Psychedelics as Novel Therapeutics in Alzheimer's Disease: Rationale and Potential Mechanisms

Serotonin 2A receptor (5-HT_2AR) agonist "classic psychedelics" are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT_2AR agonists in modulating learning and memory function with relevance for Alzheimer's Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT_2AR agonists' therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.