From mouse models to freshly isolated human nerves, researchers traced what happens when chemotherapy disrupts the cellular machinery that delivers energy to vulnerable sensory axons.
Study: Psilocybin prevents chemotherapy-induced peripheral neuropathy through mitochondrial trafficking preservation. Image Credit: YARphotographer / Shutterstock
In a recent study published in the journal Science, researchers investigated the preclinical effects of the prophylactic administration of the serotonergic psychedelic psilocybin on the development of chemotherapy-induced peripheral neuropathy (CIPN).
The study used preclinical C57BL/6J mice and human cell and nerve tissue models to evaluate the effects of the treatment on behavioral sensory metrics, electrophysiology, live mitochondrial trafficking, and human nerve tissue, with a focus on the 5-HT2A receptor.
Study findings demonstrated that two psilocybin pretreatments were sufficient to prevent mechanical hypersensitivity in an initial cisplatin model, while cycle-matched psilocybin pretreatment maintained protection against mechanical hypersensitivity across six monthly chemotherapy cycles and more than 8 months of follow-up, without measurably impairing antitumor efficacy in tumor-bearing mice.
The study also found that the non-hallucinogenic 5-HT2A agonist TBG provided comparable protection against mechanical hypersensitivity in mice, indicating that hallucinogenic activity may not be required for this neuroprotective effect and that non-hallucinogenic 5-HT2A agonists warrant further study.
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect of cancer chemotherapy that can affect up to 60% of patients receiving some neurotoxic regimens. The condition results from neurotoxic chemotherapeutic agents (e.g., cisplatin, paclitaxel, and docetaxel) damaging the peripheral nerves, leading to progressively worsening symptoms ranging from numbness and tingling to severe pain, typically affecting the patients’ hands and feet.
Despite intensive research aimed at mitigating the condition, CIPN is observed to be often irreversible, sometimes forcing clinicians to reduce patients’ chemotherapy doses or prematurely terminate the treatment cycles. Prior research has linked CIPN to distal sensory axonopathy, marked intraepidermal nerve fiber (IENF) loss in the skin, and maladaptive reorganization of cortical pain processing.
Furthermore, previous biochemical and oncological studies have found that, at the cellular level, platinum- and taxane-based chemotherapeutic agents induce severe mitochondrial dysfunction, in which active axonal transport of mitochondria is arrested, thereby starving distal terminals of adenosine 5'-triphosphate (ATP).
Unfortunately, hitherto, no preventive therapies for CIPN have been approved, restricting current interventions to symptomatic management.
About the study
The present study aimed to address these persistent therapeutic limitations and inform future CIPN research and interventions by investigating whether pre-chemotherapy exposure to psilocybin could help prevent or reduce peripheral neurotoxicity.
The study used C57BL/6J mice in cisplatin, paclitaxel, and docetaxel models, including a six-cycle cisplatin regimen designed to model repeated chemotherapy exposure. Additionally, cisplatin was tested in a syngeneic oral cancer (MOC1) model pretreated with psilocybin.
The study first evaluated sensorimotor behavior using von Frey testing, acetone cold allodynia, adhesive tape removal, and nesting assays. Next, electrophysiological network dynamics were assessed using whole-cell patch-clamp of dorsal root ganglion (DRG) neurons, medial prefrontal cortex (mPFC) microelectrode arrays, and continuous electroencephalography (EEG).
The researchers also tracked mitochondrial movement within axons and molecular signaling using live-cell mitochondrial kymography, transmission electron microscopy, reverse-phase protein arrays (RPPA), and RNA sequencing and transcriptomic profiling.
The translational relevance of the preclinical findings was examined using human stem cell-derived sensory neurons (iSNs), organ donor DRGs, and freshly harvested peripheral nerves from 29 surgical patients.
Study findings
The study’s analyses revealed that two prophylactic doses of psilocybin completely prevented cisplatin-induced mechanical hypersensitivity in the initial model, while cycle-matched pretreatment maintained protection against mechanical hypersensitivity across six repeated treatment cycles. Psilocybin also attenuated cisplatin-induced cold allodynia, preserved tactile acuity, and maintained cutaneous IENF density.
In preclinical murine models, psilocybin retained neuroprotective effects without measurable changes in tumor growth or systemic cytokine profiles in tumor-bearing mice, suggesting that neuroprotection did not measurably affect these endpoints in this model. Pharmacological evaluations confirmed that this neuroprotection was 5-HT2A receptor-dependent, as selective antagonism with volinanserin completely abolished psilocybin's protection against mechanical hypersensitivity.
Most notably, the study revealed that the non-hallucinogenic agonist TBG conferred protection against mechanical hypersensitivity comparable to that of psilocybin, supporting the conclusion that hallucinogenic activity is not required for this neuroprotective effect.
The study’s mechanistic investigations identified a dual-site mechanism wherein, centrally, psilocybin restored mPFC network activity, significantly maintained beta-band EEG power, showed a similar trend in alpha power, and prevented sigma-band suppression, consistent with protection against chemotherapy-induced central network dysfunction, while peripherally, psilocybin was found to maintain local axonal energy distribution without suppressing acute DRG nociceptor hyperexcitability.
Finally, live-cell imaging in human peripheral nerves showed that cisplatin markedly impaired mitochondrial motility, whereas psilocybin maintained mitochondrial trafficking and transport velocity. Molecular and pharmacological experiments implicated 5-HT2A-dependent activation of the TrkB-Akt-PAK5-MAP2-KIF5B pathway, together with remobilization of syntaphilin-anchored mitochondria, in preserving mitochondrial distribution and local ATP supply within distal axons.
Conclusions
The present study provides preclinical evidence that prophylactic psilocybin may prevent or reduce CIPN, with ex vivo human nerve experiments showing that psilocybin maintained mitochondrial trafficking and transport velocity, which were otherwise impaired by cisplatin.
The study further demonstrated that the non-hallucinogenic 5-HT2A agonist TBG reproduced protection against mechanical hypersensitivity in mice, suggesting that hallucinogenic activity may not be necessary for at least this aspect of neuroprotection. However, neither psilocybin nor TBG was tested clinically for CIPN prevention. Moving forward, cycle-aligned 5-HT2A agonism represents a candidate prophylactic strategy that warrants clinical evaluation, including assessment of whether neuroprotection can be achieved without compromising antitumor treatment.
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