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mr peabody

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Psychedelics as anti-inflammatory agents*

by Thomas Flanagan & Charles Nichols | 13 Aug 2018

Serotonin receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-DOI to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.

Psychedelics produce a potent blockade of the inflammation produced by TNF-α in cell and animal models of inflammation. Because of TNF-α’s controversial role in asthma and (R)-DOI’s impact on numerous factors contributing to the differentiation of multiple immune cells, we believe that the effects of 5-HT2A receptor activation likely extend far beyond the mere blockade of TNF-α signalling. Given the select nature by which (R)-DOI only blocks sub-sets of pro-inflammatory mediator expression, psychedelics may modulate histone modifications and epigenetic signalling for their therapeutic effects. In asthma, an interplay between the acetylation and de-acetylation states of histones in inflammatory genes has been well documented. Furthermore, histone de-acetylase (HDAC) inhibitors have been shown to reduce eosinophilic inflammation and AHR in mouse models of asthma. It is certainly plausible that 5-HT2A receptor activation modulates histone acetylation and methylation patterns to promote the expression of anti-inflammatory genes and repress the expression of pro-inflammatory genes. Only recently has it been establishes that 5-HT2A receptor activity can alter epigenetic factors.

The remaining questions regarding psychedelics and inflammation include:

1. Do 5-HT2A agonists have more pronounced effects in some cell types more than others?

2. Does 5-HT2A receptor activation modulate differentiation of immune-related cells to more anti-inflammatory phenotypes?

3. What are the effects of chronic administration of a 5-HT2A agonist in peripheral tissues to treat immune-related disorders?

It is tempting to speculate on the nature of 5-HT2A receptor activation in other inflammatory disorders. Because 5-HT2A receptor activation impacts the expression of several key inflammatory mediators and the variety of effects we have observed in animal models of inflammation, we believe that psychedelics may be of therapeutic value to a wide range of inflammatory disorders in humans. With regard to therapeutic aspects of psychiatric disorders like depression, putative suppression of neuroinflammation by psychedelics may play a key role in the long-term stability of the reported anti-depressant effects after a single treatment. Another putative component may be stimulation of neurogenesis. For example, the psychotropic ingredient of the Amazonian tea ayahuasca can stimulate hippocampal neurogenesis, which has been shown to reduce depression-like behaviours.

Although the use of sub-behavioural levels of psychedelics remains to be validated as an effective therapeutic strategy for inflammation in humans, the data from cellular and animal models is promising, and these agents represent small molecule, highly bioavailable, inexpensive and steroid sparing treatments for inflammatory-related diseases like asthma, atherosclerosis, inflammatory bowel disease, and rheumatoid arthritis. One possible barrier to the development of psychedelics for use in the clinic is that the majority are scheduled and controlled substances in the United States and several other countries. Nevertheless, drugs that activate the 5-HT2A receptor and that have been shown to produce psychedelic effects in humans have already been FDA approved (e.g. lorcaserin). Although the results we discuss here are promising, more research is needed to fully unlock their therapeutic potentials, and to discover the molecular mechanisms underlying their effects.

*From the article here:

 
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mr peabody

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The anti-inflammatory properties of turmeric

by University of South Australia | Medical Xpress | 5 Mar 2020

For years, curry lovers have sworn by the anti-inflammatory properties of turmeric, but its active compound, curcumin, has long frustrated scientists hoping to validate these claims with clinical studies.

The failure of the body to easily absorb curcumin has been a thorn in the side of medical researchers seeking scientific proof that curcumin can successfully treat cancer, heart disease, Alzheimer's and many other chronic health conditions.

Now, researchers from the University of South Australia (UniSA), McMaster University in Canada and Texas A&M University have shown that curcumin can be delivered effectively into human cells via tiny nanoparticles.

Sanjay Garg, a professor of pharmaceutical science at UniSA, and his colleague Dr. Ankit Parikh are part of an international team that has developed a nano formulation which changes curcumin's behaviour to increase its oral bioavailability by 117 percent.

The researchers have shown in animal experiments that nanoparticles containing curcumin not only prevents cognitive deterioration but also reverses the damage. This finding paves the way for clinical development trials for Alzheimer's.

Co-author Professor Xin-Fu Zhou, a UniSA neuroscientist, says the new formulation offers a potential solution for Alzheimer's disease.

"Curcumin is a compound that suppresses oxidative stress and inflammation, both key pathological factors for Alzheimer's, and it also helps remove amyloid plaques, small fragments of protein that clump together in the brains of Alzheimer disease patients," Prof Zhou says.


Creamy Turmeric Pasta

Turmeric is known for its anti-inflammatory properties, but do you know how to use it?

by Jennifer Wong | ABC Life

Turmeric was once known as 'the poor man's saffron': an earthy-tasting spice good for adding golden colour to food and drinks.

These days it's just at home in the health food aisles as it is in cafes (turmeric latte, anyone?) — and that's because of turmeric's anti-inflammatory properties and potential health benefits.

Of course, it's not a new discovery for everyone.

"Turmeric is in 90 per cent of Indian food, and an average Indian would eat turmeric in 10 different ways in one day," says author and chef Ragini Dey, who's been cooking a range of Indian food in Adelaide for 27 years.

In India, eating turmeric for its healthful properties has also been going on for a long time.

"All spices have some medical benefits. Years and years ago the recipes were made up by Ayurvedic priests and other medical Brahmins, not chefs, and this was all very scientifically done," says Ragini.

So how do you use turmeric in its many forms, from fresh to powdered, and how much do you need to eat or drink if you're interested in the health benefits?

Lesson 1: How to choose and store turmeric

Fresh turmeric looks a lot like ginger (they're part of the same family, along with galangal) except its flesh is a vibrant orange. It's available in shops year-round.

"Look for ones that are nice and rich in colour and a good size, about 50 millimetres long, nice and big like a finger," says Carl Richardson, who grows organic turmeric at his Glenreagh farm in the Mid North Coast of New South Wales.

As for storage, turmeric keeps in the fridge's crisper quite happily for three to four weeks, although it will deteriorate in flavour and quality over time. Carl advises against freezing turmeric because it will turn to mush upon defrosting.

When it comes to turmeric powder, there are two grades available. Madras turmeric, which is the turmeric commonly available at supermarkets, and Alleppey turmeric (more on their uses below).

To store, keep in a cool dry place, and you can expect turmeric to keep for 18 months or even two or three years with little deterioration.

Oh, and if you find yourself with turmeric stains on your hands, just rub them with some oil or salt. If it gets on your clothes, a good stain remover will do the trick, recommends Ragini.


Creamy Turmeric Chicken Skillet

Lesson 2: Curcumin and the health benefits of turmeric

Turmeric contains an active compound called curcumin, which is the source of its antioxidant and anti-inflammatory properties.

Because it can limit inflammation, some researchers believe that curcumin can reduce the risk of arthritis, Alzheimer's and heart disease.

But if you're thinking of adding liberal doses of turmeric to your cooking for greater health benefits, unfortunately it doesn't work like that.

Human trials on curcumin have been inconclusive and use curcumin supplementation in very large doses of 1 to 12 grams per day.

"Although curcumin is showing some encouraging effects in reducing markers of inflammation in humans, the majority of the pharmacological effects of curcumin are in lab studies or animal experiments," writes Gunveer Kaur, lecturer in Nutritional Sciences at Deakin University, in The Conversation.

Plus, there's taste to consider.

"Too much powdered turmeric can make your food bitter, so you have to be careful how much you use. It's not a case of, 'It's so healthy, let's just put in a bucket load'," says Ragini.

She recommends using the right amount that a recipe calls for, which may not be more than a teaspoon at the most for five people.

Lesson 3: How to cook and eat different types of turmeric

Madras turmeric (dried and ground)

Madras turmeric is a pale yellow turmeric. It's best used when you want a very bright yellow colour rather than a strong flavour, for example, when making pickles, says Ian Hemphill who owns a spice company on the Central Coast of New South Wales.

"It's also good for adding colour to make yellow rice when you haven't been to the bank and can't afford to buy enough saffron," says Ian.

"It's a very gentle flavour that's good to use with delicate seafood."

Ragini recommends sprinkling some salt and turmeric on seafood, which will not only make the seafood a little firmer, but give the seafood more texture.
Alleppey turmeric (dried and ground)

Alleppey turmeric is the best turmeric to use in curries and tagines because of its rich and more earthy taste and stronger flavour, says Ian.

Its name comes from the port of Alleppey in South India where the turmeric was originally traded, but today it doesn't necessarily mean the turmeric comes from there.

"Alleppey turmeric is a much darker yellow. It's used in the Moroccan spice mix ras el hanout, and found in most South Indian cooking. Turmeric pairs well with ginger and also goes well with seafood, to help mask that overly fishy, ammonia taste," he says.


Turmeric makes for a tasty addition to many drinks.

Fresh turmeric

"In Indian cuisine, we would use turmeric fresh in salad-y things like a fresh chutney, or just add it to a vegetable or lentil preparation," says Ragini.

She recommends slicing the turmeric very finely and adding it to a little bit of heated oil with cumin seeds or fenugreek seeds.

This forms a good base for adding chopped cauliflower or zucchini, or seafood like prawns and calamari.

"Add everything together with a pinch of salt and it's ready," says Ragini.

Carl Richardson, who makes a pre-mixed turmeric tea, recommends using turmeric in a range of drinks.

"Grate up some fresh turmeric, add some honey and lemon juice, then add some hot water and let it steep for 10 minutes," he suggests.

 

mr peabody

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Is (R)-DOI a super-potent anti-cancer medicine?*

(R)-DOI (2,5-Dimethoxy-4-iodoamphetamine) is a psychedelic first synthesized by Alexander Shulgin. It is a potent inhibitor of Tumor Necrosis Factor-a inflammation, which exerts strong anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. (R)-DOI seems to be a superpower in regulating the 5HT2a receptor to inhibit TNF-α-mediated inflammation in the body. Activation of the 5-HT2A receptor represents a novel and extraordinarily potent therapeutic avenue for treating chronic inflammatory conditions, infections and cancer.

(R)-DOI is a psychedelic and mixed 5-HT2A/5-HT2C receptor agonist which acts via 5-HT2A receptors to inhibit the inflammatory effects of tumor necrosis factor (TNF)-α. Tumor necrosis factor-alpha (TNF)-α plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of pro-inflammatory markers. Here we demonstrate that systemic administration of (R)-DOI can block the systemic effects of (TNF)-α in whole animal. Importantly, the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases.

*From the article here: http://pharmrev.aspetjournals.org/co...2/264.full.pdf
 
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mr peabody

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Dr. Attila Szabo


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

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 N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (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

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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:

 

mr peabody

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D’Or Institute


Inflammation, neurodegeneration and 5-MeO-DMT

D’Or Institute for Research and Education | Neuroscience News | 9 Oct 2017

A new study reveals psychedelic substances may have a neuroprotective role when it comes to inflammation. Researchers also report psychedelics can alter signaling pathways associated with neuroplasticity. .

A new study has identified changes in signaling pathways associated with neural plasticity, inflammation and neurodegeneration triggered by a compound from 5-MeO-DMT.

"For the first time we could describe psychedelic related changes in the molecular functioning of human neural tissue," said Stevens Rehen, study leader, Professor of Federal University of Rio de Janeiro (UFRJ) and Head of Research at D'Or Institute for Research and Education (IDOR).

Though recent studies have demonstrated that psychedelic substances, such as LSD, MDMA and ayahuasca, hold therapeutic potential with possible anti-inflammatory and antidepressant effects, the lack of appropriate biological tools has been shown as a critical limitation for the identification of molecular pathways targeted by psychedelics in the brain.

In order to unveil the effects of 5-MeO-DMT, Vanja Dakic (IDOR) and Juliana Minardi Nascimento (IDOR) have exposed cerebral organoids, which are 3D cultures of neural cells that mimic a developing human brain, to a single dose of the psychedelic.

By employing mass spectrometry-based proteomics to analyze cerebral organoids, they found that 5-MeO-DMT altered the expression of nearly one thousand proteins. Then, they mapped which proteins were impacted by the psychedelic substance and their role in the human brain.

Researchers found that proteins important for synaptic formation and maintenance were upregulated, among them, proteins related to cellular mechanisms of learning and memory, key components of brain functioning.

On the other hand, proteins involved in inflammation, degeneration and brain lesion were downregulated, suggesting a potential neuroprotective role for the psychedelic substance.

"Results suggest that classic psychedelics are powerful inducers of neuroplasticity, a tool of psychobiological transformation that we know very little about," said Sidarta Ribeiro, Director of the Brain Institute of Federal University of Rio Grande do Norte (UFRN) and coauthor of the study.

http://neurosciencenews.com/psychede...inibrain-7690/
 

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Psychedelics’ anti-inflammatory effects*

by Diana Kwon | The Scientist

Scientists have discovered that a number of psychedelics can reduce inflammation throughout the body. Animal studies with one of these drugs, DOI, which is an especially potent anti-inflammatory compound, are starting to reveal the mechanism behind these effects. According to one hypothesis, DOI binds to and activates the serotonin 2A (5-HT2A) receptor to recruit protein kinase C (PKC). This is thought to block the downstream effects of the binding of tumor necrosis factor-alpha (TNF-α) to its receptor (TNFR), which is known to initiate a signaling cascade that promotes the transcription of proinflammatory genes.

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krahenmann and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain. “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. "The effects were so bewildering," he says, "that they repeated the experiment twice to convince themselves that the results were correct." Before publishing the findings in 2008, they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says.

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch. “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition, and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. "The benefit of using DOI for these conditions," Nichols says, "is that because of its potency, only small amounts will be required—far below the amounts required to produce psychedelic effects."

"In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests that there may be some enduring changes that are mediated through anti-inflammatory effects,”
Griffiths says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression and addiction.

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. "But if psilocybin is also treating the inflammation," he adds, “it won’t have that rut to fall back into.”




Scientists have discovered that a number of psychedelics can reduce inflammation throughout the body. Animal studies with one of these drugs, DOI, which is an especially potent anti-inflammatory compound, are starting to reveal the mechanism behind these effects. According to one hypothesis, DOI binds to and activates the serotonin 2A (5-HT2A) receptor to recruit protein kinase C (PKC). This is thought to block the downstream effects of the binding of tumor necrosis factor-alpha (TNF-α) to its receptor (TNFR), which is known to initiate a signaling cascade that promotes the transcription of proinflammatory genes.

If psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus. “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

*From the article here:

https://www.the-scientist.com/features/decoding-the-tripping-brain-30240
 
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mr peabody

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Tryptamines: Endogenous regulators of inflammation and tumor immunity?*

by Attila Szabo | Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary | 14 Jul 2015

Tryptamines are members of a large family of monoamine alkaloids that are widespread in nature and abundant in all the three Kingdoms of life (plants, fungi, and animals). Their main feature is a common indole ring, a backbone that is structurally related to the amino acid tryptophan. This tryptamine backbone designates many biologically active compounds, such as psychedelics and neurotransmitters (91). To date, our knowledge about the immunomodulatory capacity of tryptamines is quite scarce. DMT is the only member of the family that has been investigated so far.

N,N-dimethyltryptamine 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 (92). 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 (93). The milestones of DMT research were laid down by Szara (94) and Axelrod (95) 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 (96, 97), and later it was proposed to be a neurotransmitter or neuromodulator (98). DMT was shown to act as an agonist at several serotonin receptors including 5-HT1A, 5-HT2A, and 5-HT2C (99102) as well as at sigmar-1 (41).

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 (103). Recently, we and others demonstrated that DMT has the capability to modulate immune responses in in vitro human primary cell cultures (88, 104). In these studies, DMT was shown to act as a non-competitive inhibitor of indoleamine 2,3-dioxygenase (IDO) and as a strong inducer of anti-tumor cytotoxic activity in the co-cultures of human PBMCs and a glioma cell line (88). Furthermore, DMT and its analog 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) were found to exert potent anti-inflammatory activity through the sigmar-1 in human monocyte-derived dendritic cell (moDC) cultures. MoDCs are key cell types of the mammalian immune system connecting and orchestrating innate and adaptive immune responses as professional antigen-presenting cells (APCs) (20). DMT or 5-MeO-DMT treatment of LPS, polyI:C or pathogen-activated human primary moDCs resulted in a significant inhibition of the secretion of the inflammatory cytokines, IL-1β, IL-6, TNFα, and the chemokine CXCL8/IL-8. In contrast, secreted levels of the anti-inflammatory IL-10 increased markedly following in vitro DMT/5-MeO-DMT administration. DMT and 5-MeO-DMT exhibited the effective inhibitory potential at the level of adaptive immune responses (T helper cell 1 and 17 priming by moDCs), as well (104). These are in line with previous findings showing the immunomodulatory potential of ayahuasca in humans mostly affecting the number and ratio of lymphocyte subpopulations. Notably, the number of circulating NK cells, a cell type involved in anti-viral and anti-cancer immune responses, increased significantly (105, 106). The anti-cancer activity of ayahuasca has already been reviewed in a paper by Schenberg (89). However, it is important to keep in mind that ayahuasca is a complex decoction that, besides DMT, contains several other components according to the admixture plants used in the making process. Furthermore, ayahuasca can be administered in various ways (single-time, long-term, etc.), thus one should be particularly careful with the study design and interpretation of the data. Nevertheless, ayahuasca consumption in a highly controlled clinical setting emerges as a very promising model for investigating the possible immunomodulatory effects of DMT in humans (107). 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 (108, 109). Moreover, the mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders (6). 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.

*From the article here:

 
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UMass Medical School researchers explain why cannabis may relieve intestinal inflammation*

Reports from cannabis users that the drug reduces the symptoms of inflammatory bowel disease (IBD) may finally be explained by new research from UMass Medical School and the University of Bath showing that endocannabinoids help control and prevent intestinal inflammation in mice.

This is the first time scientists have reported a biological mechanism to explain why some users have reported beneficial effects from cannabis on inflammatory conditions such as ulcerative colitis and Crohn’s disease. Researchers hope their findings will lead to the development of drugs and treatments for gut disorders, which affect millions of people around the world and are caused when the body’s immune defenses mistakenly attack the lining of the intestine.

The findings appear in the Journal of Clinical Investigation.

“There’s been a lot of anecdotal evidence about the benefits of cannabis, but not a lot of science to back it up,” said Beth McCormick, Director of the UMass Center for Microbiome Research. “For the first time, we have an understanding of the molecules involved in the process and how endocannabinoids and cannabinoids control inflammation. This gives clinical researchers a new drug target to explore to treat patients who suffer from inflammatory bowel diseases, and perhaps other diseases, as well.”

The researchers discovered that gut inflammation is regulated by two important processes that are constantly in flux and responding to changing conditions in the intestinal environment. The first process, identified in previous scientific research, promotes an aggressive immune response in the gut that destroys dangerous pathogens, but which can also damage the lining of the intestine when immune cells attack indiscriminately.

The second pathway, turns off the inflammation response via special molecules transported across the epithelial cells lining the gut by the same process already known to remove toxins from these cells in the intestine cavity. Crucially, this response requires a naturally-produced molecule called an endocannabinoid, which is very similar to cannabinoid molecules found in cannabis.

If the endocannabinoid isn’t present, inflammation isn’t kept in balance and it can run unchecked, as the body’s immune cells attack the intestinal lining.

Dr. McCormick and colleagues believe that because cannabis use introduces cannabinoids into the body, these molecules could help relieve gut inflammation, as the naturally produced endocannabinoids normally would.

“We need to be clear that while this is a plausible explanation for why users have reported cannabis relieves symptoms of IBD, we have so far only evaluated this in mice and have not proven this experimentally in humans. We hope that these findings will help us develop new ways to treat bowel diseases in humans” said Randy Mrsny, PhD, professor of pharmacy and pharmacology at the University of Bath.

*From the article here:

https://www.umassmed.edu/news/news-...cannabis-may-relieve-intestinal-inflammation/
 

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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
 

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Psychedelics and immunomodulation

by Dr. Attila Szabo | Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary | 14 Jul 2015

Classical psychedelics are psychoactive substances that have been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation and cell survival by 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 been shown to play crucial roles in numerous immunological processes. This emerging field offers promising treatment modalities for various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer.

Scientific investigations concerning the possible immunological effects of psychedelics date back to the 1970s, but the biomedical Renaissance of psychedelic research began only a decade ago. An important antecedent was the identification of neuro-immune communication in mammals that has 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 neuroimmunologists 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 being crucial in many immunological processes pointing to novel therapeutic avenues. Classical psychedelics have been shown to exert strong anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. Two models have been proposed to address the possible biochemical dynamics of these interactions. On the one hand, (i) regulation may occur through the alteration of the cytokine-pattern of activated cells. The anti-inflammatory cytokines, IL-10 and TGFβ, and pro-inflammatory cytokines, TNFα and IFNγ, seem to be key players in this regulation. On the other hand, (ii) a complex intracellular cross-talk of pattern-recognition receptors (PRRs), serotonin, and sigma-1 receptors might be involved in the immunomodulatory process. 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.

https://pdfs.semanticscholar.org/0967/3ff5caa5ddaa6f2abcbabc161f8ea779ba61.pdf
 
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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
 

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Psychedelics as anti-inflammatory agents

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

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

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. 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. 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 (Figure 1).


Figure 1 - Studies have shown that increased levels of inflammatory cytokines contribute to the development
of depression. These effects are due to disturbed neuronal synaptic plasticity and disturbances in the levels of
different neurotrophic factors, in particular, BDNF.


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.

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.

 

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(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.

 
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SnafuInTheVoid

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I have noticed that LSD and psilocin are both powerful when used to counter alcohol induced inflammation. I can drink however much I want and never get a hangover, headache or anything... (kind of both a good and bad thing I guess). I mentioned this before in another post not sure if anyone saw it.

I have often drank large amounts of alcohol which would normally give me a hangover, then instead of sleeping I take a few tabs of LSD and I feel great for the next 24 hours.... no pain or inflammation at all ¯\_(ツ)_/¯
 

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I have noticed that LSD and psilocin are both powerful when used to counter alcohol induced inflammation. I can drink however much I want and never get a hangover, headache or anything... (kind of both a good and bad thing I guess). I mentioned this before in another post not sure if anyone saw it.

I have often drank large amounts of alcohol which would normally give me a hangover, then instead of sleeping I take a few tabs of LSD and I feel great for the next 24 hours.... no pain or inflammation at all ¯\_(ツ)_/¯
Interesting. Thanks for weighing in on this. It is not widely known, although the evidence is considerable, that certain psychedelics are powerful anti-inflammatory agents. Good to see you here.

<3
 

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Interesting. Thanks for weighing in on this. It is not widely known, although the evidence is considerable, that certain psychedelics are powerful anti-inflammatory agents. Good to see you here.

<3
I'm very interested in this topic currently. I'm currently running/working out and drinking lots of alcohol simultaneously. Inflammation city. CBD seems effective (in higher doses), typical NSAIDs are alright, have some more LSD coming my way to experiment more.

I would totally volunteer myself as a medical guinea pig if given the chance xD
 

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I'm very interested in this topic currently. I'm currently running/working out and drinking lots of alcohol simultaneously. Inflammation city. CBD seems effective (in higher doses), typical NSAIDs are alright, have some more LSD coming my way to experiment more.

I would totally volunteer myself as a medical guinea pig if given the chance xD
Hm. I've suffered from a painful inherited arthritis condition for many years, and I FINALLY discovered... that Prednisone is the only medicine that helps me.

Many people don't realize: inflammation is commonly responsible for MOST of the pain they're suffering from. Even if it's only 50% responsible, that's a lot. Trust me, there is NOTHING better for controlling inflammation-related pain than Prednisone.

How much of an improvement might you expect? That depends on how much of your pain is due to inflammation. Prednisone will stop that portion of it COLD. 20mg daily can make an otherwise unbearable condition manageable. But try not to take more than that. (I normally limit my intake to 5 mg per day, or 10 mg at max.)

Try limiting your alcohol intake. That will certainly help control your inflammation over the long haul.

pb
 
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SnafuInTheVoid

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I've been blessed that I've never had any major physical complaints with my body over the years. Mental issues are a different story...

I was once convinced I was had cancer or a heart condition due to consistent major pain under my left shoulder blade and around my left breast on the front. After about a month of this I went to urgent care, they took x-rays and the whole shebang. Turns out I just had some severe muscle cramps and inflammation - likely due to alcohol, poor nutrition and bad posture.

I was prescribed cyclobenzaprine and some prescription NSAID I forgot the name of. Killed the pain right away.

You are certainly correct in saying most body and physical pain is due to inflammation.I am trying to limit and cut out my alcohol intake. My issue is almost two decades of heroin addiction boiled down into alcoholism. I got off the opioids but replaced it with alcohol and now that's my main issue. Maybe you saw my post about my acute liver failure diagnosis about a month ago. Scared me enough to get off the alcohol, substituted benzos and GHB and was off the sauce for almost 3 weeks. Unfortunately the doctor I went to was crap, basically told me my liver was fine and if I don't quit drinking he will refuse to treat me.... so I found a new doctor but started drinking again.

I drink a lot but not A LOT.... about 500-600ml of 80proof liquor per day. Enough to cause health issues... anyways I'm rambling.

I digress, still interested in this topic. Inflammation is the source of most pain and a way to cure it would be a miracle.

-snafu
 

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The impact of psychedelics on inflammation

by Alexander Lekhtman | LUCID News | 8 Jul 2020

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

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

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



Charles Nichols, professor of pharmacology at LSU, is examining how the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine, also known as DOI, affects immune function.

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

First synthesized by Alexander Shulgin, a radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of Nichol’s father, David E. Nichols.

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

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

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

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

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

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

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

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

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

Cautious investigations for a range of possible treatments

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

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

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

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

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

Investigating DMT

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



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

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

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

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

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

Impact of mood and motions on immunity

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

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

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

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

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

 
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