Visual Hallucinations in Serotonergic Psychedelics and Lewy Body Diseases

Background and Hypothesis Visual hallucinations (VH) are a core symptom of both Lewy body diseases (LBDs; e.g., Parkinson’s disease and dementia with Lewy bodies) and serotonergic psychedelics (SPs; e.g., psilocybin and mescaline). While these classes of VH differ in etiology, shared pathways are suggested by overlapping phenomenology and neural mechanisms. This review explores similarities and differences in VH between LBDs and SPs, focusing on phenomenology, cortical function, and serotonergic modulation. Study Design This narrative review synthesizes findings from neurology, cognitive neuroscience, and systems neuroscience to compare VH in LBDs and SPs. The literature includes studies with both human subjects and animal models that examine cortical activity patterns, neuromodulatory mechanisms, and VH phenomenology. Study Results Both LBDs and SPs exhibit distinct visual aberrations, ranging from minor metamorphopsias to complex hallucinations. Specific classes of VH in LBDs resemble those induced by SPs (e.g., illusory motion and entity encounters), suggesting shared neural mechanisms. Neuroimaging studies indicate a common pattern of hyperactive associative cortex and hypoactive sensory cortex. At the neuromodulator level, SP-induced VH involves serotonin 2A and 1A receptor (5-HT₂AR and 5-HT₁AR) modulation, while in LBDs, 5-HT₂AR upregulation correlates with increased VH, and its inhibition (e.g., with pimavanserin) reduces VH. Two shared cortical signatures are highlighted: reduced visual evoked responses and shifts toward visual excitation. Conclusions Examining cortical and neuromodulatory similarities between LBD- and SP-induced VH may elucidate the link between visual degradation, excitation, and hallucinogenesis. Future research should employ real-time neuroimaging of discrete hallucinatory episodes to identify shared mechanisms and develop targeted interventions for LBD hallucinations.