Psychedelics as anti-inflammatory agents

The extracted text does not present a formal Methods section or describe a systematic search strategy. Instead, the paper functions as a narrative review that integrates findings from prior human clinical trials, cellular assays and animal models. The authors place particular emphasis on studies that used the selective 5-HT2A agonist (R)-DOI to probe inflammation in vitro and in vivo, and they also reference work with other psychedelics (for example LSD and psilocybin) and related pharmacology (antagonists such as ketanserin and M100109). Evidence sources discussed include biochemical and gene expression assays in cultured cells, in vivo mouse experiments (acute TNF-α challenge and murine models of allergic airways disease using ovalbumin), and clinical observations from recent human trials of psilocybin. Where reported, the review highlights pharmacological controls (selective receptor antagonists) and outcome measures used in the original studies (cytokine and adhesion molecule expression, NF-κB activation, histology, airway physiology, flow cytometry and qRT-PCR).

Serotonin and inflammation: The authors summarise evidence that serotonin is intimately involved in inflammatory processes and is generally viewed as pro‑inflammatory in many peripheral contexts. Experimental findings cited include associations between elevated peripheral serotonin and increased IL-6 and TNF-α in healthy volunteers, reduced inflammation after serotonin depletion in some animal models, and modulation of monocyte cytokine and chemokine production via several serotonin receptor subtypes. 5-HT2A receptor distribution and immune relevance: 5-HT2A receptors are widely expressed in brain and peripheral tissues and their mRNA/protein has been detected in immune‑related tissues including spleen, thymus and circulating lymphocytes, as well as in PBMCs, eosinophils and T cells. Early literature yielded contradictory results about whether 5-HT2A signalling promotes or inhibits inflammatory responses; some antagonists (ketanserin, sarpogrelate) were reported to reduce inflammatory markers, but off‑target effects (for example on histamine H1 receptors) complicate interpretation. In vitro anti‑inflammatory activity of (R)-DOI: Studies in rat aortic smooth muscle cells and other cell systems showed that the 5-HT2A agonist (R)-DOI potently suppresses TNF-α‑induced inflammatory responses. (R)-DOI inhibited expression of ICAM‑1, VCAM‑1 and IL‑6, blocked NF‑κB activation and reduced nitric oxide synthase activity. The compound displayed unusually high potency, with IC50 values in the low picomolar range (reported as approximately 10–20 pM). Agonists selective for 5-HT2B/2C did not reproduce these effects, indicating 5-HT2A specificity. In vivo anti‑inflammatory effects: In mice acutely challenged with TNF-α, pretreatment with (R)-DOI (administered intraperitoneally 30 minutes before TNF-α) reduced inflammatory gene and protein expression in several tissues, including aortic arch, intestine and blood. Reported targets suppressed by (R)-DOI included ICAM‑1, VCAM‑1, IL‑6, IL‑1β, MCP‑1 and CX3CL1, and increases in circulating IL‑6 were attenuated. Use of the 5-HT2A‑selective antagonist M100109 blocked these anti‑inflammatory effects, supporting mediation via 5-HT2A receptors. Asthma model findings: In a murine ovalbumin (OVA) model of allergic airways disease, nasally delivered (R)-DOI at doses as low as 0.01 mg/kg prevented airway hyperresponsiveness (AHR), eosinophilia and pulmonary inflammation; notably, this dose was below behavioural thresholds. Gene expression analysis showed suppression of a subset of pro‑inflammatory cytokines (GM‑CSF, Il5 and Il13) but not Il4. Flow cytometry indicated reduced recruitment and Th2 polarisation in treated lungs. The authors also note unpublished observations that several other psychedelic compounds can prevent development of asthma in similar models, although (R)-DOI showed exceptional potency. Mechanistic insights and hypotheses: To reconcile apparent discrepancies between serotonin's historically pro‑inflammatory role and psychedelics' anti‑inflammatory actions at the same 5-HT2A receptor, the authors propose functional selectivity: different agonists stabilise distinct receptor conformations that engage different intracellular signalling cascades. They also raise the possibility that 5-HT2A activation modulates epigenetic mechanisms (histone acetylation/methylation) to selectively promote anti‑inflammatory gene expression, citing parallels with histone deacetylase inhibitor effects in mouse asthma models. Other mechanistic details remain unresolved in the extracted text.

Flanagan and colleagues interpret the assembled evidence as indicating that activation of 5-HT2A receptors by psychedelic agonists can produce robust anti‑inflammatory effects across cell types and tissues. They suggest these effects may contribute to therapeutic outcomes in psychiatric disorders by reducing neuroinflammation and thereby supporting longer‑term stability after an acute resetting of brain network connectivity. In peripheral disease models, the authors view psychedelics—particularly (R)-DOI—as promising small‑molecule, steroid‑sparing, disease‑modifying agents for conditions such as asthma, atherosclerosis, inflammatory bowel disease and rheumatoid arthritis. The authors acknowledge important uncertainties and limitations. Mechanistic pathways remain to be elucidated: it is unclear which cell types are most responsive, whether 5-HT2A activation directs immune cell differentiation toward anti‑inflammatory phenotypes, and what the consequences of chronic peripheral 5-HT2A agonism would be. They also note the need to validate the efficacy and safety of sub‑behavioural dosing strategies in humans. Historical contradictory findings and off‑target actions of some pharmacological tools (for example ketanserin's H1 activity) complicate interpretation of earlier work, underscoring the need for selective reagents and replication. Practical barriers to clinical development include regulatory scheduling of many psychedelics, although the authors point out that some 5-HT2A‑activating drugs have received FDA approval (for example lorcaserin). Finally, the authors highlight epigenetic modulation and neurogenesis as candidate mechanisms linking anti‑inflammatory effects to longer‑term behavioural outcomes, but emphasise these remain speculative pending further study.

The authors conclude that psychedelics, acting via 5-HT2A receptors, produce a potent blockade of TNF‑α‑driven inflammation in cellular and animal models and that these effects likely extend beyond simple TNF‑α antagonism to influence multiple inflammatory mediators and cellular differentiation pathways. They propose that functional selectivity at the 5-HT2A receptor and modulation of epigenetic states are plausible mechanisms, and that these compounds could represent inexpensive, bioavailable, small‑molecule therapeutics for a range of inflammatory disorders. At the same time, the paper emphasises that translation to humans—especially the use of sub‑behavioural dosing—requires additional research, and that regulatory scheduling of many psychedelics may pose development challenges.