The Effect of Psilocybin on Cortical Neural Dynamics, Sleep-Wake Behavior, and Persistent Pain in a Rat Model

Psilocybin, the active compound in psychedelic mushrooms, has shown promise for treating chronic pain, especially conditions like fibromyalgia where pain occurs without clear physical injury. This dissertation investigated psilocybin's effects in awake healthy rats and in a rat model of persistent pain. Psilocybin demonstrated anti-nociceptive (pain-reducing) properties, with the insula's 5-HT2A receptors identified as a likely site of action. The work also characterized psilocybin's effects on neural dynamics and sleep-wake behavior. These findings provide a foundation for understanding how serotonergic psychedelics may alleviate chronic pain, which often co-occurs with psychiatric disorders and involves brain network abnormalities like those in the default mode network.

Study at a glance

Abstract

Psilocybin containing mushrooms have been utilized for ceremonial, medicinal, and spiritual purposes for millennia. Recently there has been a surge of scientific interest in the therapeutic potential and mechanistic understanding of serotonergic psychedelics, including psilocybin. Psilocybin is classified as a serotonergic psychedelic because the non-ordinary state of consciousness that it induces—characterized by profound changes in perception, mood, and cognition—is primarily mediated by the serotonin 2A (5-HT2A) receptor. A single administration of psilocybin displays rapid therapeutic effects with limited adverse effects and has been reported to promote neuroplasticity with lasting therapeutic properties, particularly for the treatment of psychiatric disorders. Psilocybin has primarily been explored in the treatment of psychiatric disorders. However, there are case reports, retrospective surveys, and anecdotal data that support the use of psilocybin in the treatment of chronic pain. The development of chronic pain is complex and often coincides with psychiatric disorders such as depression, anxiety, and substance abuse. Chronic pain conditions have a complex etiology and high socioeconomic burden—particularly those where nociplastic pain is often present (e.g., fibromyalgia, complex regional pain syndrome type 1, and irritable bowel syndrome). Nociplastic pain is a mechanistic pain descriptor for pain that arises despite no objectively identifiable injury or disease that is typically present in nociceptive and neuropathic pain conditions. Thus, patients with conditions of chronic pain where nociplastic pain is present often look healthy despite hallmark symptoms such as the presence of multiple chronic pain conditions, widespread body pain, and accompanying central nervous system-derived symptoms including sleep disturbances, depression, fatigue and cognitive dysfunction. Human brain imaging studies have shed light on network abnormalities as neural signatures for nociplastic pain, such as alterations in the default mode network, which governs self-referential thought and is also modulated by serotonergic psychedelics like psilocybin. Brain imaging studies have also shown that serotonergic psychedelics display broad overlapping neurophysiological signatures such as reductions in low frequency oscillations, alterations in functional connectivity, surges in neuronal signal diversity, and modifications of neural networks such as the default mode network. Rodent studies aimed at understating the neurophysiological effects of serotonergic psychedelics, including psilocybin, have primarily relied on electroencephalographic or intracranial recordings. However, these studies have utilized sparse electrode arrays with limited spatial resolution, which precluded network level analysis that is of high translational value. Therefore, to address these gaps in knowledge and lay the foundation for future mechanistic studies aimed at determining the neural correlates of psilocybin-induced anti-nociception in rodent models of persistent pain, in this dissertation I investigated the neural dynamics and network effects of psilocybin in awake healthy rats (Chapter 2) and the effects of psilocybin on sleep-wake behavior and cortical neural dynamics across arousal states in healthy rats (Chapter 3). Next, I demonstrated the anti-nociceptive properties of psilocybin in a rat model of persistent pain (Chapter 4) and identified 5-HT2A receptors in the insula as one likely underlying site of action (Chapter 5). Thus, the characterization of behavioral and neurophysiological effects of psilocybin in healthy rats and a mechanistic demonstration of psilocybin’s anti-nociceptive properties, provides the foundation for further investigation of the pharmacological, neurobiological, and neurophysiological mechanisms underlying the therapeutic properties of serotonergic psychedelics such as psilocybin in chronic pain conditions.