Psychedelics for Brain Injury: A Mini-Review

The investigators performed a targeted literature search using PubMed and supplemented that search by examining bibliographies of main review articles; specific search terms are reported as available in the paper's Appendix. Study selection prioritised publications addressing psychedelic effects on neuroregeneration and neuroprotection rather than on psychotherapeutic outcomes. A narrative mini-review design was used, intended to provide a brief overview of mechanistic and translational evidence relevant to brain injury. The authors did not report a formal systematic review process, risk-of-bias assessment, or meta-analytic pooling; instead, they synthesised findings from in vitro, in vivo, organoid and limited clinical studies and case reports to illustrate potential pathways for future clinical trials.

Neuroinflammation: The review describes a body of preclinical work suggesting classical psychedelics and related compounds can modulate immune signalling relevant to brain injury. 5-HT2A receptors, implicated in the psychological effects of classical psychedelics, are also widely expressed on immune-related cell types and in the brain. In contrast to systemic immunosuppressants, psychedelics are proposed to produce a pattern of cytokine expression that favours anti-inflammatory or anti-allergic states rather than global immune suppression. DMT receives particular attention: in animal studies DMT acts via the sigma-1 receptor (S1R) to reduce pro-inflammatory cytokines (reported reductions in IL-1β, IL-6, TNFα and IL-8) and to increase the anti-inflammatory cytokine IL-10, while inhibiting Th1 and Th17 activation. S1R agonism is also linked to regulation of intracellular calcium, antioxidant responses and modulation of neuritic outgrowth, myelination and synaptogenesis. In murine middle cerebral artery occlusion (MCAO) models, DMT reduced infarct core volume at 24 hours and improved functional limb recovery at 30 days; related cytoprotective effects have been reported in human cerebral organoids. The authors note that a selective S1R agonist showed statistically significant functional recovery in a post-hoc analysis of moderately to severely affected stroke patients in a single clinical trial, indicating a plausible translational signal. Hippocampal neurogenesis: Khan and colleagues summarise animal evidence that TBI and stroke alter hippocampal neurogenesis and that 5-HT receptor stimulation is a key modulator of this process. The relationship between increased neurogenesis and functional recovery is complex: while new neuron formation has been associated with improved cognition, mood and memory encoding, it can also be linked to pro-epileptogenic changes and spatial memory impairments. In mice, acute psilocybin produced dose-dependent effects on hippocampal neurogenesis (low doses increased neurogenesis; higher doses inhibited it), whereas once-weekly high-dose administration avoided tolerance-related downregulation and was associated with increased neurogenesis. The authors highlight timing, injury type and integration of new neurons into circuits as critical variables that complicate translation. Neuroplasticity: The review collates evidence that psychedelics promote structural and functional neuroplasticity in non-injured models, a mechanism that has been proposed to underpin persistent symptom improvement in psychiatric disorders. Ly et al. found that some psychedelics rivalled or exceeded ketamine in promoting plasticity in in vivo models, and many effects appeared evolutionarily conserved across species. Brain-derived neurotrophic factor (BDNF) is discussed as a likely mediator: an RCT cited by the authors reported increases in serum BDNF for 48 hours after administration of an ayahuasca tisane (a DMT-containing preparation plus reversible MAO inhibitors). The review also mentions that a synthetic S1R agonist enhanced plasticity-mediated sensorimotor recovery in rats when treatment began up to 2 days after MCAO, potentially widening an acute therapeutic window. Translationally relevant non-pharmacologic interventions are covered briefly: mirror visual-feedback (MVF) enhances neuroplasticity and, in a case report, psilocybin combined with MVF was associated with dose-dependent reduction of phantom limb pain; randomised trials for psilocybin in phantom limb pain are noted as ongoing. Increase in brain complexity: The authors discuss measures of brain activity complexity — including perturbational complexity index and Lempel-Ziv complexity (LZC), which are used to quantify richness of brain dynamics and have been associated with levels of consciousness — as a target for disorders of consciousness (DOC) arising after brain injury. Psilocybin, LSD and ketamine at psychedelic doses have been reported to increase LZC and other complexity measures beyond normal wakefulness in healthy human studies. Scott and Carhart-Harris's proposed experimental protocol is cited, which hypothesises that increasing conscious content (reflected in complexity measures) may be a distinct and useful strategy compared with traditional stimulants that primarily increase arousal. The review notes that DMN (default-mode network) connectivity, densely expressing 5-HT receptors and implicated in conscious processing, is reduced in stroke patients with DOC and correlates with Glasgow Coma Scale scores, providing a potential neural substrate for psychedelic effects on consciousness. The authors also acknowledge a lack of direct studies of complexity measures in DOC patients treated with stimulants or psychedelics.

The authors conclude that psychedelics warrant further study as potential therapies for brain injury because preclinical and some early translational data indicate multiple plausible mechanisms — immunomodulation, promotion of hippocampal neurogenesis, enhancement of neuroplasticity and increases in brain activity complexity — that could be beneficial after stroke or TBI. They stress caution: many compounds that appeared promising in vitro have not translated to clinical benefit, and much of the current evidence comes from animal, cellular and limited human studies. Khan and colleagues discuss related clinical signals and caveats. Non-classical agents such as ketamine and cannabinoids have produced mixed results in brain injury research; for example, observational data linked THC detection to lower mortality after TBI but a randomized trial of the non-psychoactive cannabinoid dexanabinol failed to improve long-term Glasgow Coma Scores. The authors raise the possibility of an "entourage" effect (synergy among multiple constituents) as one explanation for discrepant findings and note that whole mushroom extracts have demonstrated greater potency than isolated compounds in some animal models. A core unresolved question highlighted is whether subjective hallucinogenic experiences are necessary for therapeutic benefit: some animal and analogue studies indicate separation of behavioural and anti-inflammatory effects from hallucinogenic properties, and non-hallucinogenic analogues have produced neuroplastic and anti-addiction effects in rodents, while other theoretical constructs (for example the "pivotal mental state" hypothesis) posit that the subjective state may be integral for certain psychological benefits. Practical and research implications offered by the authors include the need for phase II clinical trials to define efficacy, optimal timing after injury and suitable routes of administration; they note most discussed compounds have reasonable oral absorption but that intranasal delivery could afford more rapid CNS entry. The review also suggests an earlier clinical role for psychedelics might be in treating depression and PTSD, conditions that impede rehabilitation after stroke and TBI, because clinical evidence for those indications is currently more advanced. Finally, the authors propose further work on non-psychoactive analogues to disentangle mechanisms and to facilitate use in acute hospital settings, while emphasising that historical safety data and millennia of human use may serve as informal phase 0/Phase I precedent but do not replace the need for rigorous contemporary trials.