Psilocybin Therapy Shows Promise for Mood Dysfunction in Parkinson’s Disease

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A recent open-label pilot study published in Neuropsychopharmacology explored the safety and potential efficacy of psilocybin-assisted therapy for treating depression and anxiety in individuals with Parkinson’s disease (PD). This research marks the first investigation of psilocybin's effects in a neurodegenerative disease population.

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Study Overview:

Twelve participants with mild to moderate PD and comorbid depression and/or anxiety received two doses of psilocybin (10 mg and 25 mg) alongside psychotherapy. The treatment was well-tolerated, with no serious adverse events or exacerbation of PD symptoms.

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Key Findings:

1. Mood Improvements: Significant reductions were observed in depression and anxiety scores, with benefits persisting up to three months post-treatment.

2. Motor and Non-Motor Symptoms: Participants exhibited improvements in both motor and non-motor PD symptoms, as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).

3. Cognitive Enhancements: Improvements were noted in cognitive domains such as spatial working memory and probabilistic reversal learning.

1. 🧠Neuropsychiatric Symptoms in Parkinson’s Disease

Depression and anxiety affect up to 50% of patients with PD, often preceding motor symptoms and worsening quality of life. Conventional antidepressants have limited efficacy and can cause side effects like orthostatic hypotension or cognitive dulling. Novel strategies like psilocybin target this unmet therapeutic need.

2. 🍄Mechanisms of Psilocybin: Beyond the Serotonin 2A Receptor

Psilocybin’s primary action is as a 5-HT2A receptor agonist, promoting neuroplasticity, emotional processing, and network desegregation. This may help reorganize dysfunctional mood circuits, especially relevant in PD where serotonergic and limbic circuits are disrupted. It may also explain observed cognitive and motor benefits.

3. 🧪Psychedelic-Assisted Therapy: Evidence in Other Populations

Clinical trials in treatment-resistant depression, PTSD, and anxiety in cancer patients have shown that psilocybin, when paired with psychotherapy, can induce rapid and durable symptom relief. Understanding these parallels helps contextualize why Parkinson’s patients might also respond to this model.

4. 🧬Safety Considerations of Psychedelics in Neurodegenerative Disease

Neurologists may have concerns about hallucinogens triggering psychosis, cognitive decline, or worsening motor function. This study's favorable safety profile and lack of symptom exacerbation are critical first data points — but long-term risks and cognitive impacts in PD still require deeper study.

5. 🧘Integrative Treatment Models in PD: Psychotherapy, Neuroplasticity, and Mind-Body Therapies

This study highlights a non-pharmacologic model where psychotherapy and guided introspection play central roles. Neurologists increasingly recognize the value of combining pharmacology with CBT, mindfulness, and neuroplasticity-focused therapies to address the multifaceted nature of PD symptoms.

📚 References

1. Morley, K. C., et al. (2025). Psilocybin therapy for mood dysfunction in Parkinson’s disease: an open-label pilot trial.Neuropsychopharmacology.
   ​https://www.nature.com/articles/s41386-025-02097-0​
2. Reijnders, J. S. A. M., et al. (2008). A systematic review of prevalence studies of depression in Parkinson’s disease.Movement Disorders, 23(2), 183–189.
3. Carhart-Harris, R. L., & Goodwin, G. M. (2017). The therapeutic potential of psychedelic drugs: past, present, and future.Neuropsychopharmacology, 42(11), 2105–2113.
4. Griffiths, R. R., et al. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.Journal of Psychopharmacology, 30(12), 1181–1197.
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6. Preller, K. H., & Vollenweider, F. X. (2016). Phenomenology, structure, and dynamic of psychedelic states. In Behavioral Neurobiology of Psychedelic Drugs (pp. 221–256). Springer.
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