Psychedelics Provide Insights Into Lewy Body Diseases' Hallucinations

Some of the world’s earliest hallucinogens—N,N-Dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), mescaline, and psilocybin—are now giving researchers insight into visual hallucinations (VH) in Lewy body diseases. These hallucinations may share more than meets the eye, including similar serotonin receptor pathways and cortical signatures.

Schizophrenia Bulletin published a recent review exploring the overlapping mechanisms of visual hallucinations in Lewy body diseases and those induced by serotonergic psychedelics. The Lewy body diseases include Parkinson disease (PD), Parkinson’s disease dementia, and dementia with Lewy bodies (DLB). Researchers from the International Consortium on Hallucinations Research examined neuroimaging and pharmacologic data across human and animal studies to compare cortical patterns and neuromodulatory effects in both conditions.

Hallucinations induced by serotonergic psychedelics are temporary and externally administered, and Lewy body disease hallucinations emerge from chronic disease progression. Despite their different origins, both trigger similar patterns in the brain’s visual and associative cortices, especially through serotonin receptor activity.

The receptors for 5-HT2A and 5-HT1A share pharmacologic targets across conditions. In hallucinations induced by serotonergic psychedelics, hallucinations are linked to activation of these serotonin receptors. In Lewy body disease, upregulation of 5-HT2A receptors is tied to visual hallucination severity.

In both Lewy body diseases and hallucinations induced by serotonergic psychedelics, visual hallucinations show cortical imbalance: reduced activation in primary visual (sensory) areas and heightened excitation in associative cortices. This mismatch may create distorted visual perceptions, especially in patients with visual degradation.

Hallucinations evolve over time. In Lewy body diseases, simpler hallucinations (e.g. shadows or lights) often progress to more complex, emotionally charged scenes—a trajectory also reported with escalating psychedelic doses. Pharmacists may notice these shifts in patient descriptions over time.

Pimavanserin (Nuplazid; Acadia) is a 5-HT2A inverse agonist approved for PD psychosis. Monitoring for efficacy and adverse effects like QT prolongation is recommended in elderly patients.

Patient counseling can help destigmatize visual hallucinations. Hallucinations in PD and DLB are not always indicative of psychosis. They can occur in cognitively intact patients and acknowledging this can improve trust and reduce fear or shame in reporting.

Researchers call for real-time neuroimaging studies during active hallucinations to further understand shared mechanisms. Pharmacists and prescribers can apply emerging insights into serotonin's role in visual hallucinations and existing psychedelic models to inform treatment approaches for Lewy body disease-associated psychosis. New approaches that modulate 5-HT2A receptors could offer symptom relief with fewer cognitive side effects compared to traditional antipsychotics.

REFERENCE

Heller NH, Barrett FS, Buchborn T, et al. Visual hallucinations in serotonergic psychedelics and Lewy body diseases. Schizophr Bull. 2025;51(Suppl 3):S273–S291. doi:10.1093/schbul/sbaf068