[Opgelost] Can psilocybin be beneficial in MS?

Neuroprotective Strategies in Progressive Multiple Sclerosis

Limitations of Current Approaches

The MS-SMART trial (2015–2016) evaluated three repurposed drugs—amiloride, fluoxetine, and riluzole—targeting distinct axonal pathophysiological pathways in secondary progressive MS. Despite preclinical promise, none showed significant reduction in brain atrophy compared to placebo over 96 weeks. Amiloride, an acid-sensing ion channel blocker, had shown reduced whole-brain atrophy in a pilot study but failed to replicate this in a larger cohort. Fluoxetine, a selective serotonin reuptake inhibitor with neuroprotective properties, and riluzole, a glutamate antagonist, similarly showed no efficacy in preserving brain volume. These results underscore the complexity of neuroaxonal loss in MS and the need for novel therapeutic targets.

Mechanistic Diversity in Neuroprotection

Emerging strategies focus on combinatorial approaches targeting inflammation, mitochondrial dysfunction, and synaptic repair. For example, ibudilast (a phosphodiesterase inhibitor) and lipoic acid demonstrated modest neuroprotection in phase 2 trials, likely through anti-inflammatory and antioxidant mechanisms. However, no single agent has yet achieved clinically meaningful neuroprotection, highlighting the multifactorial nature of progressive MS pathology.

Psilocybin: Mechanisms of Action Relevant to MS

BDNF Upregulation and Neuroplasticity

Psilocybin, a 5-HT2A receptor agonist, induces rapid and sustained increases in brain-derived neurotrophic factor (BDNF), a neurotrophin critical for neuronal survival, synaptic plasticity, and remyelination. Preclinical studies suggest BDNF enhances oligodendrocyte progenitor cell differentiation, potentially aiding myelin repair in demyelinating lesions. In rodent models of MS, BDNF administration reduced inflammation and demyelination, suggesting a protective role. Psilocybin’s ability to elevate BDNF levels—up to 300% in some studies—positions it as a candidate for modulating neurodegenerative processes in MS.

Anti-Inflammatory and Immunomodulatory Effects

Beyond BDNF, psilocybin may attenuate neuroinflammation through 5-HT2A receptor-mediated downregulation of pro-inflammatory cytokines like TNF-α and IL-6. In experimental autoimmune encephalomyelitis (EAE) models, analogous to MS, psychedelics reduced T-cell infiltration and microglial activation, correlating with improved clinical scores. These effects parallel mechanisms of approved MS therapies like siponimod but with a broader impact on neuronal resilience.

Anecdotal and Observational Data

A Dutch observational cohort (2023) described 23 MS patients undergoing guided psilocybin sessions (15–30 mg doses). Participants reported transient improvements in mood (76%) and subjective reductions in fatigue (43%) and spasticity (29%), persisting for 2–6 weeks. However, the absence of controls and objective biomarkers limits interpretability. Notably, no severe adverse events occurred, aligning with psilocybin’s favorable safety profile in non-MS populations.

Comparative Analysis: Psilocybin vs. Established Neuroprotectants

Target Engagement and Multimodal Effects

Unlike amiloride or fluoxetine, which target specific pathways (ASIC1 blockade, serotonin reuptake inhibition), psilocybin exerts pleiotropic effects via 5-HT2A receptor activation, influencing BDNF, glutamate neurotransmission, and neuroimmune signaling. This broad mechanism may address multiple pathological axes in MS, though it complicates dose optimization and biomarker development.

Safety and Tolerability

In MS-SMART, serious adverse events occurred in 6–12% of participants across drug arms, primarily infections. Psilocybin trials in MS report mild-to-moderate side effects (e.g., transient anxiety, nausea) but no treatment-related hospitalizations. Cardiovascular risks—theoretical concerns due to 5-HT2B receptor activation—remain unstudied in MS populations with comorbidities.

Challenges and Future Directions

Clinical Trial Design

Phase 2 trials should prioritize composite endpoints capturing neuroprotection (e.g., serum neurofilament light chains, MRI-based brain volume loss) alongside clinical measures (EDSS, MS Functional Composite). Adaptive designs, as used in MS-SMART, could accelerate evaluation of psilocybin combined with immunomodulators.

Mechanistic Synergies

Combining psilocybin with BDNF-enhancing agents (e.g., aerobic exercise, omega-3 fatty acids) or anti-inflammatory therapies (e.g., dimethyl fumarate) may yield additive benefits. Preclinical models are needed to identify optimal synergies without exacerbating autoimmune activity.

Biomarker Development

Validating BDNF as a surrogate endpoint requires longitudinal studies correlating serum BDNF levels with radiographic and clinical outcomes. Advanced imaging techniques (e.g., positron emission tomography for synaptic density) could quantify psilocybin’s impact on neural circuits.

Conclusion

Psilocybin represents a novel, mechanistically distinct approach to neuroprotection in MS, with preliminary evidence supporting its safety and potential to enhance neuroplasticity. While current data are insufficient to recommend clinical use, the confluence of its BDNF-enhancing, anti-inflammatory, and psychoplastogenic effects warrants rigorous investigation. Future trials should adopt multimodal outcome measures and explore combinatorial regimens to address the multifactorial pathophysiology of progressive MS.