From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders

Research into classical and novel psychedelic compounds has re-emerged after decades of prohibition, driven by recent clinical studies showing long-lasting improvements in major depressive disorder (MDD) after very limited dosing. These compounds — typically acting through serotonin 5-HT2A receptor activation and including psilocybin, DMT, 5‑MeO‑DMT, mescaline and LSD — are being reconsidered not only for psychiatric indications such as treatment‑resistant depression (TRD) and PTSD but also for broader neuroscientific and therapeutic applications. The authors frame psychedelics as agents that influence core central nervous system (CNS) functions, with demonstrated effects on network connectivity, synaptic structure and certain inflammatory pathways. Kozlowska and colleagues set out to review and synthesise recent preclinical and clinical evidence on how psychedelics affect neural tissue homeostasis and immune responses in the CNS. The stated aim is to examine mechanisms — neuroplasticity, neurogenesis, gliogenesis and immunomodulation — by which psychedelics might be repurposed as therapeutics for neurodegenerative disorders and brain injury, and to identify research directions that would support such applications.

The authors summarise historical and contemporary evidence for psychedelic effects in psychiatric indications before extending to mechanisms relevant to neurodegeneration. Early mid‑20th century studies suggested potential efficacy of LSD and related compounds for TRD and substance use disorders, but most lacked modern methodological rigour. Recent controlled clinical trials reported that single or very few administrations of psilocybin produced meaningful, sometimes durable, improvements in cancer‑related distress and MDD symptoms, and imaging studies link these clinical effects to altered resting‑state functional connectivity (including changes in the default mode network). Proposed antidepressant mechanisms include 5‑HT2A stimulation, transient network “resetting,” induction of neuroplasticity and potential anti‑inflammatory effects. At the cellular and molecular level, psychedelics are reported to promote synaptogenesis and structural plasticity. Preclinical work cited shows increases in dendritic spine density and complexity, mobilisation of signalling cascades like BDNF/TrkB and mTOR, and engagement of downstream effectors such as Rac1 and kalirin‑7. DMT administration in mice increased neural progenitor proliferation and adult hippocampal neurogenesis via Sigma‑1 receptor activation in C57BL/6 animals. The review highlights gene expression and epigenetic changes as candidate mechanisms underlying sustained effects after limited dosing. Microglia and other non‑neuronal cells figure prominently in the authors’ synthesis. Multiple receptors targeted by psychedelics (5‑HT2A, 5‑HT2B, 5‑HT7 and Sigma‑1) are expressed on microglia, astrocytes and oligodendrocyte lineage cells. In vitro exposures of DMT and 5‑MeO‑DMT to monocyte‑derived dendritic cells reduced proinflammatory cytokines (IL‑1β, IL‑6, TNF‑α, IL‑8) and increased regulatory markers. The authors report pilot, unpublished data suggesting psilocin increases microglial TREM2 while reducing TLR4, p65 and CD80 proinflammatory markers, and that psychedelics may protect neurons in microglia–neuron co‑culture models, though mechanisms remain unresolved. The review considers several pathological processes central to neurodegeneration as potential therapeutic targets for psychedelics. Oxidative stress is a common feature across disorders (ALS, PD, AD, HD, SCAs), and components of ayahuasca (harmine, harmaline) and 5‑HT1A agonists are reported to induce antioxidant responses (upregulation of MT‑1/2, Nrf2, HO‑1, NQO1, SODs, catalase) in cellular and animal models. Endoplasmic reticulum stress (ERS) is discussed in relation to Sigma‑1 receptor modulation; Sigma‑1 agonism is proposed to mitigate ERS‑mediated apoptosis through effects on PERK, IRE1α and ATF6 pathways. Blood–brain barrier (BBB) integrity is another focus: microglia‑derived IL‑1β acting via Sonic Hedgehog can downregulate tight junction proteins and promote leakage, and in vivo DMT administration in a Wistar rat stroke model reduced IL‑1β, IL‑6 and TNF‑α while increasing IL‑10 and improving motor outcomes. Oligodendrocyte pathology is noted as underappreciated: oligodendrocytes are vulnerable to oxidative and inflammatory injury and show abnormalities in psychiatric and neurodegenerative conditions. Psychedelics’ anti‑inflammatory effects and Sigma‑1‑mediated promotion of oligodendrocyte progenitor differentiation are proposed as protective mechanisms for myelin and axonal support. Regarding immunomodulation, the review details receptor families implicated in psychedelic effects on immunity. 5‑HT receptors can have anti‑inflammatory effects when engaged by certain psychedelics; for example, (R)‑DOI reduced adhesion molecules (ICAM‑1, VCAM‑1) and cytokine expression in vascular and metabolic disease models. The authors invoke functional selectivity to explain why 5‑HT2A activation by psychedelics may recruit anti‑inflammatory rather than proinflammatory pathways. Sigma‑1 receptor stimulation is repeatedly linked to neuroprotection, shifts in microglial phenotype and improved outcomes in stroke and traumatic brain injury models. Trace amine‑associated receptors (TAARs), particularly TAAR1, are introduced as additional modulators of neurotransmission and immune responses; several psychedelics act as TAAR1 agonists, with possible effects on T‑cell, B‑cell and neutrophil function though data are limited. The review applies these mechanistic threads to specific neurodegenerative contexts. For spinocerebellar ataxia type 3 (SCA3), the authors describe downregulated BDNF signalling and associated proteins (Rac1, RhoA, MAPK1, MAP2K1, Pea15) in models, arguing that psychedelics—via BDNF induction and downstream signalling—could restore plasticity‑related pathways. They also note reduced antioxidant proteins in SCA3 models (Gstp1, Sod2, Fth1, Txn) and suggest that psychedelics’ antioxidant effects may be beneficial. Broader epidemiological context is provided: global burdens of depression, dementia and stroke are emphasised to motivate therapeutic development. Finally, practical translational topics are covered. The authors discuss non‑hallucinogenic derivatives and analogues (for example, ibogaine analogues reported to lack hallucinogenic effects) as a route to retain therapeutic mechanisms while avoiding subjective experiences. Evidence from preclinical asthma models shows that sub‑perceptual doses of psychedelics can have anti‑inflammatory efficacy orders of magnitude below behaviourally active doses. Implications for regenerative medicine include downregulation of co‑stimulatory molecule CD80 on microglia by DMT and psilocin, which could improve neural graft survival. Microdosing—defined here as roughly 10% of recreational doses on an intermittent schedule—is popular but understudied; controlled trials and blinded studies so far yield mixed or null cognitive and mood effects, although a small fMRI study found acute limbic connectivity changes after 13 µg LSD.

Kozlowska and colleagues interpret the assembled evidence as supporting a plausible, multi‑modal rationale for evaluating psychedelics in neurodegenerative and regenerative contexts. They highlight convergent preclinical data showing psychedelics can promote neuroplasticity, neurogenesis, antioxidant responses and anti‑inflammatory signalling, and note that multiple receptor targets (5‑HT subtypes, Sigma‑1, TAARs) expressed on neurons and glia offer mechanistic entry points to modulate disease‑relevant processes. The authors position these mechanisms relative to earlier psychiatric findings—single‑administration clinical effects in MDD and cancer‑related distress—and propose that similar cellular actions could slow or ameliorate neurodegenerative pathology if applied appropriately. Safety and translational caveats are emphasised. Clinical trials to date have generally excluded people with or at high risk for psychotic disorders, and psychedelics carry a non‑zero risk of adverse psychological effects; therefore patient selection and risk mitigation are necessary. The authors acknowledge substantial uncertainties: the precise molecular and cellular pathways that sustain long‑term benefits after short dosing regimens are not established, the role of subjective psychedelic experience versus purely pharmacological actions remains unresolved, and much of the evidence in neurodegeneration is preclinical or indirect. They also discuss the unresolved question of whether therapeutic effects can be dissociated from hallucinogenic effects, noting both the potential utility of non‑hallucinogenic derivatives and preclinical data indicating sub‑perceptual dosing may be effective for some anti‑inflammatory outcomes. Implications for research and clinical development are outlined. The paper calls for mechanistic studies focusing on neuron–glia interactions, better characterisation of microglial responses (including TREM2 and phenotype transitions), and investigation of dosing strategies suitable for chronic or early‑stage neurodegenerative disease. The authors also recommend clinical trials testing safety and efficacy in relevant patient groups, exploration of non‑hallucinogenic analogues, and evaluation of psychedelic use as adjuncts to regenerative approaches such as neural stem/progenitor cell transplantation. Throughout, they stress that existing clinical and preclinical data are promising but insufficient to support therapeutic use in neurodegeneration without targeted further study.