Psychedelics as a Novel Approach to Treating Autoimmune Conditions

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.

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.