In a landmark study, psilocybin – a psychoactive compound found in a variety of mushrooms – has been found to improve mood and motor symptoms in people with Parkinson’s Disease. The study is first-ever to look at the compound for the treatment of a neurodegenerative disease.
Parkinson’s affects around 10 million people across the globe, with rates expected to increase dramatically by 2050. Some of the most common symptoms of the condition include motor dysfunction, anxiety and depression, however, there are currently limited treatments available for these symptoms, and they do not work for everyone.
Research is increasingly showing that psilocybin-assisted psychotherapy holds promise as a treatment for conditions such as anxiety and depression. Hypothesised that the compound promotes neuroplasticity, psilocybin is an agonist of the 5-HT2A receptor which modulates dopamine release in the brain and glutamate transmission, impacting brain functions such as mood regulation and influencing inflammatory responses in the body.
The researchers at the University of California suggest these mechanisms may be relevant for targeting depression and anxiety in Parkinson’s Disease, as serotonergic dysfunction, synaptic deficits, and elevated inflammation are all pathophysiological features of the disease, which they say may contribute to the high prevalence of associated mood dysfunction.
Previously, research into psychedelics such as psilocybin have excluded people with neurodegenerative conditions due to safety concerns.
For this study, the researchers examined the feasibility of psilocybin therapy for 12 people with mild to moderate Parkinson’s Disease who had depression and/or anxiety. The participants received one 10 mg dose of psilocybin followed by one 25 mg dose in conjunction with psychotherapy.
The results showed that spatial working memory and probabilistic reversal learning improved post-treatment and sustained until the final safety assessment one month following drug exposure. Anxiety and depression symptoms also saw clinically meaningful improvement that were sustained until the final assessment at three months post-treatment.
Motor symptoms were also significantly improved at the one-week and the one-month follow-up.
The authors write: “We observed significant and sustained improvements in depression and anxiety, consistent with prior studies of psilocybin therapy for major depression and mood dysfunction associated with terminal cancer.
“Anecdotally, multiple participants described feeling better able to adapt to health-related challenges post-treatment. This may be particularly important for people with PD [Parkinson’s Disease], who commonly experience demoralisation that can interfere with the adaptive disease management that optimises function.
“While mood and cognition changes did not correlate significantly in this sample, participants’ cognitive flexibility improved post-treatment and prior work suggests that enhanced cognitive flexibility may be a mechanism by which psilocybin therapy produces lasting benefits on wellbeing.”
The researchers say they were surprised by the participants’ improvements in motor functions, suggesting three possible explanations for the improvement.
The first explanation suggested by the researchers is that psilocybin provides some degree of motor symptom relief as it modulates dopamine-regulated brain networks through its interactions with multiple serotonin receptor subtypes.
Th second possible explanation the authors suggest could be that improved mood leads to improved motor functions.
They write: “Depression itself is hypothesised to increase allostatic load through hypothalamic pituitary axis activation, inflammatory changes, mitochondrial dysfunction, and downregulation of neurotrophic factors, ultimately resulting in neurodegeneration.
“Interestingly, the “depressed frail phenotype” observed in older adults (without PD) is associated with multiple markers of accelerated ageing, including impaired dopaminergic neurotransmission.
“Mood dysfunction often precedes the development of motor symptoms of PD by several years and people with depression or anxiety earlier in life are twice as likely to develop PD. These observations offer support for the hypothesis that mood dysfunction could reflect a separate pathophysiological process that is a risk factor for PD.”
Thirdly, the researchers suggest that psilocybin impacts the pathophysiology of the condition, as psilocybin has been shown to modulate glutamatergic activity in prefrontal circuits, reduce inflammatory activity, induce gene expression relevant for neuroplasticity pathways, and promote neuronal growth.
“Each of these may be important mechanisms contributing to its effects on depression and anxiety, but could also interact with PD pathophysiology: impaired glutamate homeostasis, dysregulated inflammation, and reduced synaptic plasticity are key elements of the neurodegenerative process in PD,” they write.
The authors note that two participants experienced challenging side effects during the follow-up period, one of which included thoughts about pursuing medically assisted dying in the future.
“The experiences of these participants underscore the risks associated with high-dose psychedelic treatments, even when provided using a consistent medicinal product in a monitored setting and paired with skilled psychotherapeutic support,” the authors write.
The researchers say the findings highlight the need for further research into psilocybin for the treatment of Parkinson’s-related mood and motor symptoms, including in people at varying disease stages in order to fully characterise psilocybin’s effects on Parkinson’s Disease psychosis.
They write: “Research to uncover psilocybin’s mechanisms of action and identify predictors of treatment response will be essential for determining its real-world clinical utility.”
