Psychedelics for acquired brain injury: a review of molecular mechanisms and therapeutic potential

Allen and colleagues situate this review within the renewed scientific interest in psychedelic compounds after decades of restricted research. They note that classical psychedelics (for example psilocybin, DMT, LSD) and some non-classical agents (for example ibogaine, ketamine) act on diverse receptor systems but are most commonly associated with agonism at serotonin (5-HT) receptors, especially 5-HT2A. The authors highlight that psychedelics have been reported to produce rapid and, in some cases, long-lasting therapeutic effects across a range of psychiatric and behavioural disorders, and that these effects are thought to involve changes in neuroplasticity, neurotrophic signalling, and immune modulation. At the same time, the field lacks focused investigation of psychedelics in acquired brain injury (ABI), a heterogeneous group of conditions (including traumatic brain injury and stroke) that cause persistent cognitive, emotional and neurological deficits driven by processes such as excitotoxicity, oxidative stress, apoptosis, and chronic neuroinflammation. This paper therefore aims to review the preclinical and clinical literature relevant to using psychedelics in the context of ABI, emphasising molecular and cellular pathways that could underlie neuroprotection, neuroregeneration and anti-inflammatory effects. The authors state their focus on serotonin receptors, sigma-1 receptors, and neurotrophic signalling (notably BDNF–TrkB pathways), and they set out to assess whether the pharmacology of psychedelics provides a mechanistic rationale for acute and/or chronic interventions after ABI. The review is presented as a narrative literature synthesis intended to inform future translational and clinical work in this area.

The authors performed a narrative literature search using PubMed and Google Scholar. Search terms combined psychedelics with ABI-relevant concepts (for example “brain injury”, “traumatic brain injury”, “concussion”, “ischaemia”, “stroke”) and molecular or cellular terms (for example “neuroinflammation”, “apoptosis”, “mitochondria”, “5-HT”, “sigma”, “TrkB”). Inclusion criteria specified full-text journal articles in English published within the last 20 years, and articles had to feature the key search words in the abstract and/or provide molecular or cellular data related to psychedelic-relevant pathways. Experimental details identified in eligible papers were extracted and compiled into a table (not provided in the extracted text). The extracted text does not clearly report the date ranges of the searches, the number of records retrieved or included, nor any formal risk-of-bias or quality assessment methods, consistent with the paper being a narrative rather than a systematic review.

The review synthesises evidence across several domains relevant to ABI pathophysiology and potential psychedelic effects. The authors summarise the burden and pathophysiology of ABI: global incidence estimates for ABI vary in the extracted text (for example 300–600 per 100,000 and 50 million new cases each year are reported; elsewhere the text states seventy million people are affected by TBI annually). ABI includes traumatic and non-traumatic causes such as stroke, and symptoms can persist for months to years. Pathophysiological cascades highlighted include ionic dysregulation, glutamate-mediated excitotoxicity, mitochondrial dysfunction with lowered ATP and increased reactive oxygen species (ROS), apoptosis, proteinopathies, blood–brain barrier disruption and chronic neuroinflammation. On psychedelic pharmacology, the authors emphasise polypharmacology: classical tryptamine and phenylalkylamine psychedelics share structural similarity to 5-HT and agonise multiple serotonin receptor subtypes, notably 5-HT2A, but many compounds also modulate other receptors and transporters (for example dopamine receptors, adrenoreceptors, monoamine transporters). DMT and related compounds are also discussed as sigma-1 receptor agonists; sigma-1 receptors reside at mitochondrion-associated endoplasmic reticulum membranes and regulate calcium handling and mitochondrial efficiency. The review notes that psychedelics can access intracellular 5-HT2A receptors because of lipophilicity, which may have distinct signalling consequences compared with extracellular 5-HT. Regarding neuroprotection and oxidative stress, preclinical studies cited include in vitro reports in which 5-HT and DOI protected cells from kainate- and H2O2-mediated excitotoxicity and oxidative damage, with implicated signalling via phospholipase C and MEK but not PI3K. Some evidence indicates psychedelics can enhance mitochondrial respiration, antioxidant defences and mitochondrial DNA content via 5-HT2A-dependent mechanisms. DMT and 5-MeO-DMT are noted to engage sigma-1 receptors, and sigma-1 agonism is linked in animal models to reduced lesion volume and lower oxidative damage when administered before injury; DMT reduced lesion size in a rat stroke model and protected human iPSC-derived cortical neurons from hypoxic insult in vitro. The authors also report mixed findings about oxidative effects: certain doses of psilocybin induced DNA oxidative damage in rodents, while LSD increased levels of several antioxidant enzymes but may also raise ROS, indicating dose- and context-dependent effects. On apoptosis and neurotrophic signalling, the review summarises evidence that ABI elevates pro-apoptotic markers (for example caspase-3, BAX) and that psychedelics may modulate these pathways. DMT and other sigma-1 agonists are suggested to downregulate apoptotic mediators in preclinical models. Psychedelics are also linked to enhancements in BDNF–TrkB signalling: human studies show increased circulating BDNF after LSD and ayahuasca, and in vitro/animal data show TrkB-related plasticity. Notably, LSD and psilocin are reported to bind TrkB with higher affinity than several antidepressants, and downstream pathways (PI3K/Akt/mTOR) relevant to cell survival, protein synthesis and dendritic growth are discussed. Neuroplasticity findings include acute and sustained spinogenesis and increases in dendritic spine density after psilocybin in mice, spinogenic effects of DOI mediated via 5-HT2A, and dose-dependent effects of psilocybin on hippocampal neurogenesis. The authors cite human biomarker data (BDNF increases within hours) and multiple preclinical reports that psychedelics upregulate plasticity-related proteins (for example postsynaptic density-95, AMPA receptors). However, receptor-specific roles remain unclear: some in vitro effects are blocked by 5-HT2A antagonists, yet certain behavioural or molecular endpoints in vivo were not blocked by antagonists in other studies, and intracellular 5-HT2A signalling adds complexity to interpretation. On neuroinflammation, in vitro studies show psilocybin, DMT and 5-MeO-DMT can reduce pro-inflammatory cytokine expression (for example IL-1β, IL-6, TNF-α) and increase anti-inflammatory IL-10 in monocyte-derived cells, with sigma-1 implicated in some effects. Microglial phenotype modulation is described, including live-imaging evidence that sigma-1 agonism can cause microglia to migrate away from injury sites in models. In vivo, DMT normalised inflammatory mediators in models of cerebral ischaemia and PTSD and improved motor outcomes post-stroke; psilocybin reduced inflammation markers in LPS models, particularly when combined with an anti-inflammatory agent. DOI decreased expression of certain pro-inflammatory mediators in systemic inflammatory models. The authors underscore that acute inflammation can be beneficial and the timing of anti-inflammatory interventions after ABI will be critical. Finally, at the network level, neuroimaging studies are summarised: psychedelics typically reduce within-network functional connectivity (FC) and increase between-network FC, increase brain signal diversity and transiently reduce default-mode network (DMN) connectivity—changes that correlate with subjective phenomena such as ego dissolution and with longer-term socio-affective changes in other patient groups. The review notes the potential relevance of these network effects to disorders of consciousness and to TBI-related network dysfunction, but it emphasises that, to date, no clinical studies have directly evaluated the acute or long-term effects of psychedelics on functional connectivity in ABI populations. Across domains, the review highlights heterogeneity in findings, dose-dependent and receptor-specific uncertainties, and a predominance of preclinical data with very limited direct clinical evidence in ABI.

The authors interpret the assembled evidence as providing a plausible mechanistic rationale for exploring psychedelics in ABI because these compounds combine neuroprotective, neuroplastic and anti-inflammatory actions that map onto key pathophysiological processes after injury. Psychedelics' capacity to rapidly upregulate neurotrophic signalling (BDNF–TrkB), enhance synaptogenesis and dendritic spine density, modulate mitochondrial function and reduce pro-inflammatory cytokines is presented as convergent evidence supporting potential benefits in both the acute and chronic phases of ABI. Nevertheless, the review stresses substantial uncertainties. The polypharmacology of psychedelics makes it difficult to ascribe therapeutic effects to single receptors or pathways, and some receptor targets (for example intracellular 5-HT2A versus TrkB or sigma-1) may have opposing or context-dependent effects. Dose-dependent toxicity signals in some rodent oxidative stress assays, inconsistent blockade by receptor antagonists across studies, and sparse data from injury models that closely mimic human ABI are all flagged as limitations. The authors acknowledge the absence of clinical trials testing psychedelics specifically for ABI and call attention to translational gaps between in vitro/rodent models and human pathology. Practical and ethical considerations for clinical translation are discussed. The review notes common safety measures used in psychedelic therapy (screening, preparation, set and setting, supervised dosing, integration sessions) and lists transient adverse reactions observed in controlled studies (for example increased heart rate, nausea, anxiety, acute fear), as well as rare risks such as hallucinogen persisting perception disorder. Challenges in trial design are emphasised, particularly difficulties with blinding due to conspicuous subjective effects, the need for specialist training to safely facilitate sessions, and financial and logistical burdens associated with providing psychological support. The authors also highlight unresolved questions that would shape clinical application: whether the subjective psychedelic experience is necessary for therapeutic gains, whether non-hallucinogenic analogues or sub-perceptual dosing regimes could retain benefits with fewer risks, and how injury subtype (for example ischaemic versus traumatic) might favour particular agents (the sigma-1–targeting DMTs are proposed as potentially more suitable for ischaemic insults). Finally, the authors call for targeted preclinical studies using ABI-relevant models (for example closed-head injury), dose–response characterisation, elucidation of receptor-specific mechanisms, and well-designed clinical trials to determine safety, dosing, timing relative to injury, durability of effects and functional outcomes in ABI populations.

The review concludes that, although direct research on psychedelics in acquired brain injury is limited, accumulated preclinical and some clinical evidence supports the possibility that psychedelics exert neuroprotective, anti-inflammatory and neuroplastic effects that could be therapeutically valuable for ABI. The authors recommend further work to delineate molecular and network-level mechanisms, to test efficacy in acute and chronic ABI settings, and to assess long-term safety and clinical benefit.