The neuropharmacology of sleep paralysis hallucinations: serotonin 2A activation and a novel therapeutic drug

Sleep paralysis is a state of involuntary immobility occurring at sleep onset or offset, often accompanied by uncanny “ghost-like” hallucinations and extreme fear reactions. I provide here a neuropharmacological account for these hallucinatory experiences by evoking the role of the serotonin 2A receptor (5-HT(2A)R). Research has shown that 5-HT(2A)R activation can induce visual hallucinations, “mystical” subjective states, and out-of-body experiences (OBEs), and modulate fear circuits. Hallucinatory experiences triggered by serotonin—serotonergic (“pseudo”) hallucinations, induced by hallucinogenic drugs—tend to be “dream-like” with the experiencer having insight (“meta-awareness”) that he is hallucinating, unlike dopaminergic (“psychotic” and “life-like”) hallucinations where such insight is lost. Indeed, hallucinatory experiences during sleep paralysis have the classic features of serotonergic hallucinations, and are strikingly similar to perceptual and subjective states induced by hallucinogenic drugs (e.g., lysergic acid diethylamide [LSD] and psilocybin), i.e., they entail visual hallucinations, mystical experiences, OBEs, and extreme fear reactions. I propose a possible mechanism whereby serotonin could be functionally implicated in generating sleep paralysis hallucinations and fear reactions through 5-HT(2A)R activity. Moreover, I speculate on the role of 5-HT(2C) receptors vis-à-vis anxiety and panic during sleep paralysis, and the orbitofrontal cortex—rich with 5-HT(2A) receptors—in influencing visual pathways during sleep paralysis, and, in effect, hallucinations. Finally, I propose, for the first time, a drug to target sleep paralysis hallucinations and fear reactions, namely the selective 5-HT(2A)R inverse agonist, pimavanserin. This account implicates gene HTR2A on chromosome 13q as the underlying cause of sleep paralysis hallucinations and could be explored using positron emission tomography.