Parkinson’s Disease (PD), a neurodegenerative condition affecting over a million people in the United States, poses immense challenges due to its progressive impact on both motor and cognitive functions. While treatments like levodopa and dopamine-agonists can reduce some symptoms, they don’t address the underlying cellular damage, leaving many patients in search of better solutions. This is where neuroprotective therapies come into play, aiming to shield the brain from further damage and potentially delay the disease’s onset or progression.
My research team at Grand Canyon University recently published a systematic review examining two compounds—metformin and psilocybin—as potential neuroprotective agents against PD dementia (Ordovich-Clarkson et al, 2024). Metformin, a well-known diabetes drug, and psilocybin, a psychedelic compound, may sound unconventional, but both have shown intriguing potential to slow or even prevent some neurological decline associated with Parkinson’s. So what exactly makes these compounds so promising and why might they represent a future for PD prevention?
Metformin Beyond Diabetes vs. Psilocybin Beyond Recreation
With the rise of both diabetes and metabolic disorders in the United States, there has been growing evidence that these conditions may contribute to neurodegenerative diseases. Alzheimer’s, for instance, is now referred to as Type 3 Diabetes due to it’s shared hallmark of insulin resistance, whereby glucose cannot enter neurons resulting in chronic dysfunction (de la Monte & Wands). There is also growing evidence that diabetes serves as a risk factor for Parkinson’s disease as well (Hans et al., 2023).
For our study, the focus on metformin and psilocybin was grounded in their unique mechanisms of action at the cellular level. Metformin, widely prescribed for type 2 diabetes, regulates insulin sensitivity but also exerts beneficial effects on cellular energy management and oxidative stress reduction. Oxidative stress, which occurs when cells are damaged by free radicals, is a hallmark of neurodegenerative diseases, including Parkinson’s. In several studies outlined in our review article, metformin has shown promise in minimizing this cellular stress, thereby potentially slowing disease progression.
Psilocybin, on the other hand, represents a breakthrough in how we approach brain health. Derived from psychedelic mushrooms, psilocybin influences serotonin receptors, particularly the 5-HT2A receptor, linked to mood regulation and cognitive function. Activation of this receptor stimulates the release of brain-derived neurotrophic factor (BDNF), a compound that encourages neural growth and plasticity. This means that psilocybin could help repair or replace damaged neurons, offering hope for a therapeutic approach that does more than manage symptoms.
Key Findings from Our Systematic Review
Our research review explored studies involving animal and cellular models to understand how each compound interacts with neural pathways linked to PD:
Metformin’s Neuroprotective Role: Metformin showed potential for reducing oxidative stress and inflammation in cellular models, two significant contributors to neuron damage in PD. It appears to protect mitochondria, the energy-producing centers of cells, from degeneration—a crucial benefit since mitochondrial dysfunction is heavily implicated in Parkinson’s progression. Metformin also activates AMPK, a key enzyme involved in cellular energy regulation, and may inhibit the aggregation of α-synuclein, a protein that accumulates abnormally in Parkinson’s patients, further exacerbating neuron loss.
Psilocybin as a “Psychoplastogen”: Research on psilocybin has demonstrated its ability to promote neural plasticity, a process in which the brain forms and reorganizes synaptic connections. This neuroplastic effect is primarily due to its action on the 5-HT2A receptors in the brain, stimulating BDNF release. BDNF not only supports neuron growth but also helps protect neurons from further damage, potentially making psilocybin a dual-action treatment—fostering growth and shielding cells. In animal studies, psilocybin has shown the capacity to reduce α-synuclein levels, which could slow or prevent the cognitive decline often associated with Parkinson’s dementia.
Implications and Future Directions in Parkinson’s Treatment
The promising data on metformin and psilocybin hint at a potential new class of neuroprotective agents, one that could complement or even reshape the current treatment landscape. If future research, especially human clinical trials, supports these findings, we may be looking at safer, more effective treatments that target the root causes of PD rather than simply mitigating its symptoms.
Given the progressive nature of Parkinson’s, early intervention is key, and both metformin and psilocybin could play vital roles as preventive therapies. Metformin’s established safety profile is an advantage, potentially allowing for off-label use patients at risk of developing PD once efficacy is established. Psilocybin’s path to approval may be more complex due to regulatory and social hurdles surrounding psychedelics, but its potential to stimulate neurogenesis and neuron repair makes it worth the exploration.
The Road Ahead: Challenges and Possibilities
While our findings are hopeful, they also underscore the need for continued research to address remaining questions. Most studies to date are either preclinical or small-scale trials, which, while encouraging, need to be bolstered by larger, long-term studies. Questions about optimal dosage, long-term safety, and interactions with other medications remain. Also, because Parkinson’s models often rely on rodent studies that don’t fully mimic the human disease, future research should focus on confirming these effects in humans.
In the meantime, the growing interest in alternative neuroprotective treatments brings hope to patients and families impacted by Parkinson’s. Our research represents a step forward, pushing us closer to a future where PD treatment is not limited to symptom management but includes therapies that can genuinely alter the course of the disease.
Conclusively, Metformin and psilocybin’s neuroprotective potential exemplifies the power of innovative research to challenge traditional approaches to neurodegenerative disease. As we advance, therapies that protect and even repair the brain may redefine what is possible for patients with Parkinson’s Disease.
References
de la Monte, S. M., & Wands, J. R. (2008). Alzheimer's disease is type 3 diabetes-evidence reviewed. Journal of diabetes science and technology, 2(6), 1101–1113. https://doi.org/10.1177/193229680800200619
Han, K., Kim, B., Lee, S. H., & Kim, M. K. (2023). A nationwide cohort study on diabetes severity and risk of Parkinson disease. Npj Parkinson’s Disease, 9(1). https://doi.org/10.1038/s41531-023-00462-8
Ordovich-Clarkson, R. D., Jabbour, M., Pelayo, D. A., Lara, D., Croix, L., Mumman, M., Stukas, S., Anderson, R., Meraz, D., Bangura, A., Anderson, B., Bamrud, L., & Blake, C. (2024). Comparing psilocybin to metformin as neuroprotective agents against Parkinson’s dementia: A systematic review of evidence and efficacy. Progress in NeuroPsychopharmacology and Biological Psychiatry, 111155. https://doi.org/10.1016/j.pnpbp.2024.111155
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