoimmune conditions that are causing concern around the world.

by Robin McKie, Observer science editor | The Guardian | 9 Jan 2022

More and more people around the world are suffering because their immune systems can no longer tell the difference between healthy cells and invading micro-organisms. Disease defences that once protected them are instead attacking their tissue and organs.

Major international research efforts are being made to fight this trend – including an initiative at London’s Francis Crick Institute, where two world experts, James Lee and Carola Vinuesa, have set up separate research groups to help pinpoint the precise causes of autoimmune disease, as these conditions are known.

“Numbers of autoimmune cases began to increase about 40 years ago in the west,” Lee told the Observer. “However, we are now seeing some emerge in countries that never had such diseases before."

"For example, the biggest recent increase in inflammatory bowel disease cases has been in the Middle East and east Asia. Before that they had hardly seen the disease.”

Autoimmune diseases range from type 1 diabetes to rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. In each case, the immune system gets its wires crossed and turns on healthy tissue instead of infectious agents.

In the UK alone, at least 4 million people have developed such conditions, with some individuals suffering more than one. Internationally, it is now estimated that cases of autoimmune diseases are rising by between 3% and 9% a year. Most scientists believe environmental factors play a key role in this rise.

“Human genetics hasn’t altered over the past few decades,” said Lee, who was previously based at Cambridge University. “So something must be changing in the outside world in a way that is increasing our predisposition to autoimmune disease.”

This idea was backed by Vinuesa, who was previously based at the Australian National University. She pointed to changes in diet that were occurring as more and more countries adopted western-style diets and people bought more fast food.

“Fast-food diets lack certain important ingredients, such as fibre, and evidence suggests this alteration affects a person’s microbiome – the collection of micro-organisms that we have in our gut and which play a key role in controlling various bodily functions,” Vinuesa said.

“These changes in our microbiomes are then triggering autoimmune diseases, of which more than 100 types have now been discovered.”

Both scientists stressed that individual susceptibilities were involved in contracting such illnesses, ailments that also include celiac disease as well as lupus, which triggers inflammation and swelling and can cause damage to various organs, including the heart.

“If you don’t have a certain genetic susceptibility, you won’t necessarily get an autoimmune disease, no matter how many Big Macs you eat,” said Vinuesa. “There is not a lot we can do to halt the global spread of fast-food franchises. So instead, we are trying to understand the fundamental genetic mechanisms that underpin autoimmune diseases and make some people susceptible but others not. We want to tackle the issue at that level.”

This task is possible thanks to the development of techniques that now allow scientists to pinpoint tiny DNA differences among large numbers of individuals. In this way, it is possible to identify common genetic patterns among those suffering from an autoimmune disease.

“Until very recently, we just didn’t have the tools to do that, but now we have this incredible power to sequence DNA on a large scale and that has changed everything,” said Lee. “When I started doing research, we knew about half a dozen DNA variants that were involved in triggering inflammatory bowel disease. Now we know of more than 250.”

Such work lies at the core of Lee and Vinuesa’s efforts, which aim to find out how these different genetic pathways operate and unravel the many different types of disease doctors are now looking at. “If you look at some autoimmune diseases – for example, lupus – it has become clear recently there are many different versions of them, that may be caused by different genetic pathways,” said Vinuesa. “And that has a consequence when you are trying to find the right treatment.

“We have lots of potentially useful new therapies that are being developed all the time, but we don’t know which patients to give them to, because we now realise we don’t know exactly which version of the disease they have. And that is now a key goal for autoimmune research. We have to learn how to group and stratify patients so we can give them the right therapy.”

Lee also stressed that surging cases of autoimmune diseases across the world meant new treatments and drugs were now urgently needed more than ever before. “At present, there are no cures for autoimmune diseases, which usually develop in young people – while they are trying to complete their education, get their first job and have families,” he said.

“That means growing numbers of people face surgery or will have to have regular injections for the rest of their lives. It can be grim for patients and a massive strain on health services. Hence the urgent need to find new, effective treatments.”

Global spread of autoimmune disease blamed on western diet

New DNA research by London-based scientists hopes to find cure for rapidly spreading conditions

www.theguardian.com

 

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Toronto man treats Guillain-Barré syndrome with psilocybin mushrooms*

by Sam Riches | Regina Leader-Post | 22 Mar 2021

Guillain-Barre syndrome is a rare inflammatory disorder in which your body's immune system attacks the nerves. Weakness and tingling in your extremities are usually the first symptoms. These sensations can quickly spread, eventually paralyzing your whole body.

Michael Reynolds knew he was in trouble when he started losing the feeling in his fingertips. A musician and multi-instrumentalist, Reynolds had recovered from a case of Guillain-Barré syndrome, a disorder where the immune system attacks the nervous system, about a decade earlier.

Reynold’s initial case led to a five-week hospital stay, followed by six months in a wheelchair, and lasting nerve damage. He was treated with intravenous injections of immunoglobulins — proteins produced by the immune system that attack infecting organisms — and physiotherapy.

After several months of treatment, he made a significant recovery. But then the numbness in his hands returned.

He started cancelling gigs as his condition quickly worsened. Within a week he had almost no feeling left in his fingers. “It was affecting my playing really severely,” Reynolds tells The GrowthOp. “My drumsticks were flying out of my hands. I was very, very worried.”

Frustrated by traditional treatments and previous health care experiences, Reynolds started researching natural remedies. He’d had success using medical cannabis to manage pain symptoms in the past, so when a friend on Facebook suggested he try psilocybin, the ingredient in magic mushrooms, he decided to give it a shot.

After consuming his first dose of psilocybin, the feeling in his fingers started to return. So he took them again the next day, and then again the next day. Each time, he consumed about a gram and a half of mushrooms, a relatively low dose.

“Then it pretty much resolved,” he says. “My hands had full gripping strength. I had a proper feeling in my hands again.”

Since then, he’s managed his symptoms with a few annual doses of psilocybin, he says. He does not have a legal medical exemption, so he’s reliant on sourcing the mushrooms from the illicit market.

At a psychedelics conference several years ago, Reynolds shared his story and asked if anyone was aware of any research regarding psilocybin’s impact on Guillain-Barré syndrome. He wasn’t surprised to hear the answer was no.

“It’s a very niche thing,” he says. “And there’s not a lot of research on it.”

However, afterward, he was approached by a man with terminal cancer who was also taking psilocybin medicinally and growing his own supply. “He didn’t really have a long time left so he was just growing them and giving them to people for free,” Reynolds says.

The man offered Reynolds some of his mushrooms but that supply has since run out. He expresses some frustration about having to acquire psilocybin on the illicit market but he’s had continued success with the therapy.

“The world needs to know that this works,” he says.

Guillain-Barré syndrome is a relatively rare disorder with many unknowns. Most who develop GBS make a full recovery but some symptoms, like vision issues and difficulty swallowing, can persist. In severe cases, it can lead to respiratory failure and death.

According to the National Institute of Neurological Disorders and Stroke, GBS affects about one person in 100,000 each year and can occur at any age.

The cause of the disease is unknown and there is no known cure, though cases usually follow a respiratory or gastrointestinal viral infection.

A study published in the journal Pathogens late last year cited the only known case of COVID-19 triggering a recurrence of GBS, but there have been many reports of an association between COVID-19 and the disorder.

Dr. Michael Verbora is the medical director at Field Trip Health, a Toronto-based company that develops and delivers psychedelic therapies. He hasn’t used psilocybin to treat GBS clinically or encountered it in medical literature, but he says he’s not surprised to hear it could provide relief from symptoms of GBS.

“There are very good plausible mechanisms by which a disease like Guillain-Barré could get better through a psychedelic drug that has anti-inflammatory and antioxidant effects in the brain,” he says. “There’s not a lot of research on it but it makes a lot of sense to me.”

Dr. Verbora compares Guillain-Barré to multiple sclerosis in that both diseases eat away at the nerve lining, though GBS patients recover, and multiple sclerosis is a chronic condition.

“Inflammation takes place in the brain and it’s an immune reaction. And the proteins, the myelin sheath on the nerve cells, get digested and it affects your whole nervous system,” Dr. Verbora says. “So your peripheral nervous system doesn’t work. You can get sensory changes and motor changes. You can get paralyzed from the neck down.”

"Theoretically, through its anti-inflammatory properties, psilocybin could reduce inflammation in the brain and counteract the effects of an autoimmune reaction like Guillain-Barré Syndrome," Dr. Verbora explains.

He adds that he knows patients with Guillain-Barré who find cannabis, and its anti-inflammatory properties, to be helpful.

“It has similar anti-inflammatory effects on the brain tissue,” he says. “But again, unfortunately, the gap in knowledge and research is still there with these plants and botanicals.”

"Field Trip is actively researching treating inflammatory issues with psilocybin," he says, "along with a number of autoimmune conditions that might benefit from psilocybin and similar drugs."

“Guillain-Barré is probably not going to go anywhere. So it would be really interesting to study, not just this, but any type of neurological disorder,” he says. “It’d be really interesting to know if these anti-inflammatory molecules on the brain have long-term therapeutic effects.”

Reynolds says it’s been several months since his last dose of psilocybin. In addition to treating his GBS, he says psilocybin has also helped to ‘“significantly lessen” his Tourette syndrome.

“The thing that I hope people realize is that there are some neurological uses for psilocybin that they need to look into,” he says.

To his frustration, his own doctor, who he sought out because he wrote a book about natural remedies, appeared unmoved by his experience with psilocybin.

“He didn’t really respond,” Reynolds says, adding that he "didn’t press further on the subject as he feared his quality of care might drop."

Until the medical community offers a better treatment option, Reynolds plans to continue consuming small amounts of mushrooms a few times a year. Since 2016, he says he hasn’t involved a doctor in his treatment of the disorder.

“Guillain-Barré is one of those things where it’s rare enough that there’s no priority on it at all,” he says. “I just want people to know. This is too important to keep to myself.”

*From the article here :

This Toronto man is treating a rare neurological disorder with psilocybin mushrooms

Guillain-Barré syndrome, a disorder where the immune system attacks the nervous system, has no known cause or cure.

leaderpost.com

 

[mr peabody]

Institute of Clinical Medicine, University of Oslo

Psychedelics as a novel approach to treating autoimmune conditions

Caitlin Thompson, Attila Szabo | December 2020

With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the AiD patient population. Classic serotonergic psychedelics have recently been gaining public and professional interest as novel interventions to a number of mental health afflictions. Psychedelics have also been shown to be able to modulate immune functions, however, while there has been great interest to researching into their psychotherapeutic applications, there has so far been very little exploration into the potential to treat inflammatory and immune-related diseases with these compounds. A handful of studies from a variety of fields suggest that psychedelics do indeed have effects in the body that may attenuate the outcome of AiD. This literature review explores existing evidence that psychedelic compounds may offer a potential novel application in the treatment of pathologies related to autoimmunity. We propose that psychedelics hold the potential to attenuate or even resolve autoimmunity by targeting psychosomatic origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations.

1. Introduction

The incidence of autoimmune diseases (AiD) has been steadily increasing in the last decades, as reported by The National Institute of Health (NIH) and other sources. There are currently over 100 defined autoimmune-related diseases affecting roughly 50 million Americans, or 20 % of the population according to the American Autoimmune Related Diseases Association (AARDA). The NIH also calculates that over $100 billion in health care costs is spent annually in the United States on treating those with autoimmune diseases, compared to cancer which has an estimated cost of $50 billion annually. It is conservatively estimated that 80 % of those affected by AiD are women. There are several theories for why women are more susceptible to AiDs, but known reasons remain unclear. Different theories for the increased prevalence of AiDs include overuse of antibiotics, increase in environmental toxin exposure, increased caesarian births, reduced breast feeding, improvement of diagnostic tools, increased awareness of AiDs and increased societal stressors.

Autoimmunity is defined as the loss of tolerance to self-antigens in which the immune system attacks healthy tissues in an individual. While there are different characteristics of expression and tissues affected amongst the autoimmune disorder types, there are many shared mechanisms of action and potential origins. Many diseases that were initially considered to be unrelated to autoimmunity are now being reexplored as autoimmune-related, especially in the field of psychiatry. This includes major depressive disorder (MDD), schizophrenia, Parkinson’s disease, Alzheimer’s disease and Amyotrophic Lateral Sclerosis.

While the causes of AiDs are controversial, they appear to be multifactorial with many facets that contribute to their development such as genetic predisposition, environmental triggers, and psychosocial stress. There is strong evidence that traumatic experiences such as Adverse Childhood Events (ACEs) and prolonged stress may contribute to the development of an AiD. AiDs often encompass a variety of symptoms and features. Common characteristics observed among the various types of AiD include increased vascular and epithelial (e.g. intestinal) permeability, chronic inflammation, the presence of chronic infections, dysregulated Hypothalamic-pituitary-adrenal axis (HPA axis), mitochondrial dysfunction, and microbiome dysbiosis. Symptoms can manifest as chronic fatigue, allergies, psychiatric and mood disorders, pain, rashes, GI distress, poor cognition and more.

Currently, biologics and immunosuppressive drugs are the primary treatment tools for autoimmune disorders along with non-steroidal anti-inflammatory drugs, steroids and antidepressants. However, immunosuppressant and biologic medications designed to resemble antibodies, receptors and other immunological factors can result in an immune compromised state, putting the affected population at risk for serious infections or immune-related illnesses. Although existing biological drug approaches show evidence for producing positive treatment outcomes in some individuals, the increased risks for infection, malignancy and cardiovascular conditions, as well as contradicting results in efficacy studies have prompted interest in exploring other approaches to treating AiDs.

2. The immunopharmacology of psychedelics

2.1. The link between autoimmunity and mental disorders

The comorbidity between autoimmune conditions and mental and mood disorders, such as MDD, anxiety, schizophrenia, and bipolar disorder has become apparent in the last two decades. There is a higher risk of developing clinical depression or mood disorders if one has been diagnosed with an autoimmune condition. While there is certainly argument that the burden of having an autoimmune condition could contribute to MDD, researchers suggest that depression and anxiety symptoms could perhaps be a result of autoimmune mechanisms and resulting inflammation occurring in the nervous system, or via dysregulated inflammatory cytokine loops between peripheral and brain-resident immune cells. Potentially by their immunomodulatory activity and in part through the mobilization of cell-intrinsic neuroprotective mechanisms, psychedelics may represent a promising intervention for autoimmune-related depression and other mental illness.

2.2. Pharmacology of psychedelics substances

Psychedelic compounds have recently made their way back into mainstream medical research. Psychedelic compounds such as LSD, psilocybin, DMT, ibogaine and mescaline have been of great interest based on their apparent high efficacy for treating mental afflictions and their impressive safety profile. Psychedelic drugs were popularized in the 1960s by researchers such as Timothy Leary, Ram Dass, Terrence McKenna and other enthusiasts. Between the 1960’s and the 1980’s a number of scientific studies were being conducted on psychedelic substances including biochemical, pharmacological and psychological studies. Therapists were experimenting with using psychedelics as adjuncts to various psychotherapy methods. Due to radical activism and drug propaganda, psychedelics were scheduled as Schedule I substances by the Controlled Substances Act in 1970 and were made illegal to consume, possess or distribute. Contradictory to this scheduling decision, research currently suggests that class psychedelic compounds do not show evidence of addiction potential and exhibit anti-addiction properties while also appearing to be generally physiologically safe, non-toxic and exhibiting minimal individual and societal harms. This prohibition resulted in an abrupt halt in research on psychedelics. In the early 90’s there was the start of a new renaissance in psychedelic research with the work of Risk Strassman on intravenous DMT administration in humans. Psychedelic research currently is a rapidly accelerating field in science, psychology and medicine.

“Classic” psychedelics generally refer to LSD, psilocybin, mescaline, ibogaine, DMT, and 5-MeO-DMT, and are typically defined by their indole-containing molecular structure as illustrated in Fig. 1. Non-classic psychedelics such as ketamine and MDMA may have some similar receptor activity and hallucinogenic properties, but lack this fundamental indole structure. Classic psychedelics typically and predominately exhibit agonistic activity at various serotonin (5-hydroxytryptamine, 5-HT) receptors, with the most commonly shared feature being their 5-HT2A receptor agonist binding. The classic psychedelics vary in their receptor binding properties but overall show binding affinity for a variety of receptors including 5-HTR subtypes. LSD [Fig. 1.2] is known to bind to 5-HT1A, 1B, 1D, 1E, 2A, 2B, 2C, 5A, 6, and 7 as well as dopaminergic receptors subtypes D1 and D2. Psilocin, the active metabolite of psilocybin [Fig. 1.3], binds to 5-HT1A, 1D, 2A, 2C but does not bind to dopaminergic receptors. Mescaline exhibits the highest binding affinity to the 5-HT2A and 2C receptors.
​

Fig. 1. Structure of classic psychedelic compounds. Many classic psychedelics share an indole structure
within their molecular makeup, often characterizing them as serotonin analogues and agonists.

DMT [Fig. 1.4] and its psychopharmacologically more potent analogue 5-MeO-DMT [Fig. 1.5] bind to the 5-HT1A, 1B, 1D, 2A, 2B, 2C, 5A, 6 and 7 receptors, as well a number of iontropic and metabotropic glutamate receptors, dopamine, acetylcholine, Trace-Amine-Associated Receptors (TAAR), and the opioid-like receptor sigma-1 (Sig1R). DMT is found in trace amounts in most plant, animal (including humans) and fungal organisms with some plants, such as the Acacia and Mimosa genera, containing more substantial amounts. It is one of the components in the traditional Amazonian brew ayahuasca, which combines DMT-containing plants, such as Psychotria viridis with the Monoamine Oxidase Inhibitor (MAOI)-containing Banisteriopsis caapi (ayahuasca) vine to potentiate a psychoactive effect from the oral administration of DMT Fig. 2. The ayahuasca vine contains harmala alkaloids, such as harmine, harmaline and tetra-harmaline that act as MAOIs in the ayahuasca brew. Typically, the DMT contained in the ayahuasca brew is considered the psychoactive constituent, however a ritual called Natemamu does exist in the Shuar culture in which only the B. caapi vine is used, suggesting that at certain doses, the MAOIs from the ayahuasca vine on its own can create a hallucinatory experience.
​

Fig. 2. Naturally occuring psychedelics. (2.1) Banisteriopsis caapi, also known as the ayahuasca vine, contains monoamine-oxidase inhibitors which, when combined with a DMT-containing plant, such as Psychotria viridis, make up the psychoactive brew known as ayahuasca. (2.2) Incilius alvarius, commonly known as the Colorado River Toad, excretes 5-MeO-DMT in its defensive secretions. (2.3) Lophophora williamsii, or Peyote, has been used as a sacrament in traditional Native American ceremonies for thousands of years. (2.4) Psilocybe cubensis is a common species of psilocybin mushrooms. Images sourced from Wikipedia.

5-MeO-DMT is also found in many plants and animals including in the Amazonian shamanic snuff called “yopo” (Anadenanthera peregrinaa), mammalian tissues and within the defensive secretion of the Colorado River Toad (Incilius alvarius) Fig. 2. Because of the degradation of the DMT and 5-MeO-DMT molecules by MAO in the digestive tract, the most common way of ingesting these substances is through inhalation via vaporization. There is a long history of mixing DMT with MAOIs in various South American traditions, however, there does not appear to be any traditional practices mixing 5-MeO-DMT with MAOIs as it appears to be potentially dangerous due to higher 5-HT binding affinity and disparate metabolic degradation pathways.

Some “not-so-classic” psychedelic compounds, such as ketamine and ibogaine have complex pharmacology that is not 5-HT dominant. Ketamine [Fig. 1.6] exhibits non-competitive NMDA receptor antagonism, while displaying monoaminergic release as well as cholinergic, adrenergic, μ- and δ-opioid receptor binding. Ibogaine [Fig. 1.7], an alkaloid from the Tabernanthe iboga shrub, has a highly promiscuous binding affinity for the 5-HT and dopamine (DA) transporters, non-competitive antagonism for several types of nicotinic AChR, NMDA Glu, μ-, δ- and к- opioid, Sig1R and Sig2 receptors. MDMA [Fig. 1.8], while generally referred to as an empathogen rather than a true psychedelic, releases presynaptic vesicular monoamines 5-HT, DA and norepinephrine (NE) while inhibiting their reuptake into the presynaptic cell, flooding the synapse. It does however have some agonistic binding affinity to 5-HT2A receptors like classic psychedelics, as well as muscarinic receptor 1, and the H1 histamine receptor.

Although at this point there has been increased exploration into the use of psychedelics as tools for the treatment of MDD, post-traumatic-stress-disorder (PTSD), addiction, eating disorders, anxiety and other mental disorders, there has been very little investigation into the immune modulating and anti-inflammatory effects of psychedelics. Biochemical and anecdotal evidence suggests that psychedelics could provide a novel treatment approach to AiDs and other immune and inflammatory-related diseases. It is likely that psychedelics can attenuate autoimmunity via a number of different mechanisms. Psychedelics may directly and indirectly target a number of physiological factors and resulting dysfunctions in AiDs. This review covers the current evidence that psychedelics may offer therapeutic solutions and potential modalities for the attenuation of AiDs.

2.3. Inflammation and immune modulation

In AiD, rampant chronic inflammation is a keystone feature. Elevated levels of cytokines and their dysfunctional regulation involving interleukin(IL)-6, IL-1β, IL-17, tumor necrosis factor-α (TNF)-α, IL-12, interferon(IFN)-γ and others are a shared feature observed in many AiDs including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), systemic sclerosis, and Sjögren's syndrome. Lipopolysaccharide (LPS) is an inflammatory component of the cell wall of Gram-negative bacteria that can induce inflammation and excessive oxidative stress that may play a role in elevated inflammatory biomarkers seen in those with AiD diseases. Those with AiD display auto-antibodies and yet also display immunodeficiency. Immune modulation appears to be a feasible target in approaching the treatment of AiD.

While the area of research is quite underdeveloped, there is some evidence that psychedelic compounds have anti-inflammatory and immune-modulating effects Table 1. For instance, LSD displays the ability to suppress the proliferation of B-lymphocytes, as well as the production of the pro-inflammatory cytokines IL-2, IL-4, and IL-6 in in vitro splenic lymphocytes derived from 6−8 year old female B6C3F1 rats at concentrations of LSD between 1–100 μM. The same study observed that administered doses of LSD between 0.001−0.1 μM in rat lymphocytes increased the number of Natural Killer (NK) cells, while concentrations of 100 μM suppressed NK cell production. In another study, the substituted amphetamine DOI, was shown to reduce TNF-α levels in 10 week old adult male C57BL/6 J mice via agonism of the 5-HT2A receptor in doses ranging from 0.01 μM/kg to 10μM/kg. Furthermore, in a recent study the same group expanded the previously observed anti-inflammatory effects of 5-HT2A agonism to additional psychedelics in a rat model of lung inflammation.

Table 1. Receptor modulatory and physiological effects of psychedelics.
​

Classic psychedelics	Receptors of interest in Autoimmune Disease	Resulting effect	References
LSD	5-HT2A (partial agonism)	TNFα, IL-6, IL-2
	TrK-B (agonism)	^BDNF, ^ mTOR
Psilocybin	Trk-B (agonism)	^BDNF, ^ mTOR
DMT & 5-MeO-DMT	Sig1R (agonism)	^IL-10, IL-1β, IL-6, TNFα CXCL8/IL-8
	5-HT2A (agonism)	^BDNF, ^ mTOR
	Trk-B (agonism)	Glu excitotoxicity
		ROS damage
		Cell apoptosis
mescaline (peyote)	Trk-B (agonism)	^BDNF, ^ mTOR
		penicillin resistant staphylococcus bacteria
ayahuasca (DMT & Harmala alkaloids)	5-HT2A	Cortisol
	Sig1R	^BDNF, ^ mTOR
	Trk-B

​

Non-classic psychedelics	Receptors of interest in Autoimmune Disease	Resulting effect	References
Ketamine	NMDA Glu (antagonism)	^BDNF, ^ mTOR, Glu excitotoxicity
		IL-6, TNFα
MDMA (in assisted psychotherapy)	VMAT, SERT	Amygdala response
		HPA-axis dysregulation
Harmine/Harmaline	MAO (inhibitor)	^5-HT, NF-kB, HSV-2 ^NK cell numbers/activity, Glu excitotoxicity
Ibogaine/Noribogaine (metabolite)	5-HT2A (partial agonism)	^BDNF, ^ mTOR
	Sig1R (agonism)
	TrK-B (agonism)

One human study where ayahuasca was given to healthy volunteers recorded blood levels of lymphocytes and found a decrease in CD4 and CD3 cells, and an increase in NK cells. This was compared to controls and subjects treated with D-amphetamine. Another, more recent human study reported significant decrease in C-reactive protein levels in the blood in both healthy and depressed volunteers, but no significant reduction in IL-6 blood levels. In addition, in a human intramuscular ketamine study, levels of proinflammatory markers, including C-reactive protein (CRP), IL-6, and TNF-α, were examined prior to initiation of test infusions, 40 min post-infusion, 240 min post-infusion, and on day 3 and day 7 post-fusion in patients who received 0.5 mg/kg or 0.2 mg/ kg of R/S-ketamine hydrochloride. Acute reductions of IL-6 and TNF-α were found in the 0.5 mg/kg group between 40 min. and 240 min post-infusion, but not in day 3 or day 7. Reductions in pro-inflammatory cytokine levels were directly correlated with depression scores, except on days 3 and 7 when depression scores improved despite cytokine levels returning to pre-infusion baselines. Interestingly, a different study obtained contradicting results showing an increase in IL-6 post-infusion and no correlation of cytokine levels with anti-depression outcome, suggesting that more studies need to be conducted to understand the complex systemic immune effects of ketamine and its metabolites.

There is substantial literature on the 5-HT system and its complex inflammation and immune-regulating abilities in tissue specific manners. Functional studies showed that 5-HT modulates the release of IL-1beta, IL-6, IL-8/CXCL8, IL-12p40 and TNF-α, while it has no effect on the production of IL-18 and IFN-gamma in LPS-stimulated human blood monocytes. 5-HT can also modulate human macrophage polarization and dendritic cell functions, and can contribute to the maintenance of an anti-inflammatory state via 5-HT2B and 5-HT7 receptor binding. Given the role of the 5-HT system in immune-modulation and inflammatory properties, it is highly likely that there are undiscovered immune and inflammatory effects from exposure to psychedelic compounds due to their serotonergic activity. In the previously mentioned study where DOI was observed to reduce TNF-α in mice, in groups where the 5-HT2A antagonist drug M100907 was administered, the reduction in TNF-α was not observed supporting the theory that the 5-HT2A receptor and the 5-HT system as a whole may be fundamental to creating downstream immunological and inflammatory-regulating effects.

In addition to the 5-HT receptors, DMT and 5-MeO-DMT also have high binding affinity for the Sig1R. The Sig1R plays a fundamental role in the regulation of different cellular mechanisms such as mitochondrial function, apoptosis, proliferation, and neuroprotection. Sig1R also modulates inflammatory and immune responses by regulating the activation of the transcription factors nuclear factor kappa B (NF-кB) and several mitogen-activated protein kinases (MAPKs). Both NF-кB and MAPKs are important regulators of gene transcription involving immune responses and the production of inflammatory cytokines.

Abnormal Sig1R functions have been implicated in a number of psychiatric and inflammatory-related conditions such as MDD, Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, immune reactions, and proliferation of cancer cells. Activation of the Sig1R is also pivotal in facilitating stress responses. Dysregulated NF-кB and MAPK activity patterns have been implicated in a number of AiD pathologies. One study showed evidence of suppression of pro-inflammatory NF-кB cytokine production by administration of harmine, a component of the ayahuasca vine, via intraperitoneal injection at doses of 25 and 50 mg/kg, in response to treatment with LPS in Male Kunming mice to induce acute kidney injury. Another study found that harmine inhibited tumor necrosis factor-α (TNF-α)- and LPS-induced NF-κB transactivity and nuclear translocation in mouse macrophage RAW 264.7 cells when treated with concentration between 2.5–25 μM. 5-MeO-DMT was also found to inhibit the NF-κB signaling pathway in human cerebral organoids exposed to concentrations between 23 nM to 7.11 μM, and examined for proteomic analysis via mass spectrometry. In other in vitro and animal in vivo studies, DMT and 5-MeO-DMT have been shown to increase anti-inflammatory IL-10 while decreasing the levels of the pro-inflammatory IL-1β, IL-6, TNF-α, and the chemokine CXCL8/IL-8 in human monocyte-derived dendritic cells at concentrations of 100 μM. DMT also exhibited considerable neuroprotective and anti-neuroinflammatory effects in a rat model of stroke where male Wistar rats received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h after induced transient middle cerebral occlusion.

Furthermore, inhaled 5-MeO-DMT has recently been reported to decrease salivary IL-6 levels in a study involving a small group of human subjects. There results suggest that serotonergic psychedelics may emerge as potential candidates in the treatment of autoinflammatory and autoimmune conditions Table 1. Since pharmaceutical grade DMT and other tryptamine analogs designed for human clinical trials are already available or will soon enter the market, testing the in vivo physiological effects of serotonergic psychedelics in humans is now closer than ever before.

2.4. Trauma and emotional effects

A number of studies have suggested that significant or prolonged stress, especially in early childhood, contributes to the development of a number of diseases including AiD. The severity of childhood trauma can be clinically assessed by scoring ACEs (Adverse Childhood Experiences). Many studies have found strong correlations between ACEs and the statistical risk of developing an AiD including studies looking at associations between childhood stress and RA, SLE, and fibromyalgia.

The downstream physiological detriment due to stress and vagal nerve disruption is well documented in the literature and appears to play a significant role in the development of an AiD. Psychological stress and psychoemotional trauma can severely compromise the immune system leading to increased risk of chronic infections and gut dysbiosis. Psychosocial stress increases inflammatory cytokines, oxidative stress, glutamate excitotoxicity, inhibits effective digestion and nutrient absorption and contributes to HPA axis dysfunction. Stress has been found to increase intestinal permeability which can lead to food sensitivities and LPS-induced inflammation due to gut-blood transepithelial bacterial translocation (“Leaky Gut syndrome”). All of these inflictions are hallmark characteristics of patients with AiD, further supporting the hypothesis that stress may play a significant role in AiDs.

The psychedelic compounds psilocybin, LSD, MDMA, and ayahuasca are currently being explored for their promising potential to assist in treating trauma-derived illnesses such as PTSD, depression, and addiction. The research with MDMA assisted psychotherapy for PTSD is currently the furthest along in its drug development and approval process by the FDA than any other psychedelic-related compound with psilocybin, cannabis and ayahuasca following closely behind. MDMA assisted psychotherapy has received breakthrough status by the FDA, accelerating its entry into mainstream medical practice. The MDMA therapy for PTSD protocol developed by MAPS, consisting of two MDMA-assisted therapy sessions with the patient receiving 125 mg of MDMA orally in conjunction with non-directive psychotherapy, along with preparatory and post non-MDMA therapy sessions, has so far exceeded all existing treatments for PTSD in its symptom remission statistics. Although the classic psychedelics have not been clinically established as strongly for PTSD as MDMA has, there is evidence that they also hold potential for stress and trauma-oriented applications. There are several human and non-human primate studies that suggest that the DMT-containing ayahuasca brew has modulatory effects on salivary cortisol response and plasma cortisol in both healthy normals and in individuals with treatment-resistant MDD. Thus, potential neuroendocrine-immune modulation is one of the recently proposed mechanism for the rapid anti-depressant effects of ayahuasca in those with MDD.

Given that trauma and chronic sympathetic activation are prevalent among those with AiD, the therapeutic outcome of psychedelic-assisted psychotherapy could resolve or improve stressful psychological states that cause or contribute to physiological outcomes seen in the majority of AiD patients.

2.5. Glutamate excitotoxicity

Those with autoimmune conditions, particularly those affecting the nervous system, are more likely to have increased glutamate (Glu) binding sensitivity and post-synaptic glutamate levels which can result in cytoxicity to the nerve cell. The term glutamate excitotoxicity is used to describe the cytotoxic effects of excessive and uncontrolled release and binding of glutamate to post-synaptic neurons. Hypersensitization of Glu receptors due to cytokine-mediated transcriptional changes that affect depolarization gradients potentially play a role in this glutamate-induced cytotoxic phenomenon. Excitotoxicity appears to be implicated in a number of brain related diseases, including multiple sclerosis, depression, addiction and neurodegenerative diseases. During glutamate-excitotoxicity, excessive stimulation of the Glu receptors resulting in action potentials to be propagated through the neuron in an uncontrolled manner. This in turn activates the influx of Ca2+ ions into the cytoplasm where they may induce mitochondrial respiration and the release of reactive oxygen species (ROS). Under normal circumstances, the generated ROS are cleared from the cell and transmembrane ion gradients are restored quickly after glutamate transmission. However, in activation-induced excitotoxic cascades, the permeability transition pore (PTP) is opened and mitochondrial dysfunction occurs due to increased oxidative stress, abnormal ATP synthase activity and inhibited mitochondrial respiration. Chronic excitation of the Glu receptors can therefore contribute to oxidative stress, which may result in damage to neural structures or apoptotic cell death. Excitotoxicity from excessive Glu receptor binding may result in changes in cortical, amygdala, and hippocampal density leading to atrophy and shrinkage of brain regions.

While not a classic psychedelic compound, the dissociative anesthetic drug ketamine displays an ability to protect against glutamate-mediated excitotoxicity by non-competitively blocking the NMDA glutamate receptor. It is unclear if inhibition of the NMDA Glu receptor is the fundamental mechanism for the neuroprotective properties or if this, in turn, redirects glutamate to bind to other Glu receptors such as AMPA, Kainate and metabotropic Glu receptors. It appears that blocking the NMDA GluR, while flooding AMPA and metabotropic Glu receptors, paradoxically enhances Glu transmission in the prefrontal cortex in a way that is synaptogenic and potentially restorative for appropriate Glu receptor sensitivity. This could potentially be one mechanism for how ketamine delivers such rapid anti-depressant effects. In theory, blocking or correcting an excitotoxic effect from glutamate may alleviate the oxidative stress and tissue damage to cells by reducing the ROS released via action potentials.

Sig1R agonists such as dimemorfan, and dipentylammonium have shown neuroprotective mediation of glutamate excitotoxicity. Furthermore, DMT has been shown to possess potent neuroprotective effects via the Sig1R in both human in vitro and animal in vivo studies. It may be possible that the psychedelic Sig1R agonists DMT and 5-MeO-DMT are also capable of mediating glutamate levels and receptor activity via indirect transcriptional effects on cytokine production. Harmine, a MAOI contained in the ayahuasca vine has been found to increase Excitatory Amino Acid Transporter 2 (EAAT2) glutamate pump expression in the central nervous system, therefore raising the possibility of reducing glutamate toxicity in vivo.

5-HT receptor activation also has modulatory effects on downstream Glu release and binding activity, in particular through activity at the 5-HT1A, 5-HT1B, 5-HT2, 5-HT3 and 5-HT6 receptors in various brain regions. Downstream Glu effects from 5-HT activity of psychedelic drugs appears to play a role in the neurogenic properties of psychedelic compounds. It is possible that classic psychedelics that act on the 5-HT system may have indirect mitigation of pathological glutamate transmission and receptor sensitivity Table 1.

2.6. BDNF and neuroplasticity

The classic psychedelics psilocybin, DMT, 5-MeO-DMT, LSD, the psychedelic ritual brew ayahuasca, as well as the non-classic psychedelics ketamine have shown potential in interacting with neurogenic pathways, such as Tropomyosin receptor kinase B (Trk-B) and the mammalian target of rapamycin (mTOR), in an equivalent manner to the neurotrophin protein brain-derived neurotrophic factor (BDNF), and in influencing neuroplasticity in in vitro and in vivo models of Drosophila melanogaster, rats and humans Table 1. There are conflicting results from studies measuring BDNF gene expression and protein levels in serum with some studies showing evidence of enhanced BDNF gene expression as a result of exposure to psychedelics (LSD) in in vivo rat models, while others show no increase in gene expression but increase in BDNF protein levels in vitro and in vivo (serum) in rats. In studies, where the Trk-B selective antagonist ANA-12 was administered, the synaptogenic and neurogenic properties of psychedelics and BDNF are completely blocked. Similarly, treating rat cortical neurons with the drug rapamycin to inhibit mTOR also blocked the psychedelic-induced neuritogenesis suggesting that BDNF and psychedelics possess a shared mechanism for promoting neuritogenesis through an mTOR-related process of protein synthesis in synaptogenesis. It appears that this pathway is directly related to 5-HT2A receptor agonist activity of classic psychedelics, given that when ketanserin, a 5-HT2A antagonist, is administered the neuroplastic effects of DMT, LSD, and DOI are abrogated. Studies on ketamine’s effect on BDNF levels show increase of BDNF protein levels in the hippocampus but not an increase of BDNF mRNA. The increased BDNF levels were not sustained past 24 h after treatment, implying that BDNF interaction at TrK-B receptor sites prompts intracellular signaling that is responsible for the synaptic plasticity and anti-depressant effects.

One study that explored the neurogenic properties of indole-containing psychedelic compounds and ketamine in Drosophila and rat in vitro cortical neuron cell cultures used concentrations of each substance at 10 nM as the upper limit of each substance, with the exception of DMT, where 90 nM was used to simulate levels naturally occurring in rat brains. In in vivo rat models using Sprague-Dawley rats 10 mg/kg and 1 mg/kg doses of DMT were administered via injection and each dosage category produced similar responses in increasing density of dendritic spines. The results demonstrated that psychedelics can influence neuronal structure in vertebrates (Sprague-Dawley rats) and invertebrates (Drosophila) in both in vitro and in vivo models suggesting an evolutionarily conserved mechanism. In a similar manner, in human studies a single-dose of ayahuasca increased BDNF serum levels in both depressed and control subjects. Human brain imaging studies have also shown grey matter density changes as thinning in the posterior cingulate cortex (PCC) and thickening in the anterior cingulate cortex (ACC) in long-term ayahuasca users suggesting modulated neural plasticity and structural changes as a result of regular ayahuasca consumption.

BDNF is fundamental for facilitating the repair, maintenance and survival of neurons. Through its Trk-B-dependent signaling, BDNF prompts the growth of new synaptic spines, dendrites and new whole neurons. BDNF signaling is fundamental in dictating brain tissue density and the formation and conservation of neural networks. Low expression of BDNF mRNA in brain, and protein levels in serum and plasma in humans have been linked to MDD, anxiety, schizophrenia, and neurodegenerative diseases. Given the prevalence of MDD and glutamate excitotoxicity in patients with autoimmune diseases, it is possible that the BDNF-upregulating qualities of psychedelics could attenuate the inflammatory and cytotoxic pro-oxidative effects of glutamate excitotoxity in autoimmune disease, resulting in increased survivability of neurons that may be susceptible to ROS damage.

2.7. Microbial aspects of the physiological effects of psychedelics

Chronic infections with bacteria, fungi and viruses are common in those with AiDs. Studies suggest that infection by the Epstein-Barr virus and other herpes family viruses are prevalent in those with AiD. There is also evidence that Borrelia burgdorferi, the bacteria that causes Lyme disease, is also a common infectious agent in AiDs. Many patients with AiD display evidence of increased gut permeability, small intestinal bacterial overgrowth, and other signs of gut dysbiosis, which can be classified as chronic low-grade infections.

Constituents in psychedelic plants such as the ayahuasca vine (Banisteriopsis caapi) and Peyote cactus (Lophophora williamsii) display specific antimicrobial effects. Harmine and harmaline are beta-carboline alkaloids with MAOI properties in the B. caapi vine. Studies have demonstrated invitro anti-viral activity against the Herpes Virus Simplex 2 (HSV2) virus, a common infection in those with AiD, in HeLa, Vero, and Hec-1-A cells. The same alkaloids also appear to have antifungal properties which could perhaps be advantageous in an individual with a filamentous fungi overgrowth. Peyote extract has also shown broad antibacterial activity invitro, in particular against 18 different penicillin-resistant strains of Staphylococcus aureus. There may be mild antibiotic effects of some psychedelic plants which could potentially yield notable results in managing chronic or acute infections in AiD patients.

While there is evidence to suggest that psychedelic plants may have antimicrobial activity against pathogenic organisms, there has been no investigation of the effects on commensal bacteria and psychedelic compound exposure. With increasing interest in the roles of commensal gut ecology in health and disease, there has been more investigation into the psychoactive effects and complex host-organism interactions with bacterial colonies in the gastrointestinal tract. Microbiome bacterial populations appear to have play a significant role in a number of immune responses and have been found to influence the presence of self-antigens and AiD.

Gut bacteria have been discovered to possess the ability to manipulate neurotransmitter activity and are capable of producing serotonin, dopamine, acetylcholine, GABA, and more. Many of these neurotransmitters are derived from essential amino acids such as tryptophan, phenylalanine, and glutamine. Commensal gut bacteria possess highly conserved metabolic pathways for processing amino acids for a variety of uses. Many of the classic psychedelics are also biologically synthesized from tryptophan and share an analogous structure to serotonin and other endogenous tryptamine molecules. It is tempting to speculate that gut bacteria may produce these tryptamine metabolic products to use as signaling molecules meaning that bacteria are likely to not only produce these molecules, but also receive information from them as signal inputs. One study found that spore-forming endogenous bacteria species from Turicibacteraceae, Clostridiales, Lachnospiraceae and Ruminococcaceae were enriched in abundance when 5-HT was orally administered to wild type rats suggesting that the secretion of 5-HT from gut bacteria and the host intestine may prompt an advantage towards thriving colonies and promote the bacteria’s own community membership in the mammalian intestine, rather than 5-HT simply being a metabolic byproduct. It is very possible that the psychedelic serotonin analogues psilocybin, DMT, and 5-MeO-DMT may interact with bacterial receptors such as those found in Turicibacter sanguinis, a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. It is unclear if this SERT orthologue is solely responsible for the mechanism of transporting 5-HT into bacterial cells, but spore-forming gut bacteria do show the ability to transport 5-HT through some mechanism of action. If serotonergic psychedelic compounds were found to interact with these SERT-homologous bacterial proteins or other bacterial 5-HT uptake pathways in a way that alters the behavior of the bacterial colonies, this could have implications on gut microbe ecology and thus AiD disease outcome.

Whether there are direct pharmacological effects of psychedelics on bacteria is currently unknown, however the emotional and psychological benefits of psychedelics may indirectly alter microbial communities in the GI tract via induced changes in vagal nerve tone, stress response, and enteric environment. Several studies have explored the effects of chronic stress and resulting conditions like PTSD on microbiome pattern associations. The psychological and neurological benefits from a psychedelic experience may create biochemical cascades in systemic physiology, specifically within the HPA axis and the enteric nervous system, which may downstream influence the ecology of microbial populations.

As mentioned previously, LPS is a cell wall component of Gram-negative bacteria. LPS is known to induce inflammation and is used in research as an inflammatory trigger in animal models to simulate Parkinson’s, Alzheimer’s, MDD and general inflammatory conditions. In patients with increased gut-permeability, LPS fragments can leak past the intestinal epithelial barrier and cause inflammation while in circulation. Models using LPS-induced inflammation were used in some of the previously noted human invitro, and rat studies on the anti-inflammatory effects of psychedelics. This research may be particularly relevant to AiD as it suggests psychedelics may be helpful in mitigating inflammation caused by LPS due to increased intestinal permeability and chronic gut dysbiosis.

2.8. Mitigating the risks of psychedelic side-effects in therapeutic settings

Given the powerful psychoactive effects of psychedelic compounds, their use in medicine and psychiatry should not be taken lightly. Currently most psychedelic compounds are schedule I compounds meaning they have the highest categorical ranking of illegality in the Unites States with Schedule I stating that a substance has no acknowledged medical use, and is considered to have high-abuse potential.

Most psychological harms associated with the illegal use of psychedelics appear to be a result of poorly controlled environmental factors such as set and setting, as well as questionable sources of the drugs from the black market. In clinical administration of psychedelics, there is documented very low chance of psychological harm to properly screened patients provided with integrative support. One population study suggests that psychedelics do not appear to linked to long term mental health problems or suicidality. One 2010 analysis of psilocybin studies done between 1999 and 2008 looked at the experiences of 110 patients. Negative experiences were not common and seemed to be dose-dependent where higher doses of psilocybin were associated with higher rates of adverse reactions. All of the short-term adverse reactions were “successfully managed through interpersonal support” and did not require taking medications and seemed to have no lasting effects, based on follow-up interviews.

Hallucinogen Persisting Perception Disorder (HPPD) is a controversial neurocognitive condition where the patient reports persisting sensory effects after using a psychedelic substance. Also known as “flashbacks” the patient may experience brief re-occurrences/episodes of alterations in perception, mood, and/or consciousness, as previously experienced during a hallucinogenic intoxication. These symptoms can occur on a spectrum from occasional to near-constant. There is little conclusion about how common or debilitating these “flashback” experiences may be. Some studies suggest that they are less likely to occur in those who have taken a psychedelic in a clinical setting. Based on the phenomena existing in psychedelic-naïve patients and inconclusive data from studies that have examined the disorder, a causal relationship between persistent perceptual symptoms and use of psychedelics remains unproven.

Some precautions that may reduce harm to those receiving psychedelic medicine in clinical environments may include screening for a history of schizophrenia or psychosis, comfortable therapeutic set and settings that reduce the risk of panic or distress, interpersonal support provided by the clinicians, pharmaceutical-grade drugs, and low, subperceptual dosing, also known as micro-dosing.

3. Discussion and perspectives

There is vast opportunity to explore the effects of psychedelics on the immune system, in particular, autoimmunity. Systematic screening for various autoantibodies, inflammatory biomarkers, and for the expression of autoimmune-related genes in response to psychedelic treatments could provide intriguing observations and lead to more focused investigations.

The effects of psychedelic compounds on enteric bacterial behavior is of particular interest. Studies could be conducted examining the effects on bacterial growth and metabolism as a result of exposure to psychedelic compounds. In vitro and in vivo studies may hold many answers and even more questions about if and how serotonergic psychedelic compounds may be transported into bacterial cells and influence microbiome colonization and species composition. Studies could examine the effect of administration of psychedelics on enteric epithelial tissue integrity in the gut, or effects on LPS-induced cytotoxicity, etc.

Although results from preclinical studies on the immunomodulatory and anti-inflammatory effects are promising, the field of psychedelic research in biomedicine is still in its infancy. Current hypotheses regarding signaling mechanisms and systemic immune effects of psychedelics are based on a very limited amount of factual data. Only until we better understand the genetic and pathophysiological bases for AiD can there be appropriately and rigorously designed human clinical studies that consider psychedelics as potential therapeutic agents.

While there is a need for deeper investigation, there appears to be enough evidence of direct and indirect effects from psychedelic compounds that may benefit those with AiD to merit further exploration on the topic. Given the complexity of factors that contribute to AiD, a multi-facetted approach may be appropriate to address the multiple features and causes of AiD simultaneously. Unlike many current conventional treatment methods, it appears that psychedelics may potentially offer an efficacious strategy for relieving and perhaps even resolving autoimmunity by targeting psychospiritual origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations. The evidence presented in this paper provides support to the idea that there is untapped potential of exploring the use of psychedelics within this specific disease category. Given the limitation of efficacious treatment options for AiDs, and the physiological safety of psychedelic substances, it is likely a research topic worth pursuing. There is hope that the collection of this evidence may guide or inspire others to pioneer such studies. Overall, this direction of research is virtually unexplored and underdeveloped, providing a wealth of opportunities to discover novel applications for psychedelics in the field of immunology.

Psychedelics as a novel approach to treating autoimmune conditions

With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the Ai…

www.sciencedirect.com

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Using psychedelics to heal Autoimmune Disorders

There is vast opportunity to explore the effects of psychedelics on the immune system, in particular, autoimmunity. Systematic screening for various auto-antibodies, inflammatory biomarkers, and for the expression of autoimmune-related genes in response to psychedelic treatments could provide intriguing observations and lead to more focused investigations.

The effects of psychedelic compounds on enteric bacterial behavior is of particular interest. Studies could be conducted examining the effects on bacterial growth and metabolism as a result of exposure to psychedelic compounds. In vitro and in vivo studies may hold many answers and even more questions about if and how serotonergic psychedelic compounds may be transported into bacterial cells and influence microbiome colonization and species composition. Studies could examine the effect of administration of psychedelics on enteric epithelial tissue integrity in the gut, or effects on LPS-induced cytotoxicity, etc.

Although results from preclinical studies on the immunomodulatory and anti-inflammatory effects are promising, the field of psychedelic research in biomedicine is still in its infancy. Current hypotheses regarding signaling mechanisms and systemic immune effects of psychedelics are based on a very limited amount of factual data. Only until we better understand the genetic and pathophysiological bases for AiD can there be appropriately and rigorously designed human clinical studies that consider psychedelics as potential therapeutic agents.

*From the article here :
file:///C:/Users/user/AppData/Local/Temp/1-s2.0-S0165247820303977-main.pdf​

 

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Can CBD help Lupus?

by Jennifer Chen | Yale University | Sep 26 2019

A lupus diagnosis can be devastating. The disease causes the body's immune system to attack its own tissues and can affect internal organs—including the brain, heart, and lungs—which can start to deteriorate. Lupus flare-ups can leave patients so fatigued and in pain that they're unable to do the simplest of things, such as walk, cook, or read. Many can't go outdoors without layers of sunscreen, because the disease can make them extremely susceptible to sunburn.

Lupus affects approximately 240,000 people in the United States, and yet at present doctors neither know the exact cause nor have a cure. Instead, current treatments focus on improving quality of life by controlling symptoms and minimizing flare-ups to reduce risk of organ damage.

"The landscape for treatment of lupus is a bit bleak," says Fotios Koumpouras, MD, a rheumatologist and director of the Lupus Program at Yale Medicine. "A multitude of drugs have failed in the last ten to 15 years. Most of the drugs we use are being repurposed from other conditions and are not unique to lupus. Many of them can't be used during pregnancy, which is a problem because lupus mostly affects young women. All of these issues create the impetus to find new and more effective therapies."

This is why he's exploring an unconventional candidate for a new lupus treatment option: CBD—one of the chemicals found in the cannabis plant.

What is CBD?

CBD is a form of cannabinoid called "cannabidiol." Cannabinoids are a type of chemical that binds to (CB1 and CB2) receptors found throughout the body. CB1 receptors are mostly located in the nervous system, connective tissues, gonads, glands, and organs; CB2 receptors are primarily found in the immune system, along with the spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands, and reproductive organs. (Collectively this is called the endocannabinoid system.)

What these cannabinoids do when they bind to the receptors depends on which receptor is activated, and thus can produce effects ranging from the firing of neurotransmitters (the chemical messengers sent from the brain to the rest of the body) that alter mood, to reducing inflammation and promoting digestion.

Our bodies produce cannabinoids, but they can also be found in nature, most abundantly in the cannabis plant. The two most well-known types of cannabinoids in the cannabis plant are THC (tetrahydrocannabinol) and CBD (cannabidiol). THC binds to both the CB1 and CB2 receptors and is responsible for many of the well-known psychoactive effects of cannabis, such as euphoria, increased heart rate, slower reaction times, and red eyes. CBD, on the other hand, binds only with CB2 receptors, resulting in the production of a series of proteins to reduce inflammation. (These proteins are called "resolvins" because they appear to resolve inflammation.)

This is what caught Dr. Koumpouras' eye in his search for a new lupus medication. Reducing inflammation is crucial for patients with lupus because it is what causes the buildup of scar tissue in vital organs that can eventually lead to their deterioration and malfunction, he says. Unfortunately, none of the current lupus drugs available are uniformly effective.

In 2018, Dr. Koumpouras joined a multi-site randomized clinical trial that aims to recruit 100 participants to examine whether a drug using synthetically created CBD (called Lenabasum) can help ease pain and inflammation in patients with lupus. Participants will receive Lenabasum or a placebo for almost three months and will continue to be monitored for pain and inflammation levels, as well as lupus disease activity. The study is ongoing, but Dr. Koumpouras anticipates that it will wrap up by early next year.

From recreational drug to medicine

Dr. Koumpouras' excitement over the new drug comes at a time when products containing CBD have flooded supermarkets, labeled with claims that they treat everything from back pain to insomnia. Although CBD is not yet approved by the FDA, the hype around it stems from the popularity of the cannabis plant it is derived from.

Cannabis has been both celebrated and shunned throughout its history in the U.S. Once targeted in the "war on drugs" campaign in the 1980s, cannabis began to gain some foothold of societal acceptance in the mid-1990s when California legalized it for medical use. Since then, claims that the plant can treat a wide range of medical issues, including inflammation, pain, and even epileptic seizures, are widely covered by news outlets (legitimate and otherwise). At present, 33 states, plus the District of Columbia, have decriminalized the drug for medicinal use.

Scientists and researchers are studying these claims. One large review of those studies was published in 2017, when the National Academies of Sciences, Engineering and Medicine released a report detailing the potential health effects of cannabis and cannabinoids. A committee of 16 experts from a variety of scientific and medical fields analyzed more than 10,000 scientific abstracts, determining there is "conclusive or substantial evidence" supporting the use of cannabis or cannabinoids for chronic pain in adults, multiple sclerosis-related stiffness and muscle spasms, as well as chemotherapy-induced nausea and vomiting. The researchers also found "moderate" evidence that cannabis or cannabinoids reduce sleep disturbances in people with obstructive sleep apnea, fibromyalgia, chronic pain, and multiple sclerosis. However, there are no randomized double-blind clinical trials proving cannabis' effectiveness in patients.

Cannabis remains stigmatized as a recreational drug. That may be, in part, why CBD entrepreneurs position their products as containing an all-natural chemical with all the benefits of cannabis, but without the dissociative effects of THC.

But whether CBD actually provides those benefits in a significant way remains to be seen. Only a few studies—small ones—have definitively proven the effectiveness of CBD. To date, the only FDA-approved medication containing CBD is Epidiolex, a medication used to treat two rare forms of severe epilepsy—Lennox-Gastaut syndrome and Dravet syndrome, both which begin mostly in infancy and early childhood. In a group of three clinical trials, Epidiolex seemed to reduce the number of seizures significantly. And yet, Vinita Knight, MD, a Yale Medicine pediatric neurologist, says her patients who take Epidiolex have had mixed results. Some have had reductions in seizures and others haven't shown much improvement. "We're not seeing as much success as what's been reported on Facebook and Twitter," she says, adding that "so far it has only been prescribed for children with the most debilitating and difficult-to-treat seizures." In addition, some researchers believe that CBD works most effectively in combination with other cannabinoids and compounds found in the cannabis plant, in what is known as the "entourage effect." Thus, it would be less effective as an isolated chemical in pill form, but that, too, remains unproven.

But these questions are why Dr. Koumpouras is focusing on a compound that, until recently, few have studied. His research is one of many new studies at Yale and elsewhere looking at CBD for use in treating everything from Crohn's disease to psoriatic arthritis, and he hopes that this new data will be used to help paint a more complete picture about the chemical for future treatment options. "The more data the better," he says. "The more we're able to make informed decisions."

Can CBD help lupus and other diseases?

A lupus diagnosis can be devastating. The disease causes the body's immune system to attack its own tissues and can affect internal organs—including the brain, heart, and lungs—which can start to deteriorate. Lupus flare-ups can leave patients so fatigued and in pain that they're unable to do...

medicalxpress.com

 

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Psychedelics and Immunomodulation*

by Attila Szabo | University of Oslo | July 2015

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including DMT, 5-MeO-DMT, LSD, DOI, and MDMA will be discussed from a perspective of molecular immunology and pharmacology. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Introduction

Psychedelics are psychoactive substances that possess the ability to alter cognition and perception by triggering neurotransmitter receptors in the brain. Psychedelics are members of a wider family of psychoactive drugs known as hallucinogens, a class that also includes essentially unrelated psychotropic substances (e.g., dissociatives, deliriants, etc.). These substances affect the mind in unique ways that result in altered states of consciousness, which are qualitatively and phenomenologically different from the ordinary states. According to their pharmacological action, psychedelics usually fall into one of the following categories: tryptamines, such as psilocin and DMT; lysergamides, most importantly LSD; phenethylamines, a large group of diverse substances including DOI, and MDMA; cannabinoids; and atypical psychedelics, such as salvinorin A. Tryptamines, lysergamides, and phenethylamines are often considered as “classical psychedelics” that exert their effects via the serotonergic system, and a growing body of evidence suggests that they may have therapeutic effects in treating many psychiatric disorders.

Scientific investigations concerning the possible immunological effects of psychedelics date back to the early 70s. However, the biomedical Renaissance of psychedelic research has only begun about a decade ago. An important antecedent was the identification of neuroimmune communication in mammals that greatly expanded the domain of physiological activity of psychoactive substances. Since immune cells were found to also express many types of neurotransmitter receptors, an entirely new aspect was added to the biomedical paradigm. Early euroimmunologists considered the immune and nervous systems as separate parts, but a crucial conceptual leap led to the emergence of the modern approach. This new concept represents neuroimmune communication as an integrated physiological entity with the immune and nervous systems being its two aspects.

In the last two decades, several neurotransmitter receptors involved in the pharmacology of psychedelics have been identified as also being crucial in many immunological processes pointing out to novel therapeutic avenues. This emerging field offers very promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the paucity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as possible and effective agents of future pharmacotherapies.

Tryptamines: Endogenous regulators of inflammation and tumor immunity?

DMT is related to the neurotransmitter serotonin, the hormone melatonin, and other psychedelic tryptamines, such as bufotenin and psilocin. It is a naturally occurring indole alkaloid that is ubiquitous in plants, such as Diplopterys cabrerana and Psychotria viridis, which are used for the preparation of sacramental psychoactive brews including yage and ayahuasca. In addition to its ubiquitous presence in plant species, DMT has also been detected in animal tissues and is considered to be an endogenous trace amine. The milestones of DMT research were laid down by Szara and Axelrod who reported first the psychoactive effects and occurrence of this compound in the human brain. This led to the hypothesis that DMT is an endogenous hallucinogen, and later it was proposed to be a neurotransmitter or neuromodulator. DMT was shown to act as an agonist at several serotonin receptors including 5-HT1A, 5-HT2A, and 5-HT2C as well as at sigmar-1.

The vast majority of the initial research into the reasons for the presence of psychoactive tryptamines in the human body has sought their involvement in mental illness. Until now, very little has been known about the function of DMT in cellular and general physiological processes, and the emphasis of research mostly aimed the understanding of its psychedelic properties. Recently, we and others demonstrated that DMT has the capability to modulate immune responses in in vitro human primary cell cultures. In these studies, DMT was shown to act as a non-competitive inhibitor of IDO, and as a strong inducer of anti-tumor cytotoxic activity in the co-cultures of human PBMCs and a glioma cell line. Furthermore, DMT and its analog 5-MeO-DMT were found to exert potent anti-inflammatory activity through the sigmar-1 in human monocyte-derived dendritic cell (moDC) cultures.

Importantly, it is possible that the observed anti-inflammatory and immunosuppressive effects may counteract with the anti-cancer activity, therefore further investigations are needed to elucidate the complex in vivo consequences of DMT administration. The mentioned studies demonstrate and propose new biological roles for DMT, which may act as a systemic endogenous regulator of inflammation and immune homeostasis. According to these new results, DMT and 5-MeO-DMT possess the capability to inhibit the polarization of human moDC-primed CD4+T helper cells toward the inflammatory Th1 and Th17 effector subtypes in inflammatory settings. This is of particular importance, since Th1 and Th17 cells and the cytokines they secrete are key players in the etiology and symptomatology of many chronic inflammatory and autoimmune diseases of the CNS and other tissues. Moreover, the mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases (such as multiple sclerosis or amyotrophic lateral sclerosis) and cancer.

Phenethylamines: Regulating inflammation and cytotoxicity

Phenethylamines are members of a large and diverse group of organic compounds, which derive from phenethylamine itself. Some of them are neuro-transmitters, such as dopamine and epinephrine, other members of the family are psychoactive substances, which directly modulate the monoamine neuro-transmitter systems, such as the substituted amphetamines, the substituted methylenedioxyphenethylamines, and several other naturally occurring alkaloids. This large family also includes a variety of drug classes, such as dopamine agents (e.g., bupropion), serotonin agents (e.g., the psychedelic DOB), adrenergic agents, and monoamine oxidase inhibitors (MAOIs).

The most researched phenethylamine, MDMA, has also been described as an anti-inflammatory and immunosuppressive agent. Early studies reported that MDMA could increase the activity of mouse NK and T helper cells in in vitro cultures at low concentrations. The TNFαproduction of macrophages and the induction of CTLs were suppressed upon MDMA administration. Acute administration of MDMA led to significant immunosuppression by directly decreasing lymphocyte proliferation and blocking the mitogen or LPS-induced cytokine production of T cells in in vivo animal models. Long-term use of MDMA, however, was associated with a decrease in the total number of circulating lymphocyte populations. These alterations also involved a significant decrease in the plasma level of IL-2 and increase of TGF-β in human volunteers. These results suggest that acute administration of MDMA favors anti-inflammatory immune responses and has a tendency to polarize adaptive immunity toward antibody production. Simultaneously, the activity of NK cells is increased pointing to a complex effect on immune homeostasis. This may reflect to an anti-inflammatory potential of MDMA without significantly decreasing the effectiveness of anti-viral or anti-tumor immunity; however, further in vivo studies are needed to unravel the details of this complex immunomodulatory action.

While PRRs were shown to be crucial for innate and adaptive host defense, their inappropriate activation has been associated with autoimmunity and inflammatory diseases. Psychedelics, by modulating the activity of 5-HT1, 5-HT2, and sigmar-1 receptors, are potent anti-inflammatory agents. A more complete appreciation of the PRR-5-HTR/sigmar-1 cross-talk and their complex signaling processes would provide important insights into new therapeutic modalities that can either enhance immune responses or inhibit functions to diminish the deleterious effects of uncontrolled inflammation. Thus, these compounds emerge as very promising candidates in many diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

*From the article here :

https://www.researchgate.net/publication/280495853_Psychedelics_and_Immunomodulation_Novel_Approaches_and_Therapeutic_Opportunities

 

[mr peabody]

Why women are more prone to autoimmune disorders*

University of Michigan | Science Daily | 19 Apr 2019

Women are four times more likely than men to have an autoimmune disease. And more than nine times as likely as men to have lupus. The reason for this gender bias has evaded scientists. Researchers have hypothesized that female sex hormones like estrogen may play a role in stimulating the immune system, but others argue that this doesn’t tell the whole story. A new study by researchers at the University of Michigan suggests that part of this story may be told within the skin. Women have previously been shown to have higher levels of a protein called vestigial like family member 3 (VGLL3) in their skin. VGLL3 regulates certain immune-related genes that may play a role in autoimmune diseases.

The Michigan researchers decided to test what would happen if they increased levels of VGLL3 in the skin of mice. Would this cause them to develop autoimmune conditions more easily than control mice with normal VGLL3 levels? After six weeks, mice that had been genetically altered to have higher levels of VGLL3 started to develop thicker skin and scales around their face, a telltale symptom of lupus. They also had significantly higher inflammation and biological markers of early-onset lupus than the control mice. Next, the researchers analyzed skin samples from the mice and compared them to skin samples from humans with lupus. There was considerable similarity in gene expression between the skin of the altered mice and the lupus patients. Identifying VGLL3 as a potential trigger of increased autoimmune diseases among women is the first step—and it’s incredibly exciting. The next step, though, may be a bit more difficult: determining what causes women to have raised levels of VGLL3 and how to stop it from wreaking havoc on the body.

Part of the answer, it turns out, may lie in the skin.

New evidence points to a key role for a molecular switch called VGLL3. Three years ago, a team of University of Michigan researchers showed that women have more VGLL3 in their skin cells than men.

Now, working in mice, they've discovered that having too much VGLL3 in skin cells pushes the immune system into overdrive, leading to a "self-attacking" autoimmune response. Surprisingly, this response extends beyond the skin, attacking internal organs too.

Writing in JCI Insight, the team describes how VGLL3 appears to set off a series of events in skin that trigger the immune system to come running -- even when there's nothing to defend against.

"VGLL3 appears to regulate immune response genes that have been implicated as important to autoimmune diseases that are more common in women, but that don't appear to be regulated by sex hormones," says Johann Gudjonsson, M.D., Ph.D., who led the research team and is a professor of dermatology at the U-M Medical School.

"Now, we have shown that over-expression of VGLL3 in the skin of transgenic mice is by itself sufficient to drive a phenotype that has striking similarities to systemic lupus erythematosus, including skin rash, and kidney injury."

Effects of excess VGLL3

Gudjonsson worked with co-first authors Allison Billi, M.D., Ph.D., and Mehrnaz Gharaee-Kermani, Ph.D., and colleagues from several U-M departments, to trace VGLL3's effects.

They found that extra VGLL3 in skin cells changed expression levels of a number of genes important to the immune system. Expression of many of the same genes is altered in autoimmune diseases like lupus.

The gene expression changes caused by excess VGLL3 wreaked havoc in the mice. Their skin becomes scaly and raw. Immune cells abound, filling the skin and lymph nodes. The mice also produce antibodies against their own tissues, including the same antibodies that can destroy the kidneys of lupus patients.

The researchers don't yet know what causes female skin cells to have more VGLL3 to begin with. It may be that over evolutionary time females have developed stronger immune systems to fight off infections -- but at the cost of increased risk for autoimmune disease if the body mistakes itself for an invader.

The researchers also don't know what triggers might set off extra VGLL3 activity. But they do know that in men with lupus, the same VGLL3 pathway seen in women with lupus is activated.

Many of the current therapies for lupus, like steroids, come with unwanted side effects, from increased infection risk to cancer. Finding the key factors downstream of VGLL3 may identify targets for new, and potentially safer, therapies that could benefit patients of both sexes.

Lupus, which affects 1.5 million Americans, can cause debilitating symptoms, and current broad-based treatment with steroids can make patients far more vulnerable to infections and cancer.

Patients' role in future research

Their colleague and senior coauthor Michelle Kahlenberg, M.D., of the U-M Division of Rheumatology, is now recruiting patients with lupus for a study sponsored by U-M's A. Alfred Taubman Medical Research Institute that could provide answers to these questions and more.

Billi, a resident in dermatology, notes that when she speaks with patients who come to Michigan Medicine's dermatology clinics for treatment of the skin problems lupus can cause, she has to acknowledge the limits of current treatment. Even so, she says, patients are eager to take part in studies by contributing skin and DNA samples that could lead to new discoveries about their condition.

"Many patients are frustrated that they've had to try multiple therapies, and still nothing is working well," she says. "To be able to tell them that we're working on a mouse that has the same disease as them, and that we need their help, brings out their motivation and interest in research. They know that it's a long game, and they're in for it."

*From the articles here :

Why Women Are More Prone to Autoimmune Diseases and Other Cutting-Edge Research on Autoimmunity | Goop

Every month, we get into a different health topic and explore the research. For October, we went through the most compelling new studies on autoimmune diseases, and we’ve got the important takeaways for you.

goop.com

Discovery may help explain why women get autoimmune diseases far more often than men

New evidence points to a key role for a molecular switch called VGLL3 in autoimmune diseases, and the major gap in incidence between women and men. Building on past research showing that women have more VGLL3 in their skin cells than men, a team studied it further in mice. They show that having...

www.sciencedaily.com

 

[mr peabody]

Researchers unlock the profound anti-inflammatory properties of cannabis*

by Mark Taylor | Benzinga | Aug 23 2019

A new study deciphers for the first time the cannabis plant's biological blueprint for producing two molecules with anti-inflammatory properties.

That study, which is published in the August 2019 issue of the journal Phytochemistry delineates for the first time the biosynthesis pathway outside of the actual cannabis sativa plant that allows reproduction of the molecules cannflavin A and cannflavin B.

Those cannflavins belong to the class of plant flavonoids, plant chemicals found in almost all fruits and vegetables, known as flavones, which occur in several plant lineages.

The study shows the medicinal versatility of the cannabis plant: Beyond the intoxicating ingredient THC and therapeutic oils that often contain cannabidiol (CBD), there exist many other specialized metabolites requiring further research.

The researchers at Guelph University in Ontario, Canada, unlocked the blueprint for producing the cannflavins, which were discovered in a 1985 study and were found to display “potent anti-inflammatory activity in various animal cell models.”

The new information in the Phytochemistry study opens a pathway to figure how to engineer plant metabolism to make medicine from the cannflavin A and B enzymes.

Tariq Ahktar, lead author and assistant professor of plant biochemistry at Guelph's Department of Molecular and Cellular Biology, told Weedmaps News that “for almost 30 years nobody touched these molecules or worked extensively on them. We thought it was a good time to look at these very promising molecules more closely.”

Ahktar said his laboratory utilizes plant chemistry and genomics to determine how plants produce certain molecules and compounds that have medicinal or industrial uses.

He said the cannaflavins A and B were discovered in the United Kingdom more than 30 years ago by researcher Marilyn Barrett. Her study also introduced the name cannflavin. Barrett's research showed that cannflavins A and B have nearly 30 times the power of aspirin to inhibit inflammation in cells.

Yet that discovery is just the beginning. Ahktar explained that the two cannflavins are present in cannabis in very low amounts.

“So if you want to gain the anti-inflammatory benefits, you would have to consume copious amounts of cannabis, which is both unlikely and impractical,” he said, "necessitating the need to reproduce the molecules outside of the cannabis plant."

He said cannflavins are “definitely encouraging news” for people suffering from acute and chronic pain, who have few effective alternatives to opioids, which work by blocking the brain's pain receptors. These cannflavins appear to take a different path by attacking cells that encourage inflammation, a primary cause of much pain.

Ahktar said that for decades American and Canadian researchers have been unable to research the medicinal properties of cannabis because of prohibitions against the cultivation and sale of the plant, still considered illegal by the U.S. federal government. Ahktar said his team has demonstrated a biochemical pathway for commercial producers to allow the production of cannflavins A and B from yeast, bacteria, plants, or other means.

“That way you don't have to grow huge fields of cannabis to obtain the benefits,” he said, noting that the Guelph researchers have patented the genes and licensed their research to Toronto-based Anahit International Corp., to biosynthesize those molecules.

The ability to “hack” other plants or microorganisms to produce their medicinal compounds offers great potential benefits to science and industry. Dr. Jeff Chen, Director of the University of California, Los Angeles (UCLA) Cannabis Research Initiative, spoke at the July 2019 Microscopes and Machines conference in Los Angeles about using biosynthesis as an alternative that is more scalable, consistent and continuous than plant farming to produce cannabinoids and other beneficial compounds.

Chen cautioned that science has a long way to go to find the most efficient method of producing the cannabinoids and other beneficial compounds. Patients, however, haven't been waiting.

Ahktar said he spoke with many patients who used cannabis successfully to treat a range of conditions and swore it improved their pain levels and reduced inflammation.

“Now that we have a mechanism for reproducing this, we can start producing it and performing side by side comparisons with existing pain relievers and test their relative efficacy,” he said.

The study comes amid an ongoing opioid crisis in the United States. According to the U.S. Centers for Disease Control and Prevention (CDC), U.S. healthcare providers prescribed more than 214 million prescriptions for opioid pain in 2016, with an estimated 11 million people misusing prescription opioids that year. More than two-thirds of the 63,632 drug overdose deaths in 2016 involved prescription or illicit opioids. From 1999 to 2017, almost 218,000 people died in the United States from overdoses related to prescription opioids.

Gregory Gerdeman, chief scientific officer for the St. Petersburg, Florida-based medicinal cannabis cultivator 3 Boys Farm and a neuroscientist who has studied the effects of cannabis on the brain for 22 years, said the takeaway from the study is that herbal cannabis takes a multifaceted approach to combating inflammation and that it may offer a greater therapeutic value than the THC or CBD alone.

“It also may point to potential drug development,” Gerdeman said. “I believe in herbal cannabis as a medicine. I think it already offers a very promising strategy for replacing opioids. We now know how the plant synthesizes cannflavins A and B and we're living in an age in which pharmaceutical companies are creating genetically modified cannabis that could allow drug factories to reproduce these molecules outside of the cannabis plant. This study shows how the science of cannabis as a medicine is being taken seriously today in the medical and pharmaceutical worlds. It was not that way in 1997 or even in 2007.”

He called cannabis the “queen of medicinal plants,” adding, “We have many secrets yet to learn from her.”

Gerdeman cautioned, however, that the Canadian study did not explore the precise role of cannflavins A and B in fighting inflammation or the molecules' potential therapeutic effects.

“The assertion from a 30-year-old study that these cannflavins offer anti-inflammatory effects 30 times the strength of aspirin requires much more research and study to validate. It would be premature to say that using isolated cannflavins as a drug would be desirable or without safety concerns.”

*From the article here :

Researchers Unlock What Gives Cannabis its Anti-Inflammatory Qualities

A new study deciphers for the first time the cannabis plant's biological blueprint for producing two molecules thought to have anti-inflammatory properties, a discovery that could pave the way for...

news.weedmaps.com

 

[mr peabody]

Therapeutic potential of 5-MeO for cancer "very promising"

by Dr. Attila Szabo | Frontiers In Imunology | 14 Jul 2015

Research on the therapeutic potential of 5-MeO for cancer is still in the early stages, but the few studies that have been done are very promising. It has been shown to exert powerful anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. Its regulatory effect on the sigma-1 receptor, which plays a significant role in cancer, is especially interesting.

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-kB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes.

This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies.

In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including DMT, 5-MeO-DMT, LSD, 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology.

Special attention is given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Since both NF-kB and type I IFN signaling contribute to the transcriptional regulation of genes that are involved in cellular proliferation and survival, and many psychedelics exhibit in vitro anti-cancer potential through 5-HTRs, these compounds could be promising candidates in novel therapies of cancer.

Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases (such as Multiple Sclerosis or Amyotrophic Lateral Sclerosis) and cancer.

Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500993/​

 

[mr peabody]

DMT and 5-MeO-DMT found to modulate inflammatory responses through the sigma-1 receptor

Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands, DMT, its derivative 5-MeO-DMT and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cells (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses.

Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1b, IL-6, TNFa and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Introduction

The term sigma receptor dates back historically to the sigma/ opioid receptor described by Martin et al. and reported to mediate the psychotropic effects of N-allylnormetazocine (NANM). It was originally thought to be an opioid receptor due to its modulation by NANM that could be antagonized by naloxone, a universal opioid antagonist. Later, Su and colleagues clarified the pharmacological features of the ligand-binding site and the name was changed to ‘sigma receptor’ differentiating it from the sigma/opioid receptor. According to its tissue expression profile and ligand selectivity the receptor was subsequently classified to the sigma-1 and sigma-2 receptor subtypes (sigmar-1/2). In the last two decades several clinical studies demonstrated the importance of sigmar-1 in many diseases ranging from cancer, pain and addiction to different psychiatric and neurological disorders among them Major depression, Alzheimer’s disease, schizophrenia, and stroke.

Early studies showed that sigmar-1 is expressed not only in distinct regions of the CNS but also in immune cells. It was shown to regulate cell differentiation and survival by acting as a chaperone at the mitochondria-associated endoplasmic reticulum membrane. Murine studies also demonstrated that the specific activation of sigmar-1 resulted in immunosuppression, and in vivo decreased lymphocyte activation and proliferation. Sigma-1 receptor ligands possess potent immuno-regulatory properties via increasing the secretion level of anti-inflammatory IL-10, and suppressing IFNc and GM-CSF expression. These important studies showed that sigmar-1 may cause significant alterations in immune functions.

The endogenous ligands for sigmar-1 involve neurosteroids, dehydro-epiandrosterone (DHEA), and naturally occuring indole alkaloids/tryptamines, such as DMT and its closely related analogue 5-MeO-DMT. Psychedelic indole alkaloids are widespread in nature and abundant in plants, which are used in preparation of sacramental psychoactive decoctions such as yage and ayahuasca. DMT and 5-MeO-DMT have also been detected in animal tissues; furthermore, DMT is considered as an endogenous trace amine neurotransmitter that regulates brain physiology. It has recently been shown that DMT is a natural ligand for sigmar-1, and its administration was reported to influence the number of circulating lymphocytes in humans, but the exact mechanism has not been uncovered yet. In the light of these findings it is tempting to speculate that DMT and 5-MeO-DMT may have impact on inflammatory responses through sigmar-1.

In this study we aimed to investigate the effects of DMT and 5-MeO-DMT-mediated activation of sigmar-1 on human primary moDC functions under inflammatory conditions as compared to resting state. To our best knowledge this is the first study reporting that dimethyltryptamines are potent anti-inflammatory agents, which have the capacity to modulate the functions of moDCs in a sigmar-1-dependent manner. Our results envision that dimethyltryptamines targeted to the sigmar-1 receptor could emerge as promising candidates for future pharmacological therapies in chronic inflammatory and autoimmune conditions of the CNS or peripheral tissues. We also propose a new biological role for DMT, which, through the sigmar-1 of myeloid immune cells, may act as an endogenous regulator of inflammation and immune homeostasis.

Discussion

Psychedelic trypamines are members of the indole alkaloid family, the largest and most common class of alkaloids in the Animal and Plant Kingdoms. DMT and bufotenine, the metabolic product of 5-MeO-DMT in mammals, have been detected in animal and human blood, urine, cerebrospinal fluid, brain, intestine and many other tissues suggesting that these compounds may have important biological roles other than their psychotropic and neuromodulatory properties.

The orphan receptor sigmar-1 has been shown to regulate many physiological processes inculding cell survival and proliferation. The expression of sigma receptors is not limited to the brain as high level expression was detected in mammalian liver, kidney, gut and other tissues as well. Sigmar-1 has also been detected in immune cells mediating strong immunosuppressive and anti-inflammatory effects. It has recently been reported that DMT is an endogenous ligand for sigmar-1, and its agonistic activity may be expanded to analogues, such as the methoxy derivative 5-MeO-DMT. However, very little is known about the physiological functions of dimethyltryptamines in human and the emphasis of contemporary research is mostly related to understanding its psychedelic properties and to our best knowledge, the biological effects of DMT via sigmar-1 has not been investigated yet. In this study we adressed the question whether sigmar-1 is expressed in human primary myeloid cells, and if so, what is its functional role in human physiology. According to our results, sigmar-1 is expressed in human monocytes and its expression is increasing during the differentiation process to macrophages and dendritic cells.

These results demonstrated for the fist time that DMT and 5-MeO-DMT have the capability to inhibit the polarization of human moDC-primed CD4+T helper cells towards inflammatory Th1 and Th17 effector lymphocytes in infectious/inflammatory settings. This is of particular importance, since Th1 and Th17 cells and the cytokines they secrete are key players in the etiology and symptomatology of many chronic inflammatory and autoimmune diseases of the CNS and other tissues. Moreover, the mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. In neuropsychiatric research it is an increasingly accepted hypothesis that a number of diseases affecting large populations, such as Alzheimer’s, Parkinson’s disease, Major depression are caused by chronic inflammation of the central nervous system. High-resolution whole genome-wide association studies found significant correlations between gene polymorphisms of innate immune receptors and the frequency of late onset Alzheimer’s disease (AD). Since blood-derived monocytes were shown to be able to translocate to the CNS, our results could expand the role of moDCs to a more global context by suggesting their regulatory role under autoimmune or infectious inflammatory conditions in the brain.

We conclude that the function of dimethyltryptamines may extend the central nervous system activity and may play a more universal role in immune regulation. Here we demonstrate for the first time that DMT and 5-MeO-DMT have potent immunomodulatory effects on the functional activities of human dendritic cells operating through the sigma-1 receptor. We also show that DMT-mediated sigmar-1 activation can interfere with both innate and adaptive immune responses. On the one hand, it strongly decreases the levels of pro-inflammatory cytokines and chemokines such as IL-1b, IL-6, TNFa and IL8, while upregulates the production of the anti-inflammatory cytokine IL-10. On the other hand, DMT and 5-MeO-DMT pre-treatment of pathogen-activated moDCs abolishes their capacity to initiate adaptive immune responses mediated by inflammatory Th1 and Th17 cells. These findings greatly expand the biological role of dimethyltryptamines, which may act not only as neuromodulators or psychedelics, but also as important regulators of both innate and adaptive immunity. Thus, the DMT-sigmar-1 axis emerges as a promising candidate for novel pharmacotherapies of chronic inflammatory and autoimmune diseases.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0106533&type=printable​

 

[mr peabody]

Psychedelic (R)-DOI stymies Asthma development*

Genetic Engineering & Biotechnology News | 10 Feb 2015

Scientists at the Louisiana State University Health New Orleans School of Medicine have found that the psychedelic drug, (R)-DOI, prevents the development of allergic asthma in a mouse model. The effects are potent and effective at a concentration 50-100 times less than would influence behavior. The research (“Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model”) appears in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

The team looked at the effects of (R)-DOI, a serotonin 5-hydroxytryptamine (5-HT)2A receptor agonist which contains serotonin, a molecule known to be tied to inflammation, but not asthma.

“We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)2A receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues,” the authors wrote in the American Journal of Physiology - Lung Cellular and Molecular Physiology.

These drugs, while their neurological effects have been researched extensively, identified its role in asthma development—a discovery, lead researcher Charles Nichols, PhD, an Associate Professor of Pharmacology and Experimental Therapeutics at the LSU Health New Orleans School of Medicine, believes could pave the way for breakthrough inhalers and medications.

“These drugs are known only for their effects in the brain,” notes Charles Nichols, Ph.D., associate professor of pharmacology and experimental therapeutics. “What we have demonstrated for the first time is that they are also effective in treating physiological diseases outside of the brain, a completely new and exciting role for this class of drug. Not only is this a significant breakthrough in the field of study of serotonin and psychiatric drugs, but it is a breakthrough in the field of asthma as well. We have identified an entirely new anti-inflammatory mechanism for the treatment of asthma in the clinic that could someday be administered in an inhaler or a daily pill.”

Previously, Dr. Nichols' lab found that activation of the serotonin receptor 5-HT2A with psychedelics produces powerful anti-inflammatory activity in tissues of the blood vessels and gut. Building on that, the researchers identified a drug they believed would be effective against the inflammatory disease asthma. They found that administration of (R)-DOI blocked pulmonary inflammation, mucus hyperproduction, airways hyperresponsiveness, and turned off certain key genes in the lung involved in immune response that together blocked the development of allergic asthma in their mouse model.

“Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma,” write the investigators.

According to the National Heart, Lung, and Blood Institute, asthma is a chronic lung disease that inflames and narrows the airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. Asthma affects people of all ages, but it most often starts during childhood. In the U.S., more than 25 million people are known to have asthma.

“Overall, given the recent interest and success using these drugs for psychiatric therapies in the clinic, our research at LSU Health New Orleans is the first to show that they have potential to heal the body as well as the mind,” notes Dr. Nichols.

*From the article here :

Mind-altering Drug Stymies Asthma Development

Psychedelic drug prevents the development of allergic asthma in a mouse model.

www.genengnews.com

 

[mr peabody]

Cambridge

Psychedelics as anti-inflammatory agents​

A look into the less discussed therapeutic aspect of psychedelics: the anti-inflammatory effect.

by Shane O'Connor, MS | Psychedelic Science Review | 14 Nov 2019

In recent years, compounds that act as agonists (aka activators) at the serotonin 2A receptor (5-HT2A) have emerged as a prominent therapy for several disorders including depression, obsessive-compulsive disorder (OCD), anxiety, and addiction.¹⁻³ The recently discovered therapeutic effect of psychedelic agonists has led to a reevaluation in the way these compounds are perceived in the medical sphere and amongst the general population at large.

One recently identified therapeutic characteristic of psychedelics that holds notable promise is their anti-inflammatory effect.⁴ This article explores the anti-inflammatory effect of psychedelics – thought to be mediated through 5-HT2A activation – and how this effect pertains to disorders of the central nervous system (CNS) and other, more recently identified indications.

Inflammation and depression

Inflammation is generally defined as an endogenous repair or host defense mechanism in response to a biological or physical insult. The inflammatory response aims to eliminate invading agents and facilitate healing. This response not only initiates an acute defense against damaging agents but also contributes to the renewal of normal tissue functioning following a harmful occurrence. Within minutes to hours of a biological insult, the body initiates an innate immune response. This response acts by recruiting immune cells to injury sites and promotes inflammation through cytokine release. Some of these cytokines include Tumour Necrosis Factor – Alpha (TNF-α) and Interleukin 6 (IL-6).

Researchers have established that inflammation plays a vital role in the pathophysiology underlying psychiatric disorders such as depression. For example, the introduction of the pro-inflammatory cytokines TNF-α and IL-1β into healthy animal subjects generates behaviors similar to social withdrawal. A meta-analysis examining the connection between inflammation and response to depression treatment found that antidepressants lower IL-6 levels, regardless of treatment outcome. Furthermore, the same analysis found that increased TNF-α levels are associated with treatment resistance and that treatment non-responders display higher baseline inflammation levels.

Psychedelics and the 5-HT2A receptor

Where do psychedelics fit into this inflammation scenario? Several psychedelic compounds such as psilocybin, initiate the psychedelic state through the activation of 5-HT2A. Activation of this receptor is thought to acutely reset resting-state functional connectivity (RFSC) to healthy networks to rapidly alleviate depression.

However, some research groups posit that the long-lasting effects of psychedelic-assisted therapy are a result of reduced neuroinflammation. 5-HT2A activation is thought to mediate this reduction in neuroinflammation. However, to build a case for this claim, the focus must shift from the CNS to more peripheral locals.

Peripheral insights

While HT2A is found in high densities extensively throughout the CNS, it is also present in peripheral tissues. These include but are not limited to, endothelial, muscle, endocrine, and immune tissues. The selective 5-HT2A agonist and psychedelic compound (R)-2,4-dimethoxy-4-iodoamphetamine ((R)-DOI) demonstrated a potent anti-inflammatory effect when administered on rat aortic smooth muscle cells. Several 5-HT2A agonists have demonstrated significant anti-inflammatory characteristics, including lysergic acid diethylamide (LSD). However, (R)-DOI was effective at levels in the low picomolar range (IC50 concentrations 10–20 pM).

This low IC50 means that (R)-DOI has an anti-inflammatory effect at doses far below that needed to produce behavioral effects. Furthermore, (R)-DOI was effective in significantly attenuating TNF-α induced inflammation and reduced levels of inflammatory cytokine IL-6. These results may provide an insight into the long-lasting antidepressant effects observed in psychedelic-assisted therapy, as dysregulated TNF-α and IL-6 are associated with the onset and symptomatology of depression.

Other indications for psychedelics and inflammation

Interestingly, one biotech company has identified a potential therapeutic effect of (R)-DOI for indications outside of the realm of neuropsychiatric disorders, but still involving inflammatory mechanisms.

Eleusis, a clinical-stage life science company, recently funded a study that examined the effect of (R)-DOI in treating cardiovascular disease. Leading the study was Dr. Charles Nichols, son of professor emeritus of pharmacology at Purdue University, David Nichols. Using (R)-DOI, Nichols and his team observed a reduction in aorta inflammation and a decrease in overall and HDL cholesterol levels. The vascular study showed physiological without any psychological effects (this is important because mice given a psychedelic can sometimes show behavior consistent with psychosis).

Nichols told Endpoints news in a recent interview, “Translated into the clinic in humans, it would be as if someone was obese, had diabetes, had high cholesterol, and was able to take a low dose of this drug at a sub-behavioral level and really treat several different aspects of the complications of being obese.” He went on to add that the study was translatable to a clinical trial, and was optimistic of drug development within 10 to 20 years.

Eleusis has also begun examining the potential therapeutic benefits of (R)-DOI in the treatment of asthma. Early studies demonstrated the prevention of inflammation associated with acute allergic asthma in a mouse model. Treatment with (R)-DOI significantly reduced pulmonary inflammation and improved airway function.¹²

Summary of psychedelics and inflammation

Science has only relatively recently begun understanding the significance of inflammation in the pathophysiology of neuropsychiatric disorders. The same is true for the role of 5-HT2A agonists in treating the same class of disorders. Much of the current research concerning the therapeutic action of 5HT2A agonists centers around disorders of the CNS (e.g., depression), with short-term amelioration of symptoms thought to stem from changes in the functional connectivity between specific brain regions.

The recent literature outlined in this article posits that the long-term changes observed following psychedelic-assisted therapy may be a result of the anti-inflammatory actions of the compounds. Moreover, this anti-inflammatory effect may be exploited to treat entirely new indications, such as asthma and cardiovascular diseases. However, the reader must recognize that much of the data presented here are still in very early preclinical stages. Nevertheless, it is not unreasonable to think that in 10-20 years, the anti-inflammatory potential of psychedelics will be unlocked, allowing for their use in a multitude of age-related diseases.

Psychedelics as Anti-Inflammatory Agents

A look into the less discussed therapeutic aspect of psychedelics: the anti-inflammatory effect.

psychedelicreview.com

 

[mr peabody]

Psychedelics modulate innate and adaptive inflammatory responses through the Sigma-1R receptor

Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi

The orphan receptor Sigma-1R is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models.

Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via Sigmar-1R that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the Sigma-1R receptor.

http://publichealthwell.ie/journal/p..._complete=true​

 

[mr peabody]

Expression of GLUT3 on activated T cells. GLUT3 (green) is localized on the cell surface, the mitochondria (violet)
and the nucleus (blue) were also shown.

How Sugar Promotes Inflammation

University of Würzburg | Neuroscience News | 22 Mar 2022

Excessive glucose consumption directly promotes the pathological function of certain cells within the immune system. Calorie-reduced diets can have beneficial effects on the immune system and those with autoimmune diseases.

People who consume sugar and other carbohydrates in excess over a long period of time have an increased risk of developing an autoimmune disease. In affected patients, the immune system attacks the body’s own tissue and the consequences are, for example, chronic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, type 1 diabetes and chronic inflammation of the thyroid gland.

New targets for therapy

The underlying molecular mechanisms that promote autoimmune diseases are multilayered and complex. Now, scientists at the Julius Maximilians University of Würzburg (JMU) have succeeded in deciphering new details of these processes.

Their work support the notion that excessive consumption of glucose directly promotes the pathogenic functions of certain cells of the immune system and that, conversely, that a calorie-reduced diet can have a beneficial effect on immune diseases.

Based on these findings, they also identified new targets for therapeutic interventions: A specific blockade of glucose-depended metabolic processes in these immune cells can suppress excessive immune reactions.

Dr. Martin Väth is responsible for the study, which has now been published in the journal Cell Metabolism. He is a junior research group leader at the Institute of Systems Immunology—a Max Planck research group under the umbrella of JMU that focuses on the interplay of the immune system with the organism. Collaborators from Amsterdam, Berlin, Freiburg and Leuven were also involved in this study.

Glucose transporter with a side job

Martin Väth explains that “immune cells need large amounts of sugar in the form of glucose to perform their tasks. With the help of specialized transporters at their cell membrane, they can take up glucose from the environment.”

Together with his team, Väth has showed that a specific glucose transporter—scientifically named GLUT3—fulfills additional metabolic functions in T cells besides the generating energy from sugar.

In their study, the scientists focused on a group of cells of the immune system that have not been known for very long: T helper cells of type 17, also called Th17 lymphocytes, which play an important role in regulating (auto-) inflammatory processes.

“These Th17 cells express lots of GLUT3 protein on their cell surface,” Väth explains. "Once taken up, glucose is readily converted to citric acid in the mitochondria before it is metabolized into acetyl-coenzyme A (acetyl-CoA) in the cytoplasm. Acetyl-CoA is involved in numerous metabolic processes, including the biosynthesis of lipids."

However, acetyl-CoA fulfills additional functions in inflammatory Th17 cells. Väth and his team showed that this metabolic intermediate can also regulate the activity of various gene segments. Thus, glucose consumption has a direct influence on the activity of proinflammatory genes.

According to the researchers, theses new findings pave the way for the development of targeted therapy of autoimmune diseases. For example, blocking GLUT3-dependent synthesis of acetyl-CoA by the dietary supplement hydroxycitrate, which is used to treat obesity, can mitigate the pathogenic functions of Th17 cells and reduce inflammatory-pathological processes.

The so-called “metabolic reprogramming” of T cells opens new possibilities to treat autoimmune diseases without curtailing protective immune cell functions.

How Sugar Promotes Inflammation - Neuroscience News

Excessive glucose consumption directly promotes the pathological function of certain cells within the immune system. Calorie-reduced diets can have beneficial effects on the immune system and have autoimmune diseases.

neurosciencenews.com

 

[mr peabody]

Psychedelics in the treatment of Autoimmune Disorders*

by Jeff Nielson | PSW | 2 Mar 2021

Psychedelic drugs are our best hope to address the Mental Health Crisis.

Clinical research on these drugs is showing spectacular potential to revolutionize treatment of mental health conditions that currently afflict roughly 1 out of 6 people on the planet.

However, as the psychedelic drug industry has evolved, it has begun to expand its reach – rapidly. Look at some of the new fields of research being targeted by psychedelic drug R&D.

Autoimmune Disorders

“Autoimmune disorder” is an umbrella term that encompasses roughly 100 different diseases. These diseases exhibit drastically different symptoms, but are all derived from the same underlying cause: the body attacks and damages its own tissues.

New research into this branch of medicine postulates that these disorders are derived from “psychosocial stress”, which manifests itself in the gut microbiome. Now researchers are exploring whether psychedelic drugs can “modulate” the gut microbiome and “normalize” physiological stress responses.

As with psychedelics-based research into mental health disorders, this research is addressing the underlying cause of (all) these conditions, not merely attempting to treat symptoms. Thus, as with psychedelics-based mental health research, this R&D has the potential to revolutionize the treatment of autoimmune disorders.

Chronic Pain

Chronic pain is another gigantic treatment market. It shares similarities with many mental health treatment markets in that existing treatment options have produced very mixed results, and led directly to a “crisis”: the Opioid Crisis.

A 2020 research paper published in Regional Anesthesia and Pain Medicine “proposed a mechanism by which psychedelics may relieve chronic pain.” Specific treatment markets would include cancer pain, phantom limb pain, cluster headaches and migraines.

This is not a novel theory. Scientists have long believed that psychedelic drugs have potential in pain management. Ketamine, the only widely legal psychedelic, has been used off-label to address chronic pain for many years.

MindMed Inc (CAN:MMED / US:MMEDF) is already in a Phase 2 clinical trial testing the potential of psychedelic drugs to treat cluster headaches. Other psychedelic drug companies are also currently pursuing pain-related applications for psychedelic drugs.

Traumatic Brain Injury (TBI)

The previous categories of medical conditions are well-established, with long histories of mixed treatment results. In contrast, as with psychedelic drug research itself, traumatic brain injury is an emerging field of medical study.

It is only in recent years that our healthcare system has paid closer attention to TBIs (most notably concussions). Diagnostics have improved and physicians have become much more proactive in addressing these injuries.

But treatment options have not caught up (yet) with the diagnostics.

Dr. Dan Engle, author of The Concussion Repair Manual, is lead researcher with Mind Cure Health (CAN:MCUR / US:MCURF) in its recently announced psychedelics R&D for TBI. Dr. Engle frames the current picture with respect to the treatment of traumatic brain injuries.

“Historically, the treatment options for TBI recovery have been severely limited. Thankfully that is changing, and psychedelic medicine therapy is one of those ripening areas of research and benefit.”

Unfortunately, many (most?) people will suffer at least one ‘knock on the head’ over the course of their lives that could potentially result in TBI. Currently, patients suffering from these injuries have limited options in recovering.

MINDCURE is hoping that its psychedelic drug R&D can lead to greatly improved treatment outcomes in the future. Dr. Engle expands on this.

“The reason for the excitement here is because this class of medicines (which include ketamine, psilocybin, cannabis and others) are supportive for helping repair both of the underlying ramifications of the injury - neurologic and psychologic. No other class of medicines today has the same potential to positively address both issues simultaneously.”

Psychedelic drugs: a half-century of R&D to catch up on

Research on the medicinal applications of psychedelic drugs was still in its early stages when drug Prohibition slammed shut the door – for roughly half a century. As the failure of the War on Drugs is widely acknowledged, the research door is now wide open.

These drugs are still generally illegal for consumption (even for medicinal use). But as Psychedelic Stock Watch recently explained, prospects for the near-term legalization of some of these substances are better than most investors might think.

That article was focusing purely on the mental health applications of psychedelic drugs. If some of these newer fields of research start to produce similar success in clinical trials, how much additional pressure will that put onto politicians to legalize these drugs – and normalize their usage?

The Psychedelics Revolution has been viewed to date as a revolution in mental health care. But as the industry evolves and the R&D expands and deepens, this Revolution may transform into a general healthcare revolution.

The Psychedelics Revolution is now underway. And it may be a much, much bigger Revolution than even the most bullish investors originally suspected.

*From the article here :

Biggest Opportunities for Psychedelic Drugs OUTSIDE of Mental Health? | Psychedelic Stock Watch

The Mental Health Crisis is a huge opportunity for psychedelic drugs. But the BIGGEST potential markets may exist outside...

psychedelicstockwatch.com

 

[mr peabody]

Psychedelics and Autoimmune Disease​

 

[mr peabody]

Microdosing Psychedelics with Autoimmune Diseases

Community Member "Edo" | Microdosing Institute | 11 Oct 2021

Community member Edo shares with us how microdosing psychedelics led to an unexpectedly wide range of improvements in his life – both mentally and physically. He summarizes his journey to date as follows: “It was a long search, but after some ups and downs it led to a reduction of medication use and an increased quality of life.”​

Inflammatory diseases​

My microdosing story is mainly a medical story. I was diagnosed with type 1 diabetes when I was 28. When I was 36 I also got scleroderma (systemic sclerosis). A rare form of rheumatism in which, in short, the skin and everything that has connective tissue, hardens. With some bad luck, the disease quickly escalates into the lungs and heart. I turned out to have an atypical form, the cause of the inflammation could not be found. I was lucky that the disease developed slowly. In a few years my skin hardened, and movement became more difficult. At a certain point, the complaints became such that I had to take immune-suppressing medication. This stopped further deterioration.​

Initial research​

At first microdosing psychedelics caught my eye, because I experienced a leak in my intelligence and creativity. (Later I found out that a link is suspected between scleroderma and Alzheimer’s disease.) It would also be nice to do something about my age old problems with concentration and recurring depressions. My first concern was if I could combine it with the medication I was taking. This had become quite a collection by now. I inject insuline daily, I take immunosuppressants, pills for the thyroid and an antacid. But in my search for articles about that, I stumbled upon an article that talked about the healing effects of psychedelics on atheroscleroses, arthritis, psoriasis, type 2 diabetes, depression and Alzheimer’s disease. Multiple diseases that are related to scleroderma. The results were very promising. It was suspected that psychedelics could prevent inflammation, and possibly even repair damage already done.​

A difficult choice​

I bought ALD52 which was still legal during that time [an LSD analogue similar to 1p-LSD and 1cp-LSD, MDI], but after that I remained in doubt for a long time. I worried most about whether I dared to tinker with my immune system myself; I have a chronic variant now, what if I turn it into an escalating variant. I’m not a scientist and my medical-scientific English is poor at best. I found it difficult to decide whether I would be doing the right thing. Contact with my doctors, however, yielded little. The studies were conducted by experimental pharmacists and too little was known about the subject. No one dared to say anything specific about it. Doctors become very cautious when there is no scientific consensus. Rightly so, you don’t want a gambler for a doctor, but for an individual patient everything then comes to a standstill. If scientific consensus is reached in 20 years’ time, it won’t be of much use to me. An aside: Online, via written consultations, it is easier to contact a doctor these days, but I found that when it comes to these kinds of questions, it’s better to consult in direct contact. I suspect that doctors will talk more freely. In the end, those conversations boiled down to this; there is no evidence that psychedelics can improve your situation, but there is also no evidence that it will make the problems worse. In the meantime I strongly suspected that microdosing LSD could help me. Not only to get my thinking back on track, but perhaps even to suppress the scleroderma.​

Experiments and results​

It was now almost a year later and I dared to start my first experiment. Under the guidance of a coach of Microdosing Institute, I took the lowest recommended dose of ALD52, twice within one week. I didn’t really notice it that much. Only visually it looked like windows had been washed again after a long time, similar to the CBD oil I took a year earlier. But in the next two weeks, the skin on my arms started to loosen and my joints became more flexible. I could handle the chaos of our young family better, I managed to concentrate for a longer period of time and I even dared to jump on a trampoline with my stiff body without the fear of breaking in half. And this after only two microdoses. That I wanted more of. If I was going to continue with this it would be good to get some new ALD52, since I had it laying around for almost a year. Unfortunately, in the meantime, ALD52 had been declared illegal and was no longer available. I then opted for 1P-LSD. This time no drops, but a quarter of a blotter, the lowest recommended dose. Again I took the microdose twice within one week. I felt pressure on my eyes and I had energy, but it felt a bit artificial. My vision was very clear and the colours became more intense. As if it was the photographic ‘golden hour’ all day long. I felt good, but my eyes needed rest.​

Panic​

A week later I had an appointment with my immunologist. This was the first meeting with a new doctor who had yet to get to know my skin. (I know, I could have timed my experiments better) This doctor was a lot less enthusiastic about my skin than I was. During the conversation there was a very serious, dark mood and I was suddenly not so sure of my own observations. On the drive home, I suddenly felt my face tighten and my shoulders and arms harden. Never before had I experienced such a rapid aggravation of my disease. In the days that followed, panic set in. All fearful thoughts raced through me. Had I given my immune system too hard a blow and had the escalation started? Within a week I felt like I was wearing a shirt way too tight. Till two weeks later I had panic attacks and every now and then the colours became more intense again. Two weeks after the last microdose, the colours became so intense during a bike ride that I became anxious. It lasted for up to three weeks that, especially during dinner, everything around me turned a deep orange. It’s speculation, but it may have taken this long because I swallowed the quarter blotter the second time I took one, maybe some of it got stuck. Apparently I react very strongly to low doses and I had a three weeks long sort-of semi-trip. Fortunately, in the weeks that followed, the skin softened and I got calm. In the end the result was that I was more flexible and my skin was far softer than before this whole adventure.​

Psychosomatic symptoms​

Although this was a very bad mistake, it did teach me a lot. Because my body suddenly changed so much after a very unpleasant visit to the doctor, it seems that my problems are partly psychosomatic. The ALD52 enhanced this effect. In this case it worked negatively, but I know it could also work in my favor.​

The journey goes on​

I had experienced anxious moments, but the positive changes in my body were such that, two months later, I wanted to try again with my old drops. The problem was that I found myself drifting back into depression. Because the last time my mindset was so influential on the result, I decided to wait. A month later I was ready to start. Over a period of two months, I took four drops once a week. In the beginning I saw some intense colours again, so I brought it back to three drops. On a microdosing day I sometimes felt restless, but otherwise I didn’t notice much. Little by little, my skin became more flexible. After those two months I took a month off from microdosing and it was during this period that my skin improved even faster. I started to learn more about the world of psychedelics. The ALD52 made me a bit restless. The idea came up to give it a try with XP truffles in combination with Lion’s Mane. Chaga also caught my attention because of its claim that it could balance the immune system.​

XP truffles: finally able to sleep well and have more control over the diabetes​

For two months I microdosed XP truffles according to the Fadiman protocol. In combination with a daily dose of Lion’s Mane and Chaga. I started with 0.3 grams, the lowest recommended dose of truffles. I tried to increase it twice, but that made me restless again. During those restless days I saw the world in the colours of the ‘golden hour’ again. Another side effect is that I felt some muscle pain in my neck on the microdosing day. I now know how to compensate for the sleepiness after taking the truffles with a drop of extra Lion’s Mane. Or I take them in the evening. And also with the Lion’s Mane and Chaga, I intuitively found out that I needed less than advised. The Lion’s Mane in particular made me hyperactive at the prescribed dose. Almost immediately after the first dose of truffles, I noticed improvements in my life that I wasn’t looking for beforehand.

I have been sleeping badly since I was about 13 years old. Sometimes I managed to maintain a good sleep rhythm for a few days in a row, but often I quickly lost it again. Sleep has always been a battle for me, a battle I mostly lost. When I started with the truffles I immediately slept a lot better. In the past I sometimes needed hours to fall asleep and I also needed multiple hours in the morning to really wake up (Using many cups of coffee). Now I get much more return from my sleep. I fall asleep quickly, I regularly wake up a few minutes before the alarm and really feel refreshed. That has never happened to me since I was a teenager.

In addition, my mental condition has drastically improved. A few years after I was diagnosed with scleroderma, I noticed that I was becoming less witty. In chaotic situations, I quickly became confused. I got annoyed quickly, I was always tired and became depressed for a long time. In bad moments it was like wearing a closed helmet and I was having a hard time connecting with anything that went on outside of my own mind. All this seems to have completely disappeared. (Okay, I still get annoyed sometimes, but that really is to blame on the other person…)

At the time of writing this, excluding one bad day, I am free of depression for eight months. And another unexpected success. My glucose levels calmed down. I can live-monitor the sugar level in my blood. Normally at night the glucose levels looked very messy with a lot of rises and falls. Now suddenly I saw a straight line. Also during the day I kept my glucose levels neatly within the lines. My need for insulin has decreased by about a quarter. I have become more active during the day, so I don’t know whether that decrease is directly or indirectly caused by the microdosing. The functioning of my thyroid has remained unchanged, tests showed no change and the amount of medication has remained the same.​

More ‘strange’ improvements​

Nowadays I only drink 1 cup of coffee in the morning, I don’t need any more. I think I’ve replaced the coffee with the Lion’s Mane, but the energy I get from that feels much more natural and a not stressed. I have become more relaxed. I get a lot more done in a day than I used to and I no longer constantly have that rushed feeling. Strangely enough, my eyebrows are also coming back, as is the hair on my arm. These had been slowly disappearing in recent years. I suspect the Chaga is at work here. Another unexpected by-catch, a relief from light compulsive behavior. This wasn’t a real big burden in my life, but almost always after I locked the car or the house, I checked to see if it was really locked, sometimes I walked back dozens of meters to check what I already knew. I don’t do this anymore.​

Decrease in medication​

I can now draw wrinkles across my skin. The hardened skin recedes further and further and my face is slowly returning to its old self. Meanwhile, I have more energy than I have had since childhood. Not hyperactive, but an energy level comparable to a healthy person. My doctor has also seen how much I’ve improved. In consultation, I reduced the immunosuppressants to a third of the original dose. If the improvements continue for another two months, I will stop taking the immunosuppressants completely.​

After a month long break from the XP truffles​

During this break it became a bit more difficult to keep my glucose levels in order, I use more insulin again and the good sleep also decreased slightly. But both are still way better than what they once were. At the time of writing this there has been no deterioration of my skin, so I am going to stop taking the immunosuppressants altogether. Now I’ll have to see for some time if I really can do without.​

Looking back, half way through​

It has now been a year since I first took a microdose. I searched for information from various sources, but with that in hands I acted intuitively and above all listened carefully to the feedback from my body. I’ve tried a number of different things, so I can’t always say which one caused which improvement. There is a good chance that one improvement, like a domino, caused the other. It seems that there is a psychosomatic side to my illness. Stress and depression translated directly into physical ailments. And in my life, those two were always just below the surface. The psychedelics have set me on a different path, both physically and mentally. The improvements I am experiencing are so comprehensive that I have come to believe that the psychedelics are tackling the problem at the source.

Microdosing Experience: Microdosing psychedelics with autoimmune diseases | Microdosing Institute | Education, community & research

Microdosing psychedelics helped community member Edo find relief from diabetes type 2 and auto-immune inflammatory disease scleroderma.

microdosinginstitute.com

 

[mr peabody]

Psychedelics as a novel approach to treating Autoimmune Disorders*

by CaitlinThompson, Attila Szabo | December 2020

With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the AiD patient population. Classic serotonergic psychedelics have recently been gaining public and professional interest as novel interventions to a number of mental health afflictions. Psychedelics have also been shown to be able to modulate immune functions, however, while there has been great interest to researching into their psychotherapeutic applications, there has so far been very little exploration into the potential to treat inflammatory and immune-related diseases with these compounds. A handful of studies from a variety of fields suggest that psychedelics do indeed have effects in the body that may attenuate the outcome of AiD. This literature review explores existing evidence that psychedelic compounds may offer a potential novel application in the treatment of pathologies related to autoimmunity. We propose that psychedelics hold the potential to attenuate or even resolve autoimmunity by targeting psychosomatic origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations.
​

Inflammation and immune modulation

In autoimune diseases (AiD), rampant chronic inflammation is a keystone feature. Elevated levels of cytokines and their dysfunctional regulation involving interleukin(IL)-6, IL-1β, IL-17, tumor necrosis factor-α (TNF)-α, IL-12, interferon(IFN)-γ and others are a shared feature observed in many AiDs including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), systemic sclerosis, and Sjögren's syndrome. Lipopolysaccharide (LPS) is an inflammatory component of the cell wall of Gram-negative bacteria that can induce inflammation and excessive oxidative stress that may play a role in elevated inflammatory biomarkers seen in those with AiD diseases. Those with AiD display auto-antibodies and yet also display immunodeficiency. Immune modulation appears to be a feasible target in approaching the treatment of AiD.

While the area of research is quite underdeveloped, there is some evidence that psychedelic compounds have anti-inflammatory and immune-modulating effects Table 1. For instance, LSD displays the ability to suppress the proliferation of B-lymphocytes, as well as the production of the pro-inflammatory cytokines IL-2, IL-4, and IL-6 in in vitro splenic lymphocytes derived from 6−8 year old female B6C3F1 rats at concentrations of LSD between 1–100 μM. The same study observed that administered doses of LSD between 0.001−0.1 μM in rat lymphocytes increased the number of Natural Killer (NK) cells, while concentrations of 100 μM suppressed NK cell production. In another study, the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine (DOI) was shown to reduce TNF-α levels in 10 week old adult male C57BL/6 J mice via agonism of the 5-HT2A receptor in doses ranging from 0.01 μM/kg to 10μM/kg. Furthermore, in a recent study the same group expanded the previously observed anti-inflammatory effects of 5-HT2A agonism to additional psychedelics in a rat model of lung inflammation.

There is substantial literature on the 5-HT system and its complex inflammation and immune-regulating abilities in tissue specific manners. Functional studies showed that 5-HT modulates the release of IL-1beta, IL-6, IL-8/CXCL8, IL-12p40 and TNF-α, while it has no effect on the production of IL-18 and IFN-gamma in LPS-stimulated human blood monocytes [66]. 5-HT can also modulate human macrophage polarization and dendritic cell functions, and can contribute to the maintenance of an anti-inflammatory state via 5-HT2B and 5-HT7 receptor binding. Given the role of the 5-HT system in immune-modulation and inflammatory properties, it is highly likely that there are undiscovered immune and inflammatory effects from exposure to psychedelic compounds due to their serotonergic activity. In the previously mentioned study where DOI was observed to reduce TNF-α in mice, in groups where the 5-HT2A antagonist drug M100907 was administered, the reduction in TNF-α was not observed supporting the theory that the 5-HT2A receptor and the 5-HT system as a whole may be fundamental to creating downstream immunological and inflammatory-regulating effects.

In addition to the 5-HT receptors, DMT and 5-MeO-DMT also have high binding affinity for the Sig1R. The Sig1R plays a fundamental role in the regulation of different cellular mechanisms such as mitochondrial function, apoptosis, proliferation, and neuroprotection. Sig1R also modulates inflammatory and immune responses by regulating the activation of the transcription factors nuclear factor kappa B (NF-кB) and several mitogen-activated protein kinases (MAPKs). Both NF-кB and MAPKs are important regulators of gene transcription involving immune responses and the production of inflammatory cytokines.

Serotonergic psychedelics may emerge as potential candidates in the treatment of autoinflammatory and autoimmune conditions Table 1. Since pharmaceutical grade DMT and other tryptamine analogs [84] designed for human clinical trials are already available or will soon enter the market, testing the in vivo physiological effects of serotonergic psychedelics in humans is now closer than ever before.

Discussion and perspectives

There is vast opportunity to explore the effects of psychedelics on the immune system, in particular, autoimmunity. Systematic screening for various autoantibodies, inflammatory biomarkers, and for the expression of autoimmune-related genes in response to psychedelic treatments could provide intriguing observations and lead to more focused investigations.

The effects of psychedelic compounds on enteric bacterial behavior is of particular interest. Studies could be conducted examining the effects on bacterial growth and metabolism as a result of exposure to psychedelic compounds. In vitro and in vivo studies may hold many answers and even more questions about if and how serotonergic psychedelic compounds may be transported into bacterial cells and influence microbiome colonization and species composition. Studies could examine the effect of administration of psychedelics on enteric epithelial tissue integrity in the gut, or effects on LPS-induced cytotoxicity, etc.

Although results from preclinical studies on the immunomodulatory and anti-inflammatory effects are promising, the field of psychedelic research in biomedicine is still in its infancy. Current hypotheses regarding signaling mechanisms and systemic immune effects of psychedelics are based on a very limited amount of factual data. Only until we better understand the genetic and pathophysiological bases for AiD can there be appropriately and rigorously designed human clinical studies that consider psychedelics as potential therapeutic agents.

While there is a need for deeper investigation, there appears to be enough evidence of direct and indirect effects from psychedelic compounds that may benefit those with AiD to merit further exploration on the topic. Given the complexity of factors that contribute to AiD, a multi-facetted approach may be appropriate to address the multiple features and causes of AiD simultaneously. Unlike many current conventional treatment methods, it appears that psychedelics may potentially offer an efficacious strategy for relieving and perhaps even resolving autoimmunity by targeting psychospiritual origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations. The evidence presented in this paper provides support to the idea that there is untapped potential of exploring the use of psychedelics within this specific disease category. Given the limitation of efficacious treatment options for AiDs, and the physiological safety of psychedelic substances, it is likely a research topic worth pursuing. There is hope that the collection of this evidence may guide or inspire others to pioneer such studies. Overall, this direction of research is virtually unexplored and underdeveloped, providing a wealth of opportunities to discover novel applications for psychedelics in the field of immunology.

*From the article here :

Psychedelics as a novel approach to treating autoimmune conditions

With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the Ai…

www.sciencedirect.com

 

[mr peabody]

The Science and Healing Benefits of Psychedelics ​

by Wendy Kagan | Chronogram

Since she was a kid, visual artist and musician Emily Ritz has struggled with Lyme disease and juvenile arthritis, an autoimmune disease that has wreaked permanent havoc on her body. Both conditions are under control and arthritis medication keeps her functional, but self-care remains a full-time job. "I've tried everything—holistic treatments, diet changes, exercise with a physical therapist and personal trainer to gain back some strength," she says. "I was doing all this hard work and still having really bad days of inflammation and exhaustion," she says. "I was frustrated by that, and obviously you get depressed because it all adds up."

About two years ago, Ritz heard about microdosing, which involves taking small amounts of psychedelics for a therapeutic effect. "I had done psychedelics recreationally growing up and loved them," she says, "though I stopped tripping a long time ago because I felt like I had received all the messages I needed to download." Exponentially more subtle, microdosing is very different from tripping and generally acts like a mood enhancer; the idea is to take a miniscule dose every few days to experience its benefits. So Ritz filed it away in her mind as something she might try in the future. Psychedelics are illegal, making access tricky. Yet after finding a source for magic mushrooms last winter, she let a stash sit in her medicine cabinet for a couple of months. Come spring, it was calling to her.



"After embarking on some other big efforts to feel better, including a ketogenic diet, I felt like I had space to add this other element in," she says. "And honestly, from day one, it completely changed everything. I stopped having bad days, physically and mentally." Ritz had dreamed of hiking and swimming in the magical places near her home in Hudson but had been too exhausted for adventures like that. Until now. "The day after I started microdosing, I would hop out of bed in the morning early to go hike and swim. I felt so energized. I was living my fantasy." Ingesting a wee bit of mushrooms periodically also seems to help Ritz produce more of her art (featured in our August issue), lending her extra focus and inspiration. "It's the most powerful antidepressant and anti-inflammatory for me, and I think it could help so many people. It's amazing to me that a tiny bit of this fungus could give me such a leg up."

Journeying, with white lab coats

Interest in psychedelics is mushrooming these days, with research looking into use of the substances in a range of doses for a wide array of therapeutic applications—whether it's LSD-assisted psychotherapy for anxiety, ayahuasca or ibogaine for drug addiction, or ketamine for treatment-resistant depression. The science of psychedelics is not new, as an initial wave of enthusiasm swelled after LSD's discovery in the 1940s. Yet after Timothy Leary's infamous Harvard Psilocybin Project went up in smoke in 1963, and after the criminalization of psilocybin mushrooms and LSD in 1968, hallucinogens exited the scientific arena and went underground. About a generation later, in the early 2000s, public interest surfaced again thanks to the resuscitative efforts of a small group of scientists, psychotherapists, and "psychonauts" like Dr. Stanislav Grof. Last year, science and food writer Michael Pollan (Omnivore's Dilemma) shone a national spotlight on the topic with his bestselling book How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence.

"We have more clinical trials happening now than at any time in history, even before psychedelics were criminalized," says Brad Burge, spokesperson for MAPS. "The key challenge for psychedelic research for the last 40 years has been the chilling effect of the stigma. Once people see that this is a legitimate area of research, and the research is really promising, that encourages a lot more people to get involved."

The research is promising, indeed. MAPS itself supports a wealth of studies involving psychoactive substances, including a clinical trial on MDMA-assisted psychotherapy that shows remarkable results in treating PTSD. In that trial, researchers found that MDMA (a methamphetamine commonly referred to as Molly and a purer form of ecstasy, which is generally cut with adulterants) is safe when combined with psychotherapy and, in most cases either drastically improves PTSD or—56 percent of the time—cures the patient completely of PTSD symptoms. "In combination with therapy, MDMA reduces fear, enhances therapeutic alliance, enhances trust and intimacy, and helps people talk very clearly about their memories," says Burge. "I've heard it said that if you could design a drug to treat PTSD, it might look a lot like MDMA." And patients need only take it two or three times, in a guided therapy session, to reap lasting benefits. The FDA designated MDMA a "breakthrough therapy" for PTSD in 2017, fast-tracking its approval. If all goes as planned, MDMA will be the first drug of its kind available for clinical use, which MAPS expects to happen in 2021.

Knowledge around psilocybin, the hallucinogenic compound in magic mushrooms, is leaping forward too, alongside a push toward legalization of the substance by certain advocacy groups. Last year, the FDA granted breakthrough therapy status to a psilocybin-assisted therapy for treatment-resistant depression in trials conducted by a London-based life sciences company. And two 2016 studies from Johns Hopkins University and NYU Langone Medical Center found that a single, large dose of psilocybin in a closely monitored session could substantially decrease depression, anxiety, and the fear of death in terminal cancer patients, while increasing a sense of "life meaning" and optimism. Meanwhile, Johns Hopkins has active trials exploring psilocybin as a treatment for smoking cessation.

Notably, psychedelics science has focused mainly on high doses rather than on microdoses—despite the growing popularity of microdosing mushrooms and LSD, which is largely a grassroots phenomenon. One popular use for microdosing is to enhance performance, whether it's athletic, creative, or cognitive performance, although none of these applications have been tested scientifically. "Right now, there's very little or maybe no completed research on microdosing for its specific beneficial effects," cautions Burge. "All we have are case reports. We also know that a lot of people are doing it—and that the headlines about microdosing have gotten way out in front of what we actually know about microdosing." Trials are starting, including a basic safety study by the Beckley Foundation in the UK to see if small doses of acid can improve things like problem solving and creativity in healthy patients. (An LSD microdose is about 10 micrograms, roughly one-tenth of a typical recreational dose, taken once every four days or so.) Yet before running out to try Lucy in the Sky with Diamonds for your self-improvement project du jour, it's best to stay tuned and wait for the science to catch up with the hype.

Laboratory of the mind

The psychedelics community is certainly tuning in to the science, but not everyone is waiting for legalization, or even a prescription, to get started. Brandon Richards, a counselor and life coach based in New Paltz who works as a "sitter" for people undertaking psychedelic tripping and as a guide for microdosing, says, "When we know that something works, we do it. We do it as safely and as ethically as we can." Richards (not his real name) recently sat with a woman doing MDMA-assisted therapy, following a protocol laid out by MAPS. "This woman has been haunted by physical and emotional abuse by each of her parents, and it's made her life almost undoable. She's been in therapy for years and does yoga and prayer and journaling—all the right things. But the MDMA is the only thing that gave her the courage and the clarity to speak from a perspective that lifted the burden of what happened to her." Self-medicating with psychedelics is risky business, and Richards notes that his client is working closely with professionals throughout her treatment journey.

Of course, interest in psychedelics doesn't just apply to people struggling with a mental health issue or physical illness. Plenty of regular folks are turning to hallucinogens as a route to personal growth and mind expansion. Jake Singer (a pseudonym) first explored psychedelics about five years ago with his partner at the time and had a "very profound experience." Setting out to understand what happened, he discovered the work of James Fadiman, psychologist and author of The Psychedelic Explorer's Guide: Safe, Therapeutic, and Sacred Journeys. Singer followed Fadiman's protocols and embarked on a program of microdosing mushrooms (one day on, two days off) for four months to see how it might benefit him. He noticed two impacts right away, including a change in the way he perceived light ("everything had more depth to it") and "a much better sense of empathy for the people I interacted with, whether it was coworkers, my partner, or people I would meet," he says. But the impacts did not end there. He also gained deeper clarity about what he valued and a new ability to turn "vague notions" into concrete actions. Within a year of his foray into microdosing, Singer had uprooted his old life—leaving an education-technology job in New York City and moving upstate to start a career in agriculture technology. "It was an intentional shift as a result of doing a lot of work around my beliefs and values," he says. It was, in short, a new understanding of his life's purpose.

Psychedelics, perhaps, have a unique power to shake us loose from habitual thinking patterns, making seismic shifts possible. "Habits are undeniably useful tools, relieving us of the need to run a complex mental operation every time we're confronted with a new task or situation," observes Michael Pollan in How to Change Your Mind. "Yet they also relieve us of the need to stay awake to the world: to attend, feel, think, and then act in a deliberate manner.... One of the things that commends travel, art, nature, work, and certain drugs to us is the way these experiences...immerse us in the flow of a present that is literally wonderful—wonder being the by-product of precisely the kind of unencumbered first sight, or virginal noticing, to which the adult brain has closed itself." Pollan wrote about full-dose psychoactive experiences—not microdosing—as he set out to follow in the footsteps of current science. As we learn more about microdosing, we might find that it, too, gives us the power to break away from sleepy old patterns and wake up to new possibilities.

A roadmap for exploring with intention

It's easy to get swept away by a starry-eyed vision of psychedelics and human potential—although Pollan, ever the practical thinker, espouses a cautious approach. Embarking on a full-dose psychoactive experience is best done under the guidance of a sitter who will faithfully adhere to safety measures and other protective guidelines. In his own sitter work, Brandon Richards says that having an intention—a clear sense of what you want to get out of it—is very important when you're about to trip with psychedelics. "Without an intention, it's like hitchhiking: it can go well or it might not. It can be dangerous though it's usually not, and it's often uneventful unless you direct it in some way." Equally important is having a positive "set and setting"—a phrase coined by Timothy Leary to describe a bulwark for your experience via your mindset (shortened to "set") and physical and social environment (setting).

Finally, dose makes a big difference. Microdosing mushrooms, the mildest experience, involves a miniscule dose of .1 to .2 grams and "is very beautiful, creative, and expansive," according to Richards. Between half a gram and a gram is elevating and energizing; it can raise the libido, fuel creative pursuits, or even help you create a plan for yourself. When you get to a gram, "The visuals kick in, so you don't want to be doing anything that requires any responsibility," he advises. And one to three grams is full-on journeying. "You're going to another dimension where the room can disappear. I've had the awareness that there's something brilliantly useful for me in this playground, in this laboratory," he says. "It's a place to go and bring something back." It's not always comfortable, but that's not necessarily a reason to shy away. "A lot of people are afraid of a bad trip," Richards notes. "But a so-called 'bad trip' teaches you more than a fun-filled fantasy adventure ride where you see colors and shapes, because you're facing fear." Some people describe experiencing a "dissolution of the ego" that can feel unstable or heart-opening, depending on how you look at it. A sitter can gently steer you back to a place of confidence and comfort so you can freely explore.

Still, there are risks. Tripping is not recommended for those with a personal history or family history of psychosis. Certain prescription drugs interact poorly or even dangerously with psychedelics. Dependency is rarely an issue with larger doses, because a full trip is too intense to be habit-forming. Yet when microdosing, people with addictive tendencies might need to check themselves against craving that luminous, supercharged feeling every day. In fact, microdosing doesn't work unless you take days off—otherwise you build up a tolerance for it. Emily Ritz learned this the hard way. "I was so excited about the effects that I took it every day at first," she says. "I was like, 'I need this.' It was fine for a week or two, and then I wasn't feeling the effects anymore." Experienced mushroom microdosers recommend taking it every three days or so, though more research is needed into what constitutes the safest and most effective rhythm.

A peek into the mystical

For many psychedelic journeyers—whether they do an ayahuasca ceremony every three to four months, or embark on an annual mushroom trip as a mental health tune-up—it's about transcendence and experiencing the numinous. Such pursuits are therapeutic too, affecting our sense of wellbeing, purpose, and connectedness to the world. One participant in the Johns Hopkins' psilocybin trial for cancer patients described feeling "bathed in God's love," even though she was a staunch atheist.

"Psychedelics give you the direct experience of seeing that everything is made of the same energy," says Aaron Dias, a Kingston-based meditation coach and yoga teacher who is studying shamanism. "Meditation does it too, though it's a slower process. You can read spiritual books all day that say, 'We're all one energy.' But some part of me doesn't believe it until I see it. Psychedelics wake you up. They show you that you have direct access to all of it, and you don't need to have it mediated by anybody else."

Recognizing this potential, Dias adds that it's essential not to belittle the experience by saying, 'Oh, it's drugs.' Such thinking reflects the kind of stigma that needs to dissolve if we want to absorb the teachings that psychedelics bring. "That's why I call it medicine," she says. "In shamanic circles, you don't use the word drug, because right away it starts to separate you from the profundity of the experience. We have to treat psychedelics like they're our teachers. They're our guru. And so you treat them with great respect. Humans have been engaging with all sorts of psychotropics all over the world for a very long time. They're some of the most powerful tools we have for self-realization, healing, and empowerment. I think it's great that people are starting to get hip to that in the mainstream."

Ritz agrees that psychedelics, used cautiously, can help initiate a shift in consciousness that's deeply needed in our world today—even just through the subtle effects of microdosing magic mushrooms. "Maybe if everybody were microdosing, we could fix the climate crisis," she muses. Yet it could be a long and bumpy road toward psilocybin's legalization, if it happens at all. In the meantime, Ritz is grateful to have access to her self-administered therapy, even if it is untested. She regards it as natural medicine, and for her, it works. "It opens my heart and it opens my mind," she says. "It makes me feel more connected."

The Science and Healing Benefits of Psychedelics

Researchers explore the therapeutic benefits of psychedelics from magic mushrooms to Molly.

www.chronogram.com

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