Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics

Abstract

Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Although beyond the scope of this work, OT is a neurotransmitter hormone involved in sociability and anxiety that is dysregulated across psychiatric disorders (Panksepp, 1992;Costa et al, 2009;Cochran et al, 2013). Oxytocin is thought to mediate at least partially the empathogenic, antidepressant, and anxiolytic effects elicited by psychedelic compounds and SSRIs (Uvnäs-Moberg et Schindler et al, 2018) via modulating corticolimbic circuits (Lahoud and Maroun, 2013;Sobota et al, 2015;Triana-Del Rio et al, 2019). Transient OT increase and prosocial effects were reported in response to LSD (Schmid et al, 2015a;Duerler et al, 2020) and MDMA (Dumont et al, 2009;Kirkpatrick et al, 2014a,b) in healthy subjects through 5-HT 1A/2A receptor stimulation (Thompson et al, 2007).…”

Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

“…Strikingly, mRNA upregulation after administration of a psychedelic seems to be directly linked to 5-HT2A receptor activation (discussed in [101]). Another prominent theory is the idea that psychedelic drugs induce long-term effects through alterations in gene expression induced by the profound subjective psychedelic experience (so-called "peak" experiences) [107], although plausible evidence for experience-induced epigenetic modifications is lacking.…”

Pivotal mental states

“…Supplementing these findings, direct agonism of the 5-HT2AR via psychedelic drugs can sometimes induce psychological states exhibiting phenomena that mimic those seen in extreme stress states, for example, enhanced associative learning and a significant capacity for mediating psychological transformation ( Briere et al, 2015 ; Hefferon et al, 2009 ; Joëls et al, 2006 ), as can occur via traumatic encounters. Psychedelics have also been shown to increase the release of stress hormones ( Alper, 1990 ; Calogero et al, 1989 ; Dos Santos et al, 2012 ; Hasler et al, 2004 ; Owens et al, 1991 ; Schmid et al, 2015 ; Strajhar et al, 2016 ; see Schindler et al, 2018 for review).…”