This literature review (2020) argues that psychedelics may be used to treat autoimmune conditions. This may be done via inflammatory pathways, immune modulation or other methods.

Abstract

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

Authors: Caitlin Thompson & Attila Szabo

Notes

Key points highlighted by the authors:

“Classic/serotonergic psychedelic compounds display immunomodulatory properties
Psychosocial stress may contribute to the development of ADs
The gut microbiota modulates physiological pathways involved in stress
Modulation of the gut microbiome by psychedelics may influence immune functions
Normalization of physiological stress responses may be key in the application of psychedelics to treat ADs”

Autoimmune diseases (AiD/ADs) affect about 20% (50 million) of Americans. Currently, there are many hypotheses about how ADs are linked to mental health disorders such as depression (MDD), schizophrenia, and Alzheimer’s disease. This paper also makes the link between the correlation of ADs and mental disorders. This could even be causal as inflammation itself may lead to depression.

The paper does a great job of summarizing what we know about psychedelics and their effect on the immune system. This contributes a great deal to the biological (not only focused on the brain – and next to psychological/subjective) effects of psychedelics.

Summary

Classic/serotonergic psychedelic compounds display immunomodulatory properties, and psychosocial stress may contribute to the development of ADs. The gut microbiota modulates physiological pathways involved in stress, and psychedelics may influence immune functions.

Psychedelic compounds have been shown to modulate immune functions and may be able to treat diseases related to autoimmunity. These compounds may be used to treat psychosomatic origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations.

The incidence of autoimmune diseases has been steadily increasing in the United States, and over $100 billion in health care costs is spent annually on treating those with autoimmune diseases, compared to cancer which has an estimated cost of $50 billion annually. Autoimmunity is a multifactorial disorder in which the immune system attacks healthy tissues in an individual. There is strong evidence that traumatic experiences such as Adverse Childhood Events (ACEs) and prolonged stress may contribute to the development of autoimmune disorders.

Autoimmune disorders (AiDs) are characterized by increased vascular and epithelial permeability, chronic inflammation, the presence of chronic infections, dysregulated Hypothalamic-pituitary-adrenal axis (HPA axis), mitochondrial dysfunction, and microbiome dysbiosis. Biologicals and immunosuppressive drugs are the primary treatment tools for AiDs.

There is a higher risk of developing clinical depression or mood disorders if one has been diagnosed with an autoimmune condition. Psychedelic compounds may be able to treat these disorders by modulating inflammatory cytokine loops between peripheral and brain-resident immune cells.

Psychedelic compounds were made illegal in 1970 due to radical activism and drug propaganda, but research indicates they are safe, non-toxic and have minimal individual and societal harms. Classic psychedelics include LSD, psilocybin, mescaline, ibogaine, DMT, and 5-MeO-DMT, and are typically defined by their indole-containing molecular structure. They exhibit agonistic activity at various serotonin (5-HT) receptors, with the most commonly shared feature being their 5HT2a receptor agonist binding.

DMT is found in trace amounts in most plant, animal and fungal organisms, and is one of the components in the traditional Amazonian brew ayahuasca, which combines DMT-containing plants with the Monoamine Oxidase Inhibitor (MAOI)-containing Banisteriopsis caapi (ayahuasca) vine to potentiate a psychoactive effect from the oral administration of DMT. 5-Meo-DMT is found in many plants and animals, including the Amazonian shamanic snuff called “yopo” and the defensive secretion of the Colorado River Toad.

DMT has a long history of mixing with MAOIs in various South American traditions, however, mixing 5-MeO-DMT with MAOIs appears to be potentially dangerous due to higher 5HT binding affinity and disparate metabolic degradation pathways. Although there has been increased exploration into the use of psychedelics for the treatment of mental disorders, little has been investigated into the immune modulating and anti-inflammatory effects of psychedelics.

Psychedelic compounds may offer therapeutic solutions and potential modalities for the attenuation of AiD diseases, including the suppression of inflammation and the production of pro-inflammatory cytokines. LSD has been shown to have anti-inflammatory and immune-modulating effects.

0.001-0.1 m of DOI increased the number of Natural Killer (NK) cells in rat lymphocytes and suppressed TNF- levels in 10 week old adult male C57BL/6J mice via agonism of the 5HT2a receptor. In human studies, ayahuasca decreased CD4 and CD3 cells and increased NK cells, while ketamine decreased C-reactive protein and IL-6 but not TNF-. These effects were correlated with depression scores, except on days 3 and 7 when depression scores improved despite increased IL-6 levels.

The 5HT system has been shown to regulate a number of inflammatory and immune-related processes, including the release of IL-1b, IL-6, IL-8/CXCL8, IL-12p40 and TNF-. It is likely that the 5HT system is involved in the immune-modulation and inflammatory-regulating effects of psychedelic compounds. DMT and 5meo-DMT have high binding affinity for the Sig1R, which plays an important role in the regulation of different cellular mechanisms such as mitochondrial function, apoptosis, proliferation, and neuroprotection.

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 are associated with abnormal Sig1R functions. 5-MeO-DMT has been found to inhibit the NF-B signaling pathway in human cerebral organoids. DMT and 5-MeO-DMT have been shown to increase anti-inflammatory IL-10 and decrease pro-inflammatory IL-1, IL-6, TNF, and the chemokine CXCL8/IL-8 in human monocyte-derived dendritic cells and in a rat model of stroke.

Inhaled 5-MeO-DMT decreased salivary IL-6 levels in a study involving a small group of human subjects, suggesting that serotonergic psychedelics may emerge as potential candidates in the treatment of autoinflammatory and autoimmune conditions. Trauma and emotional effects can contribute to the development of a number of diseases including AiD. Psychosocial stress increases inflammatory cytokines, oxidative stress, glutamate excitotoxicity, inhibits effective digestion and nutrient absorption, and contributes to HPA axis dysfunction.

The psychedelic compounds psilocybin, LSD, MDMA, and ayahuasca are being explored for their promising potential to assist in treating trauma-derived illnesses such as PTSD, depression, and addiction. MDMA assisted psychotherapy for PTSD has received breakthrough status by the FDA.

Neuroendocrine-immune modulation is one of the recently proposed mechanism for the rapid anti-depressant effects of ayahuasca in those with MDD. Glutamate excitotoxicity is another mechanism that may contribute to the physiological outcomes seen in the majority of AiD patients.

Excitotoxicity may result from chronic excitation of Glu receptors, which can lead to oxidative stress, which can lead to damage to neural structures or apoptotic cell death. Ketamine, a dissociative anesthetic drug, protects against glutamate-mediated excitotoxicity by noncompetitively blocking the NMDA glutamate receptor, while flooding AMPA, Kainate and metabotropic Glu receptors. This could be one mechanism for how ketamine delivers such rapid anti-depressant effects.

Classic psychedelics such as psilocybin, DMT, 5-MeO-DMT, LSD, the psychedelic ritual brew ayahuasca, as well as the non-classical psychedelic ketamine have been found to interact with neurogenic pathways and influence neuroplasticity in in vitro and in vivo models of Drosophila melanogaster, rats and humans.

Psychedelics induce neuritogenesis in rat cortical neurons through an mTOR-related process of protein synthesis. This process is directly related to 5HT2a receptor agonist activity of classic psychedelics, given that ketanserin, a 5HT2a antagonist, abrogates the neuroplastic effects of DMT, LSD, and DOI. One study used concentrations of indole-containing psychedelic compounds and ketamine at 10 nM as the upper limit of each substance, and used in vivo rat models at 10 mg/kg and 1mg/kg doses of DMT.

Psychedelics can influence neuronal structure in vertebrates and invertebrates, and can also increase BDNF levels in humans. BDNF is fundamental for facilitating the repair, maintenance and survival of neurons, and has been linked to MDD, anxiety, schizophrenia, and neurodegenerative diseases.

AiDs are common among those with Epstein-Barr virus, herpes family viruses, and Borrelia burgdorferi infections. Many patients with AiDs have signs of gut dysbiosis and chronic low-grade infections. Studies have shown that the ayahuasca vine and Peyote cactus contain alkaloids with MAOI properties that have antimicrobial effects against the Herpes Virus Simplex 2 virus, HeLa, Vero, and Hec-1-A cells, and may have mild antibiotic effects that could be useful in managing chronic or acute infections in AiD patients.

Gut bacteria have been found to influence a number of immune responses and have been found to produce serotonin, dopamine, acetylcholine, GABA, and more. It is tempting to speculate that gut bacteria may produce these neurotransmitters to use as signaling molecules. The psychedelic serotonin analogues psilocybin, DMT, and 5-MeO-DMT may interact with bacterial receptors, such as those found in Turicibacter sanguinis.

The mechanism of transporting serotonergic psychedelic compounds into bacterial cells is currently unknown, however changes in vagal nerve tone, stress response, and enteric environment may influence the ecology of microbial populations and thus AiD disease outcome. LPS is a cell wall component of Gram-negative bacteria that induces inflammation. LPS-induced inflammation can be mitigated by Journal Pre-proof psychedelics in patients with increased intestinal permeability and chronic gut dysbiosis.

Psychedelic compounds can have powerful psychoactive effects, but when used properly there is very low chance of psychological harm. The short-term adverse reactions were “successfully managed through interpersonal support” and did not require taking medications.

There is little conclusion about how common or debilitating hallucinogen persisting perception disorder may be, but some precautions may reduce harm to those receiving psychedelic medicine in clinical environments, such as screening for a history of schizophrenia or psychosis, comfortable therapeutic set and settings, and low, subperceptual dosing.

Research on the effects of psychedelic compounds on enteric bacterial behavior is of particular interest, as well as studies on the effect of administration of psychedelics on enteric epithelial tissue integrity in the gut, or effects on LPS-induced cytotoxicity, etc.

The authors of this paper present evidence that suggests there is untapped potential of exploring the use of psychedelics within this specific disease category, and hope that this evidence may guide or inspire others to pioneer such studies.

Sex differences in autoimmune disease are a pathological perspective, and trained immunity and autoimmune disease are related. Autoimmunity in psychotic disorders is a place to stand, challenges and opportunities, and novel treatment targets are revealed.

Responses directed against multiple neoepitopes in depression are new pathways that underpin the inflammatory and neuroprogressive pathophysiology. These cells are also involved in the development of autoimmunity and neuroinflammation in Parkinson’s disease.

A systematic review of the safety and efficacy of Rituximab in treating inflammatory immune-mediated systemic diseases was published in 2019. The review included a discussion of the role of hierarchical control systems for the regulation of physiological homeostasis and affect in autoimmune diseases.

Systematic review and meta-analysis of the role of inflammation in depression. Nichols DE, Grob CS, Strassman RJ, Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse.

Psilocybin and psilocin metabolism in humans: clinical and forensic toxicological relevance. DMT displays potent protective effects against hypoxia via Sigma-1 receptor activation in human primary iPSC-Derived cortical neuron and microglia-like immune cells.

The psychedelic ayahuasca vine, without DMT, is powerful and traditional, and alters cortico-thalamic activity in freely moving mice. It may heal traumatic memories via a Sigma-1 receptor-mediated epigenetic-mnemonic process.

Ketamine’s mechanism of action is mediated by the endogenous opioid system and involves the interaction of 5-HT1A and 5-HT2A receptors. Ibogaine a also interacts with nicotinic acetylcholine receptors and may be a potential new treatment for rheumatoid arthritis.

LSD exposure induces immune responses in vitro and in vivo and is associated with increased intestinal tight junction permeability, which may be a potential therapeutic target in autoimmune diseases.

Ayahuasca’s antidepressant effects are related to changes in inflammatory biomarkers, and a low-dose ketamine infusion in treatment-resistant depression is associated with rapid inflammation modulation and antidepressant efficacy.

Ketamine, 5-Hydroxytryptamine, and Sierra-Filardi E modulate human monocyte polarization through 5-HT2B and HTR 7 receptors, and serotonin has an immunomodulatory capacity through the Sigma-1 receptor of human monocyte-derived dendritic cells.

The Sigma-1 Receptor is an intracellular chaperone that regulates neuroinflammation in neurological diseases. It plays an important role in the regulation of the non-canonical NF-B pathway in immunity and inflammation.

Harmine mitigates LPS-induced acute kidney injury through inhibition of the TLR4-NF-B/NLRP3 inflammasome signalling pathway in mice, and reduces infarct size and improves functional recovery following transient focal brain ischemia in rats.

Adverse childhood experiences are associated with a variety of health problems in adults, including chronic diseases and autoimmune disorders. In particular, adverse childhood experiences are associated with a higher risk of developing systemic lupus erythematosus.

The brain on stress is an article that describes the role of the vagus nerve at the interface of the microbiota-gut-brain axis in brain and body health over the life course.

Psilocybin and MDMA are novel psychopharmacological therapies for psychiatric disorders, and ayahuasca may be an effective treatment for depression. Glutamate receptors, neurotoxicity and neurodegeneration are discussed, and the biological mechanisms underlying the persisting psychedelic effects are discussed.

IL-17 signalling in astrocytes promotes glutamate excitotoxicity, and Ca2+-activated mitochondrial transporters (CaMCs) are involved in the process. Serotonin modulates glutamatergic transmission to neurons in the lateral habenula.

Psychedelics promote structural and functional neural plasticity and alter gene expression profiles in the mPFC relevant to schizophrenia. Ayahuasca modulates serum Brain-Derived Neurotrophic Factor in a dose-dependent manner.

The authors of this article review the literature and discuss the association of low serum BDNF with depression in patients with Parkinson’s disease, the role of BDNF/NF-B signaling in the neurobiology of depression, and the potential role of Helicobacter pylori in autoimmune disease.

There are several studies that suggest that the gut microbiota may play an important role in host metabolism, and that psychedelics may be able to modulate the immune system.

Psychedelics are not linked to mental health problems or suicidal behavior: A population study. The gut microbiota is affected by psychological, environmental and physical stressors, and alterations in the interplay between neuron, astrocyte and microglia are observed in experimental models of neurodegeneration.

The ayahuasca vine contains monoamine-oxidase inhibitors that, when combined with a DMT-containing plant, make up the psychoactive brew known as ayahuasca. The Colorado River Toad excretes 5-MeO-DMT in its defensive secretions.