Amnestic mild cognitive impairment (aMCI) is viewed as a precursor to Alzheimer’s Disease (AD) for which there are no effective treatments. Evidence suggests that psilocybin exerts its psychedelic, and possibly its clinical effects, through activating cellular serotonin receptors in the brain. Intriguingly, reduced serotonin receptor density in the brain is associated with cognitive impairment and neurodegenerative disorders. Promisingly, results of animal studies indicate that psilocybin may increase cellular connections in brain areas responsible for cognition.

This pilot study will help us establish the feasibility, safety and tolerability of a randomized double-blind-placebo controlled design (i.e., the study staff and study participants are not aware whether participants are randomized to receive placebo or psilocybin) to determine whether psilocybin increases the density of cellular connections in the brain, referred to as synaptic density, and improves cognition, in participants with aMCI.

To our knowledge, no other studies are investigating psilocybin’s effect on synaptic density and cognition in aMCI or other conditions. Participants will receive two doses of psilocybin or placebo separated by one week. Synaptic density will be measured in the brain using a type of medical imaging called positron emission tomography (PET)before and one week after psilocybin administration. We also aim to examine if changes in synaptic density are associated with improvements in cognition.

We hypothesize that administration of psilocybin will not only be safe, feasible, and tolerable in an aMCI population, but will also increase synaptic density in the brain and improve participants’ cognition. Developing a novel approach to increase cellular connections in the brain in the early stages of AD may be effective in halting or countering the neurodegenerative process, ultimately improving the lives of individuals and families affected by neurodegenerative disorders.

As there is no clinically effective treatment for aMCI, this project may uncover a novel approach to treating early-stage dementia by slowing down disease progression. Ultimately, this work will elucidate psilocybin’s safety, feasibility, and tolerability in aMCI, to guide future studies to discover the efficacy of a potential novel and alternative intervention to increase cellular connections in the brain and improve memory and other cognitive processes.