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

Sleep paralysis involves involuntary immobility at sleep onset or offset, often with 'ghost-like' hallucinations and intense fear. This account proposes that serotonin 2A receptor (5-HT2AR) activation underlies these hallucinatory experiences, drawing parallels to serotonergic hallucinations induced by drugs like LSD and psilocybin, which are dream-like and retain insight, unlike dopaminergic hallucinations. The mechanism suggests 5-HT2AR activity generates visual hallucinations, mystical states, out-of-body experiences, and fear. The role of 5-HT2C receptors in anxiety and the orbitofrontal cortex in visual pathways is speculated. Pimavanserin, a selective 5-HT2AR inverse agonist, is proposed as a first drug to target these symptoms, implicating gene HTR2A on chromosome 13q.

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Abstract

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-HT2AR). Research has shown that 5-HT2AR 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-HT2AR activity. Moreover, I speculate on the role of 5-HT2C receptors vis-à-vis anxiety and panic during sleep paralysis, and the orbitofrontal cortex—rich with 5-HT2A 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-HT2AR 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.