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.
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.
Thompson and colleagues open by situating the problem: autoimmune diseases (AiD) are increasingly prevalent and impose substantial health and economic burdens. The paper notes over 100 defined autoimmune-related conditions affecting an estimated 50 million Americans and highlights that roughly 80% of those affected are women. The authors emphasise that AiDs are multifactorial in origin, with genetic predisposition, environmental exposures, infections, microbiome dysbiosis and psychosocial stress all implicated. They also point out frequent comorbidity between autoimmune conditions and psychiatric disorders such as major depressive disorder (MDD), anxiety and schizophrenia, and suggest bidirectional mechanisms linking immune dysfunction and mental illness. Against this background, the review proposes psychedelic compounds as a potentially novel, multi‑modal approach to AiD. Thompson frames classic/serotonergic psychedelics (for example LSD, psilocybin, DMT and 5‑MeO‑DMT) and certain non‑classical compounds (ketamine, MDMA, ibogaine) as agents with pharmacology that could modulate immune and inflammatory pathways, stress physiology, glutamate excitotoxicity, neuroplasticity and the gut microbiome. The introduction positions the paper as a narrative synthesis of biochemical, animal and preliminary human evidence that psychedelics may exert immunomodulatory and anti‑inflammatory effects relevant to autoimmunity and calls for further investigation.
Papers cited by this study that are also in Blossom
Nichols, C. D., Nichols, D. E., Johnson, M. W. · Clinical Pharmacology and Therapeutics (2016)
Strassman, R. J. · Journal of Nervous and Mental Disease (1984)
Nichols, D. E. · Pharmacological Reviews (2016)
Dinis-Oliveira, R. J. · Drug Metabolism Reviews (2017)
Strassman, R. J., Qualls, C. R., Berg, L. M. · Biological Psychiatry (1996)
The extracted text does not present a formal Methods section or a reproducible search strategy. There is no clear reporting of databases searched, date ranges, inclusion/exclusion criteria, or a risk‑of‑bias assessment. From the content it is evident the article is a narrative review drawing on a heterogeneous literature base, including in vitro experiments, animal models, small human studies, biochemical analyses and anecdotal or observational reports. The review integrates pharmacological descriptions of multiple compounds, preclinical studies (cell culture and rodent models), and a few human investigations (for example on ayahuasca, ketamine and inhaled 5‑MeO‑DMT). Where experimental parameters are reported in the text (concentrations, doses, timing), these have been cited directly; however, the paper does not appear to follow a systematic meta‑analytic methodology and does not report pooled quantitative analyses. In short, the methods of evidence selection are not specified in the extracted text and the paper should be interpreted as a broad narrative synthesis rather than a systematic review.
Pharmacology and receptor targets: The review summarises pharmacological profiles of classic serotonergic psychedelics (LSD, psilocybin/psilocin, mescaline, DMT, 5‑MeO‑DMT) as predominantly 5‑HT (serotonin) receptor agonists, with shared activity at 5‑HT2A. It contrasts these with non‑classical agents: ketamine (NMDA antagonist with multiple monoaminergic and opioid interactions), MDMA (monoamine releaser/uptake inhibitor), and ibogaine (broad transporter/receptor activity including Sig1R). DMT and 5‑MeO‑DMT are noted to bind Sig1R, a receptor implicated in stress responses and neuroprotection. Inflammation and immune modulation: Thompson reviews preclinical evidence that psychedelic compounds have anti‑inflammatory and immunomodulatory effects. Specific findings reported include: LSD suppressing B‑lymphocyte proliferation and production of IL‑2, IL‑4 and IL‑6 in rat splenic lymphocytes at concentrations between 1–100 µM, while very low concentrations (0.001–0.1 µM) increased natural killer (NK) cell numbers; the substituted amphetamine DOI reduced TNF‑α in mice via 5‑HT2A agonism at doses reported between 0.01 µM/kg and 10 µM/kg; harmine (an ayahuasca component) inhibited NF‑κB activity and reduced TNF‑α in both in vivo (25–50 mg/kg IP in mice) and in vitro (2.5–25 µM in RAW 264.7 cells) models. Human and translational findings: A small human ayahuasca study reportedly observed decreases in CD4 and CD3 lymphocyte counts and increases in NK cells compared with controls and subjects treated with D‑amphetamine, although sample sizes are not specified in the extracted text. Another human study found decreased C‑reactive protein (CRP) after ayahuasca in healthy and depressed volunteers but no change in IL‑6. Ketamine infusion studies in humans (0.5 mg/kg and 0.2 mg/kg) showed acute reductions in IL‑6 and TNF‑α between 40 and 240 minutes post‑infusion in the 0.5 mg/kg group, with cytokines returning to baseline by day 3 and day 7 despite persisting antidepressant effects; a different ketamine study reported an increase in IL‑6 post‑infusion, highlighting inconsistent findings. DMT, 5‑MeO‑DMT and related effects: In vitro and animal data suggest DMT and 5‑MeO‑DMT increase anti‑inflammatory IL‑10 and decrease proinflammatory cytokines (IL‑1β, IL‑6, TNF‑α, CXCL8/IL‑8) in human monocyte‑derived dendritic cells at 100 µM. DMT showed neuroprotective effects in a rat stroke model using a 1 mg/kg IP bolus followed by maintenance 2 mg/kg/h over 24 hours. Inhaled 5‑MeO‑DMT was reported to decrease salivary IL‑6 in a small human group. Trauma, stress physiology and psychotherapy: The paper links psychosocial trauma and chronic stress to AiD risk via HPA axis dysregulation, increased inflammatory cytokines and gut permeability. Evidence for MDMA‑assisted psychotherapy for PTSD is described as the most advanced clinical programme among psychedelic therapies, citing MAPS protocols (125 mg MDMA in assisted sessions) and strong remission statistics for PTSD; classic psychedelics and ayahuasca are reported to modulate cortisol responses in some human and primate studies. Glutamate excitotoxicity and neuroprotection: The authors discuss glutamate‑mediated excitotoxicity as relevant to neurological AiDs. Ketamine is noted to protect against excitotoxicity via NMDA antagonism, while Sig1R agonists (including DMT) have demonstrated neuroprotective mediation of glutamate toxicity in vitro and in vivo. Harmine was reported to increase EAAT2 (a glutamate transporter) expression, potentially reducing extracellular glutamate. BDNF and neuroplasticity: Multiple preclinical and some human data indicate psychedelics can engage neuroplastic pathways tied to brain‑derived neurotrophic factor (BDNF), Trk‑B and mTOR signalling. Examples include increased dendritic spine density in rats after DMT (1–10 mg/kg reported) and increased serum BDNF after a single dose of ayahuasca in depressed and control subjects. Antagonism of Trk‑B or mTOR blocked psychedelic‑induced neuritogenesis in animal/cell models, supporting mechanistic overlap with BDNF signalling. Microbiome and antimicrobial effects: The review summarises preliminary evidence that certain psychedelic plant constituents have antimicrobial activity in vitro: harmine/harmaline showed activity against HSV‑2 in cell lines and antifungal properties; peyote extracts exhibited antibacterial activity against multiple penicillin‑resistant Staphylococcus aureus strains. The authors also discuss theoretical interactions between serotonergic psychedelics and gut bacteria, noting that some gut species respond to serotonin and that bacterial genomes may encode SERT‑like proteins, but they stress direct pharmacological effects on commensals remain uninvestigated. Safety and adverse effects: The paper reports that when administered in controlled clinical settings with screening and support, psychedelics have a low incidence of lasting psychological harm. A 2010 review of 110 psilocybin participants (1999–2008) found short‑term adverse reactions were dose‑related and manageable with interpersonal support. Hallucinogen Persisting Perception Disorder (HPPD) is acknowledged as a contested condition with unclear prevalence and uncertain causal attribution. The text also notes the regulatory history—scheduling and research interruptions—and reiterates the importance of screening (for psychosis history), therapeutic set and setting, pharmaceutical‑grade drugs and clinician support to mitigate risks.
Thompson frames the evidence as suggestive but preliminary. The authors argue there is substantial opportunity to explore psychedelic effects on immunity and autoimmunity, and they recommend systematic screening for autoantibodies, inflammatory biomarkers and expression of autoimmune‑related genes in response to psychedelic treatments. They identify the microbiome as an especially promising area for mechanistic work, calling for in vitro and in vivo studies of bacterial growth, metabolism and host–microbe interactions after exposure to serotonergic compounds. The discussion underscores that most hypotheses presented are based on limited data from diverse models. The authors acknowledge the field is in its infancy and that current mechanistic proposals rely on a patchwork of in vitro, animal and small human studies. They therefore recommend carefully designed human clinical trials that account for genetic and pathophysiological heterogeneity in AiD populations. Thompson and colleagues envisage a multi‑faceted therapeutic strategy—targeting psychospiritual contributors, maladaptive stress responses, inflammatory pathways, immune modulation and gut ecology—rather than a single‑target pharmacological fix. Key limitations are explicitly noted: sparse factual data, heterogeneous study designs, occasional contradictory findings (for example ketamine's variable cytokine effects) and absence of direct evidence that psychedelic interventions modify clinical autoimmune disease endpoints. The authors conclude that while firm therapeutic claims are premature, there is sufficient convergent preclinical and preliminary clinical evidence to justify further research into psychedelics as potential adjuncts or novel treatments for autoimmune conditions.
The incidence of autoimmune diseases (AiD) has been steadily increasing in the last decades, as reported by The National Institute of Health (NIH) and other sources.
There are currently over 100 defined autoimmune-related diseases affecting roughly 50 million Americans, or 20% of the population according to the American Autoimmune Related Diseases Association (AARDA). The NIH also calculates that over $100 billion in health care costs is spent annually in the United States on treating those with autoimmune diseases, compared to cancer which has an estimated cost of $50 billion annually. It is conservatively estimated that 80% of those affected by AiD are women. There are several theories for why women are more susceptible to AiDs, but known reasons remain unclear. Different theories for the increased prevalence of AiDs include overuse of antibiotics, increase in environmental toxin exposure, increased caesarian births, reduced breast feeding, improvement of diagnostic tools, increased awareness of AiDs and increased societal stressors. Autoimmunity is defined as the loss of tolerance to self-antigens in which the immune system attacks healthy tissues in an individual. While there are different characteristics of expression and tissues affected amongst the autoimmune disorder types, there are many shared mechanisms of action and potential origins. Many diseases that were initially considered to be unrelated to autoimmunity are now being reexplored as autoimmune-related, especially in the field of psychiatry. This includes major depressive disorder (MDD), schizophrenia, Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis. While the causes of AiDs are controversial, they appear to be multifactorial with many facets that contribute to their development such as genetic predisposition, environmental triggers, and psychosocial stress. There is strong evidence that traumatic experiences such as Adverse Childhood Events (ACEs) and prolonged stress may J o u r n a l P r e -p r o o f contribute to the development of an AiD. AiDs often encompass a variety of symptoms and features. Common characteristics observed among the various types of AiD include increased vascular and epithelial (e.g. intestinal) permeability, chronic inflammation, the presence of chronic infections, dysregulated Hypothalamic-pituitary-adrenal axis (HPA axis), mitochondrial dysfunction, and microbiome dysbiosis. Symptoms can manifest as chronic fatigue, allergies, psychiatric and mood disorders, pain, rashes, GI distress, poor cognition and more. Currently, biologics and immunosuppressive drugs are the primary treatment tools for autoimmune disorders along with non-steroidal anti-inflammatory drugs, steroids and antidepressants. However, immunosuppressant and biologic medications designed to resemble antibodies, receptors and other immunological factors can result in an immune compromised state, putting the affected population at risk for serious infections or immunerelated illnesses. Although existing biological drug approaches show evidence for producing positive treatment outcomes in some individuals, the increased risks for infection, malignancy and cardiovascular conditions, as well as contradicting results in efficacy studies have prompted interest in exploring other approaches to treating AiDs.
The comorbidity between autoimmune conditions and mental and mood disorders, such as MDD, anxiety, schizophrenia, and bipolar disorder has become apparent in the last two decades. There is a higher risk of developing clinical depression or mood disorders if one has been diagnosed with an autoimmune condition. While there is certainly argument that the burden of having an autoimmune condition could contribute to MDD, researchers suggest that depression and anxiety symptoms could perhaps be a result of autoimmune mechanisms and resulting inflammation occurring in the nervous system, or via dysregulated inflammatory cytokine loops between peripheral and brain-resident immune cells. Potentially by their immunomodulatory activity and in part through the mobilization of cell-intrinsic neuroprotective mechanisms, psychedelics may represent a promising intervention for autoimmune-related depression and other mental illness.and were made illegal to consume, possess or distribute. Contradictory to this scheduling decision, research currently suggests that classical psychedelic compounds do not show evidence of addiction potential and exhibit anti-addiction properties while also appearing to be generally physiologically safe, non-toxic and exhibiting minimal individual and societal harms. This prohibition resulted in an abrupt halt in research on psychedelics. In the early 90's there was the start of a new renaissance in psychedelic research with the work of Risk Strassman on intravenous DMT administration in humans. Psychedelic research currently is a rapidly accelerating field in science, psychology and medicine.
"Classic" psychedelics generally refer to LSD, psilocybin, mescaline, ibogaine, DMT, and 5-MeO-DMT and are typically defined by their indole-containing molecular structure as illustrated in Figure. Non-classical psychedelics such as ketamine and 3,4-Methylenedioxymethamphetamine (MDMA) may have some similar receptor activity and hallucinogenic properties, but lack this fundamental indole structure. Classic psychedelics typically and predominately exhibit agonistic activity at various serotonin (5hydroxytryptamine, 5-HT) receptors, with the most commonly shared feature being their 5HT2a receptor agonist binding. The classic psychedelics vary in their receptor binding properties but overall show binding affinity for a variety of receptors including 5HT subtypes. LSD [figis known to bind to 5ht 1A, 1B, 1D, 1E, 2A, 2B, 2C, 5A, 6, and 7 as well as dopaminergic receptors subtypes D1 and D2. Psilocin, the active metabolite of psilocybin [fig, binds to 5HT 1A, 1D, 2A, 2C but does not bind to dopaminergic J o u r n a l P r e -p r o o f receptors. Mescaline exhibits the highest binding affinity to the 5HT2A and 2C receptors. DMT [fig] and its psychopharmacologically more potent analogue 5-MeO-DMT [figbind to the 5-HT1A, 1B, 1D, 2A, 2B, 2C, 5A, 6 and 7 receptors, as well a number of iontropic and metabotropic glutamate receptors, dopamine, acetylcholine, Trace-Amine-Associated Receptors (TAAR), and the opioid-like receptor sigma-1 (Sig1R). DMT is found in trace amounts in most plant, animal (including humans) and fungal organisms with some plants, such as the Acacia and Mimosa genera, containing more substantial amounts. It is one of the components in the traditional Amazonian brew ayahuasca, which combines DMT-containing plants, such as Psychotria viridis with the Monoamine Oxidase Inhibitor (MAOI)-containing Banisteriopsis caapi (ayahuasca) vine to potentiate a psychoactive effect from the oral administration of DMT. The ayahuasca vine contains harmala alkaloids, such as harmine, harmaline and tetra-harmaline that act as MAOIs in the ayahuasca brew. Typically, the DMT contained in the ayahuasca brew is considered the psychoactive constituent, however a ritual called Natemamu does exist in the Shuar culture in which only the B. caapi vine is used, suggesting that at certain doses, the MAOIs from the ayahuasca vine on its own can create a hallucinatory experience. 5-Meo-DMT is also found in many plants and animals including in the Amazonian shamanic snuff called "yopo" (Anadenanthera peregrinaa), mammalian tissues and within the defensive secretion of the Colorado River Toad (Incilius alvarius). Because of the degradation of the DMT and 5-MeO-DMT molecules by MAO in the digestive tract, the most common way of ingesting these substances is through inhalation via vaporization.
There is a long history of mixing DMT with MAOIs in various South American traditions, however, there does not appear to be any traditional practices mixing 5-MeO-DMT with MAOIs as it appears to be potentially dangerous due to higher 5HT binding affinity and disparate metabolic degradation pathways. Some "not-so-classic" psychedelic compounds, such as ketamine and ibogaine have complex pharmacology that is not 5HT dominant. Ketamine [fig] exhibits noncompetitive NMDA receptor antagonism, while displaying monoaminergic release as well as cholinergic, adrenergic, μ-and δ-opioid receptor binding. Ibogaine [fig., an alkaloid from the Tabernanthe iboga shrub, has a highly promiscuous binding affinity for the 5HT and dopamine (DA) transporters, non-competitive antagonism for several types of nicotinic AChR, NMDA Glu, μ-, δand кopioid, Sig1R and Sig2 receptors. MDMA [fig, while generally referred to as an empathogen rather than a true psychedelic, releases presynaptic vesicular monoamines 5HT, DA and norepinephrine (NE) while inhibiting their reuptake into the presynaptic cell, flooding the synapse. It does however have some agonistic binding affinity to 5HT2a receptors like classical psychedelics, as well as muscarinic receptor 1, and the H1 histamine receptor. Although at this point there has been increased exploration into the use of psychedelics as tools for the treatment of MDD, post-traumatic-stress-disorder (PTSD), addiction, eating disorders, anxiety and other mental disorders, there has been very little investigation into the immune modulating and anti-inflammatory effects of psychedelics. Biochemical and anecdotal evidence suggests that psychedelics could provide a novel treatment approach to AiDs and other immune and inflammatory-related diseases. It is likely that psychedelics can attenuate autoimmunity via a number of different J o u r n a l P r e -p r o o f mechanisms. Psychedelics may directly and indirectly target a number of physiological factors and resulting dysfunctions in AiDs. This review covers the current evidence that psychedelics may offer therapeutic solutions and potential modalities for the attenuation of AiDs.
In AiD, rampant chronic inflammation is a keystone feature. Elevated levels of cytokines and their dysfunctional regulation involving interleukin(IL)-6, IL-1β, IL-17, tumor necrosis factor-α (TNF)-α, IL-12, interferon(IFN)-γ and others are a shared feature observed in many AiDs including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), systemic sclerosis, and Sjögren's syndrome. Lipopolysaccharide (LPS) is an inflammatory component of the cell wall of Gram-negative bacteria that can induce inflammation and excessive oxidative stress that may play a role in elevated inflammatory biomarkers seen in those with AiD diseases. Those with AiD display auto-antibodies and yet also display immunodeficiency. Immune modulation appears to be a feasible target in approaching the treatment of AiD. While the area of research is quite underdeveloped, there is some evidence that psychedelic compounds have anti-inflammatory and immune-modulating effects. For instance, LSD displays the ability to suppress the proliferation of B-lymphocytes, as well as the production of the pro-inflammatory cytokines IL-2, IL-4, and IL-6 in in vitro splenic lymphocytes derived from 6-8 year old female B6C3F1 rats at concentrations of LSD between 1-100 µM. The same study observed that administered doses of LSD between J o u r n a l P r e -p r o o f 0.001-0.1 µM in rat lymphocytes increased the number of Natural Killer (NK) cells, while concentrations of 100 µM suppressed NK cell production. In another study, the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine (DOI) was shown to reduce TNF-α levels in 10 week old adult male C57BL/6J mice via agonism of the 5HT2a receptor in doses ranging from 0.01 µM/kg to 10µM/kg. Furthermore, in a recent study the same group expanded the previously observed anti-inflammatory effects of 5HT2a agonism to additional psychedelics in a rat model of lung inflammation. One human study where ayahuasca was given to healthy volunteers recorded blood levels of lymphocytes and found a decrease in CD4 and CD3 cells, and an increase in NK cells. This was compared to controls and subjects treated with D-amphetamine. Another, more recent human study reported significant decrease in C-reactive protein levels in the blood in both healthy and depressed volunteers, but no significant reduction in IL-6 blood levels. In addition, in a human intramuscular ketamine study, levels of proinflammatory markers, including C-reactive protein (CRP), IL-6, and TNF-α, were examined prior to initiation of test infusions, 40 min post-infusion, 240 min post-infusion, and on day 3 and day 7 post-fusion in patients who received 0.5 mg/kg or 0.2 mg/ kg of R/S-ketamine hydrochloride. Acute reductions of IL-6 and TNF-α were found in the 0.5 mg/kg group between 40 mins and 240 min post-infusion, but not in day 3 or day 7. Reductions in pro-inflammatory cytokine levels were directly correlated with depression scores, except on days 3 and 7 when depression scores improved despite cytokine levels returning to pre-infusion baselines. Interestingly, a different study obtained contradicting results showing an increase in IL-6 post-infusion and no correlation of cytokine levels with anti-depression outcome, suggesting that more studies need to be J o u r n a l P r e -p r o o f conducted to understand the complex systemic immune effects of ketamine and its metabolites. There is substantial literature on the 5HT system and its complex inflammation and immune-regulating abilities in tissue specific manners. Functional studies showed that 5-HT modulates the release of IL-1b, IL-6, IL-8/CXCL8, IL-12p40 and TNF-α, while it has no effect on the production of IL-18 and IFN-c in LPS-stimulated human blood monocytes. 5HT can also modulate human macrophage polarization and dendritic cell functions, and can contribute to the maintenance of an anti-inflammatory state via 5HT2B and 5HT7 receptor binding. Given the role of the 5HT system in immune-modulation and inflammatory properties, it is highly likely that there are undiscovered immune and inflammatory effects from exposure to psychedelic compounds due to their serotonergic activity. In the previously mentioned study where DOI was observed to reduce TNF-α in mice, in groups where the 5HT2a antagonist drug M100907 was administered, the reduction in TNF-a was not observed supporting the theory that the 5HT2a receptor and the 5HT system as a whole may be fundamental to creating downstream immunological and inflammatory-regulating effects. In addition to the 5HT receptors, DMT and 5meo-DMT also have high binding affinity for the Sig1RActivation of the Sig1R is also pivotal in facilitating stress responses. Dysregulated NF-кB and MAPK activity patterns have been implicated in a number of AiD pathologies. One study showed evidence of suppression of pro-inflammatory NF-кB cytokine production by administration of harmine, a component of the ayahuasca vine, via intraperitoneal intraperitoneal injection at doses of 25 and 50 mg/kg, in response to treatment with LPS in Male Kunming mice to induce acute kidney injury. Another study found that harmine inhibited tumor necrosis factor-α (TNF-α)and LPS-induced NF-κB transactivity and nuclear translocation in mouse macrophage RAW 264.7 cells when treated with concentration between 2.5-25µM. 5-MeO-DMT was also found to inhibit the NF-κB signaling pathway in human cerebral organoids exposed to concentrations between 23 nM to 7.11 μM, and examined for proteomic analysis via mass spectrometry. In other in vitro and animal in vivo studies, DMT and 5-MeO-DMT have been shown to increase anti-inflammatory IL-10 while decreasing the levels of the proinflammatory IL-1β, IL-6, TNFα, and the chemokine CXCL8/IL-8 in human monocytederived dendritic cells at concentrations of 100 µM. DMT also exhibited considerable neuroprotective and anti-neuroinflammatory effects in a rat model of stroke where male Wistar rats received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h after induced J o u r n a l P r e -p r o o f transient middle cerebral occlusion. Furthermore, inhaled 5-MeO-DMT has recently been reported to decrease salivary IL-6 levels in a study involving a small group of human subjects. There results suggest that serotonergic psychedelics may emerge as potential candidates in the treatment of autoinflammatory and autoimmune conditions. Since pharmaceutical grade DMTand other tryptamine analogsdesigned for human clinical trials are already available or will soon enter the market, testing the in vivo physiological effects of serotonergic psychedelics in humans is now closer than ever before.
A number of studies have suggested that significant or prolonged stress, especially in early childhood, contributes to the development of a number of diseases including AiD. The severity of childhood trauma can be clinically assessed by scoring ACEs (Adverse Childhood Experiences). Many studies have found strong correlations between ACEs and the statistical risk of developing an AiD including studies looking at associations between childhood stress and RA, SLE, and fibromyalgia. The downstream physiological detriment due to stress and vagal nerve disruption is well documented in the literature and appears to play a significant role in the development of an AiD. Psychological stress and psychoemotional trauma can severely compromise the immune system leading to increased risk of chronic infections and gut dysbiosis. Psychosocial stress increases inflammatory cytokines, oxidative stress, glutamate excitotoxicity, inhibits effective digestion and nutrient absorption and J o u r n a l P r e -p r o o f contributes to HPA axis dysfunction. Stress has been found to increase intestinal permeability which can lead to food sensitivities and LPS-induced inflammation due to gut-blood transepithelial bacterial translocation ("Leaky Gut syndrome"). All of these inflictions are hallmark characteristics of patients with AiD, further supporting the hypothesis that stress may play a significant role in AiDs. The psychedelic compounds psilocybin, LSD, MDMA, and ayahuasca are currently being explored for their promising potential to assist in treating trauma-derived illnesses such as PTSD, depression, and addiction. The research with MDMA assisted psychotherapy for PTSD is currently the furthest along in its drug development and approval process by the FDA than any other psychedelic-related compound with psilocybin, cannabis and ayahuasca following closely behind. MDMA assisted psychotherapy has received breakthrough status by the FDA, accelerating its entry into mainstream medical practice. The MDMA therapy for PTSD protocol developed by the Multidisciplinary Association for Psychedelic Studies (MAPS) consisting of two MDMAassisted therapy sessions with the patient receiving 125mg of MDMA orally in conjunction with non-directive psychotherapy, along with preparatory and post non-MDMA therapy sessions, has so far exceeded all existing treatments for PTSD in its symptom remission statistics. Although the classical psychedelics have not been clinically established as strongly for PTSD as MDMA has, there is evidence that they also hold potential for stress and trauma-oriented applications. There are several human and non-human primate studies that suggest that the DMT-containing ayahuasca brew has modulatory effects on salivary cortisol response and plasma cortisol in both healthy normals and in individuals with treatment-resistant MDD. Thus, potential J o u r n a l P r e -p r o o f neuroendocrine-immune modulation is one of the recently proposed mechanism for the rapid anti-depressant effects of ayahuasca in those with MDD. Given that trauma and chronic sympathetic activation are prevalent among those with AiD, the therapeutic outcome of psychedelic-assisted psychotherapy could resolve or improve stressful psychological states that cause or contribute to physiological outcomes seen in the majority of AiD patients.
Those with autoimmune conditions, particularly those affecting the nervous system, are more likely to have increased glutamate (Glu) binding sensitivity and postsynaptic glutamate levels which can result in cytoxicity to the nerve cell. The term glutamate excitotoxicity is used to describe the cytotoxic effects of excessive and uncontrolled release and binding of glutamate to post-synaptic neurons. Hypersensitization of Glu receptors due to cytokine-mediated transcriptional changes that affect depolarization gradients potentially play a role in this glutamate-induced cytotoxic phenomenon. Excitotoxicity appears to be implicated in a number of brain related diseases, including multiple sclerosis, depression, addiction and neurodegenerative diseases. During glutamate-excitotoxicity, excessive stimulation of the Glu receptors resulting in action potentials to be propagated through the neuron in an uncontrolled manner. This in turn activates the influx of Ca 2+ ions into the cytoplasm where they may induce mitochondrial respiration and the release of reactive oxygen species (ROS). Under normal circumstances, the generated ROS are cleared from the cell J o u r n a l P r e -p r o o f and transmembrane ion gradients are restored quickly after glutamate transmission. However, in activation-induced excitotoxic cascades, the permeability transition pore (PTP) is opened and mitochondrial dysfunction occurs due to increased oxidative stress, abnormal ATP synthase activity and inhibited mitochondrial respiration. Chronic excitation of the Glu receptors can therefore contribute to oxidative stress, which may result in damage to neural structures or apoptotic cell death. Excitotoxicity from excessive Glu receptor binding may result in changes in cortical, amygdala, and hippocampal density leading to atrophy and shrinkage of brain regions. While not a classic psychedelic compound, the dissociative anesthetic drug ketamine displays an ability to protect against glutamate-mediated excitotoxicity by noncompetitively blocking the NMDA glutamate receptor. It is unclear if inhibition of the NMDA Glu receptor is the fundamental mechanism for the neuroprotective properties or if this, in turn, redirects glutamate to bind to other Glu receptors such as AMPA, Kainate and metabotropic Glu receptors. It appears that blocking the NMDA GluR, while flooding AMPA and metabotropic Glu receptors, paradoxically enhances Glu transmission in the prefrontal cortex in a way that is synaptogenic and potentially restorative for appropriate Glu receptor sensitivity. This could potentially be one mechanism for how ketamine delivers such rapid anti-depressant effects. In theory, blocking or correcting an excitotoxic effect from glutamate may alleviate the oxidative stress and tissue damage to cells by reducing the ROS released via action potentials. Sig1R agonists such as dimemorfan, and dipentylammonium have shown neuroprotective mediation of glutamate excitotoxicity. Furthermore, DMT has been shown to possess potent neuroprotective effects via the Sig1R in both human in vitro J o u r n a l P r e -p r o o f and animal in vivo studies. It may be possible that the psychedelic Sig1R agonists DMT and 5-meo-DMT are also capable of mediating glutamate levels and receptor activity via indirect transcriptional effects on cytokine production. Harmine, a MAOI contained in the ayahuasca vine has been found to increase Excitatory Amino Acid Transporter 2 (EAAT2) glutamate pump expression in the central nervous system, therefore raising the possibility of reducing glutamate toxicity in vivo. 5-HT receptor activation also has modulatory effects on downstream Glu release and binding activity, in particular through activity at the 5-HT1A, 5-HT1B , 5-HT2 , 5-HT3 and 5-HT6 receptors in various brain regions. Downstream Glu effects from 5-HT activity of psychedelic drugs appears to play a role in the neurogenic properties of psychedelic compounds. It is possible that classic psychedelics that act on the 5HT system may have indirect mitigation of pathological glutamate transmission and receptor sensitivity.
The classic psychedelics psilocybin, DMT, 5-MeO-DMT, LSD, the psychedelic ritual brew ayahuasca, as well as the non-classical psychedelics ketamine have shown potential in interacting with neurogenic pathways, such as Tropomyosin receptor kinase B (Trk-B) and the mammalian target of rapamycin (mTOR), in an equivalent manner to the neurotrophin protein brain-derived neurotrophic factor (BDNF), and in influencing neuroplasticity in in vitro and in vivo models of Drosophila melanogaster, rats and humans. There are conflicting results from studies measuring BDNF gene expression J o u r n a l P r e -p r o o f and protein levels in serum with some studies showing evidence of enhanced BDNF gene expression as a result of exposure to psychedelics (LSD) in in vivo rat models, while others show no increase in gene expression but increase in BDNF protein levels in vitro and in vivo (serum) in rats. In studies, where the Trk-B selective antagonist ANA-12 was administered, the synaptogenic and neurogenic properties of psychedelics and BDNF are completely blocked. Similarly, treating rat cortical neurons with the drug rapamycin to inhibit mTOR also blocked the psychedelic-induced neuritogenesis suggesting that BDNF and psychedelics possess a shared mechanism for promoting neuritogenesis through an mTOR-related process of protein synthesis in synaptogenesis. It appears that this pathway is directly related to 5HT2a receptor agonist activity of classic psychedelics, given that when ketanserin, a 5HT2a antagonist, is administered the neuroplastic effects of DMT, LSD, and DOI are abrogated. Studies on ketamine's effect on BDNF levels show increase of BDNF protein levels in the hippocampus but not an increase of BDNF mRNA. The increased BDNF levels were not sustained past 24 hours after treatment, implying that BDNF interaction at TrK-B receptor sites prompts intracellular signaling that is responsible for the synaptic plasticity and anti-depressant effects. One study that explored the neurogenic properties of indole-containing psychedelic compounds and ketamine in Drosophila and rat in vitro cortical neuron cell cultures used concentrations of each substance at 10 nM as the upper limit of each substance, with the exception of DMT, where 90 nM was used to simulate levels naturally occurring in rat brains. In in vivo rat models using Sprague-Dawley rats 10 mg/kg and 1mg/kg doses of DMT were administered via injection and each dosage category produced similar responses in increasing density of dendritic spines. The results demonstrated that J o u r n a l P r e -p r o o f psychedelics can influence neuronal structure in vertebrates (Sprague-Dawley rats) and invertebrates (Drosophila) in both in vitro and in vivo models suggesting an evolutionarily conserved mechanism. In a similar manner, in human studies a single-dose of ayahuasca increased BDNF serum levels in both depressed and control subjects. Human brain imaging studies have also shown grey matter density changes as thinning in the posterior cingulate cortex (PCC) and thickening in the anterior cingulate cortex (ACC) in long-term ayahuasca users suggesting modulated neural plasticity and structural changes as a result of regular ayahuasca consumption. BDNF is fundamental for facilitating the repair, maintenance and survival of neurons. Through its Trk-B-dependent signaling, BDNF prompts the growth of new synaptic spines, dendrites and new whole neurons. BDNF signaling is fundamental in dictating brain tissue density and the formation and conservation of neural networks. Low expression of BDNF mRNA in brain, and protein levels in serum and plasma in humans have been linked to MDD, anxiety, schizophrenia, and neurodegenerative diseases. Given the prevalence of MDD and glutamate excitotoxicity in patients with autoimmune diseases, it is possible that the BDNF-upregulating qualities of psychedelics could attenuate the inflammatory and cytotoxic pro-oxidative effects of glutamate excitotoxity in autoimmune disease, resulting in increased survivability of neurons that may be susceptible to ROS damage.
Chronic infections with bacteria, fungi and viruses are common in those with AiDs. Studies suggest that infection by the Epstein-Barr virus and other herpes family viruses are prevalent in those with AiD. There is also evidence that Borrelia burgdorferi, the bacteria that causes Lyme disease, is also a common infectious agent in AiDs. Many patients with AiD display evidence of increased gut permeability, small intestinal bacterial overgrowth, and other signs of gut dysbiosis, which can be classified as chronic low-grade infections. Constituents in psychedelic plants such as the ayahuasca vine (Banisteriopsis caapi) and Peyote cactus (Lophophora williamsii) display specific antimicrobial effects. Harmine and harmaline are beta-carboline alkaloids with MAOI properties in the B. caapi vine. Studies have demonstrated invitro anti-viral activity against the Herpes Virus Simplex 2 (HSV2) virus, a common infection in those with AiD, in HeLa, Vero, and Hec-1-A cells. The same alkaloids also appear to have antifungal properties which could perhaps be advantageous in an individual with a filamentous fungi overgrowth. Peyote extract has also shown broad antibacterial activity invitro, in particular against 18 different penicillin-resistant strains of Staphylococcus aureus. There may be mild antibiotic effects of some psychedelic plants which could potentially yield notable results in managing chronic or acute infections in AiD patients. While there is evidence to suggest that psychedelic plants may have antimicrobial activity against pathogenic organisms, there has been no investigation of the effects on commensal bacteria and psychedelic compound exposure. With increasing interest in the roles of commensal gut ecology in health and disease, there has been more investigation into the psychoactive effects and complex host-organism interactions with bacterial J o u r n a l P r e -p r o o f colonies in the gastrointestinal tract. Microbiome bacterial populations appear to have play a significant role in a number of immune responses and have been found to influence the presence of self-antigens and AiD. Gut bacteria have been discovered to possess the ability to manipulate neurotransmitter activity and are capable of producing serotonin, dopamine, acetylcholine, GABA, and more. Many of these neurotransmitters are derived from essential amino acids such as tryptophan, phenylalanine, and glutamine. Commensal gut bacteria possess highly conserved metabolic pathways for processing amino acids for a variety of uses. Many of the classic psychedelics are also biologically synthesized from tryptophan and share an analogous structure to serotonin and other endogenous tryptamine molecules. It is tempting to speculate that gut bacteria may produce these tryptamine metabolic products to use as signaling molecules meaning that bacteria are likely to not only produce these molecules, but also receive information from them as signal inputs. One study found that spore-forming endogenous bacteria species from Turicibacteraceae, Clostridiales, Lachnospiraceae and Ruminococcaceae were enriched in abundance when 5HT was orally administered to wild type rats suggesting that the secretion of 5HT from gut bacteria and the host intestine may prompt an advantage towards thriving colonies and promote the bacteria's own community membership in the mammalian intestine, rather than 5HT simply being a metabolic byproduct. It is very possible that the psychedelic serotonin analogues psilocybin, DMT, and 5-MeO-DMT may interact with bacterial receptors such as those found in Turicibacter sanguinis, a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. It is unclear if this SERT orthologue is solely responsible for J o u r n a l P r e -p r o o f the mechanism of transporting 5HT into bacterial cells, but spore-forming gut bacteria do show the ability to transport 5HT through some mechanism of action. If serotonergic psychedelic compounds were found to interact with these SERT-homologous bacterial proteins or other bacterial 5HT uptake pathways in a way that alters the behavior of the bacterial colonies, this could have implications on gut microbe ecology and thus AiD disease outcome. Whether there are direct pharmacological effects of psychedelics on bacteria is currently unknown, however the emotional and psychological benefits of psychedelics may indirectly alter microbial communities in the GI tract via induced changes in vagal nerve tone, stress response, and enteric environment. Several studies have explored the effects of chronic stress and resulting conditions like PTSD on microbiome pattern associations. The psychological and neurological benefits from a psychedelic experience may create biochemical cascades in systemic physiology, specifically within the HPA axis and the enteric nervous system, which may downstream influence the ecology of microbial populations. As mentioned previously, LPS is a cell wall component of Gram-negative bacteria. LPS is known to induce inflammationand is used in research as an inflammatory trigger in animal models to simulate Parkinson's, Alzheimer's, MDD and general inflammatory conditions. In patients with increased gut-permeability, LPS fragments can leak past the intestinal epithelial barrier and cause inflammation while in circulation. Models using LPS-induced inflammation were used in some of the previously noted human invitro, and rat studies on the anti-inflammatory effects of psychedelics. This research may be particularly relevant to AiD as it suggests J o u r n a l P r e -p r o o f psychedelics may be helpful in mitigating inflammation caused by LPS due to increased intestinal permeability and chronic gut dysbiosis.
Given the powerful psychoactive effects of psychedelic compounds, their use in medicine and psychiatry should not be taken lightly. Currently most psychedelic compounds are schedule I compounds meaning they have the highest categorical ranking of illegality in the Unites States with Schedule I stating that a substance has no acknowledged medical use, and is considered to have high-abuse potential. Most psychological harms associated with the illegal use of psychedelics appear to be a result of poorly controlled environmental factors such as set and setting, as well as questionable sources of the drugs from the black market. In clinical administration of psychedelics, there is documented very low chance of psychological harm to properly screened patients provided with integrative support. One population study suggests that psychedelics do not appear to linked to long term mental health problems or suicidality. One 2010 analysis of psilocybin studies done between 1999 and 2008 looked at the experiences of 110 patients. Negative experiences were not common and seemed to be dose-dependent where higher doses of psilocybin were associated with higher rates of adverse reactions. All of the short-term adverse reactions were "successfully managed through interpersonal support" and did not require taking medications and seemed to have no lasting effects, based on follow-up interviews.
Hallucinogen Persisting Perception Disorder (HPPD) is a controversial neurocognitive condition where the patient reports persisting sensory effects after using a psychedelic substance. Also known as "flashbacks" the patient may experience brief reoccurrences/episodes of alterations in perception, mood, and/or consciousness, as previously experienced during a hallucinogenic intoxication. These symptoms can occur on a spectrum from occasional to near-constant. There is little conclusion about how common or debilitating these "flashback" experiences may be. Some studies suggest that they are less likely to occur in those who have taken a psychedelic in a clinical setting. Based on the phenomena existing in psychedelic-naïve patients and inconclusive data from studies that have examined the disorder, a causal relationship between persistent perceptual symptoms and use of psychedelics remains unproven. Some precautions that may reduce harm to those receiving psychedelic medicine in clinical environments may include screening for a history of schizophrenia or psychosis, comfortable therapeutic set and settings that reduce the risk of panic or distress, interpersonal support provided by the clinicians, pharmaceutical-grade drugs, and low, subperceptual dosing, also known as micro-dosing.
There is vast opportunity to explore the effects of psychedelics on the immune system, in particular, autoimmunity. Systematic screening for various autoantibodies, inflammatory biomarkers, and for the expression of autoimmune-related genes in response J o u r n a l P r e -p r o o f to psychedelic treatments could provide intriguing observations and lead to more focused investigations. The effects of psychedelic compounds on enteric bacterial behavior is of particular interest. Studies could be conducted examining the effects on bacterial growth and metabolism as a result of exposure to psychedelic compounds. In vitro and in vivo studies may hold many answers and even more questions about if and how serotonergic psychedelic compounds may be transported into bacterial cells and influence microbiome colonization and species composition. Studies could examine the effect of administration of psychedelics on enteric epithelial tissue integrity in the gut, or effects on LPS-induced cytotoxicity, etc. Although results from preclinical studies on the immunomodulatory and antiinflammatory effects are promising, the field of psychedelic research in biomedicine is still in its infancy. Current hypotheses regarding signaling mechanisms and systemic immune effects of psychedelics are based on a very limited amount of factual data. Only until we better understand the genetic and pathophysiological bases for AiD can there be appropriately and rigorously designed human clinical studies that consider psychedelics as potential therapeutic agents. While there is a need for deeper investigation, there appears to be enough evidence of direct and indirect effects from psychedelic compounds that may benefit those with AiD to merit further exploration on the topic. Given the complexity of factors that contribute to AiD, a multi-facetted approach may be appropriate to address the multiple features and causes of AiD simultaneously. Unlike many current conventional treatment methods, it appears that psychedelics may potentially offer an efficacious strategy for relieving and J o u r n a l P r e -p r o o f perhaps even resolving autoimmunity by targeting psychospiritual origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations. The evidence presented in this paper provides support to the idea that there is untapped potential of exploring the use of psychedelics within this specific disease category. Given the limitation of efficacious treatment options for AiDs, and the physiological safety of psychedelic substances, it is likely a research topic worth pursuing. There is hope that the collection of this evidence may guide or inspire others to pioneer such studies. Overall, this direction of research is virtually unexplored and underdeveloped, providing a wealth of opportunities to discover novel applications for psychedelics in the field of immunology.
J o u r n a l P r e -p r o o f Ketamine NMDA Glu (antagonism) ^BDNF, ^ MTOR, ˅Glu excitotoxicity ˅IL-6, ˅TNFαMDMA (in assisted psychotherapy) VMAT, SERT ˅Amygdala response ˅HPA-axis dysregulationHarmine/Harmaline MAO (inhibitor) ^5HT, ˅NF-kB, ˅HSV 2 ^NK cells, ˅Glu excitotoxicityIbogaine/Noribogaine (metabolite) 5HT2a (partial agonism) Sig1R (agonism) TrK-B (agonism) ^BDNF, ^ MTOR
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