Potential Differences in Psychedelic Actions Based on Biological Sex

Abstract

The resurgence of interest in psychedelics as treatments for psychiatric disorders necessitates a better understanding of potential sex differences in response to these substances. Sex as a biological variable (SABV) has been historically neglected in medical research, posing limits to our understanding of treatment efficacy. Human studies have provided insights into the efficacy of psychedelics across various diagnoses and aspects of cognition, yet sex-specific effects remain unclear, making it difficult to draw strong conclusions about sex-dependent differences in response to psychedelic treatments. Compounding this further, animal studies used to understand biological mechanisms of psychedelics predominantly use one sex and present mixed neurobiological and behavioral outcomes. Studies that do include both sexes often do not investigate sex differences further, which may hinder the translation of findings to the clinic. In reviewing sex differences in responses to psychedelics, we will highlight the direct interaction between estrogen (the most extensively studied steroid hormone) and the serotonin system (central to the mechanism of action of psychedelics), and the potential that estrogen-serotonin interactions may influence the efficacy of psychedelics in female participants. Estrogen influences serotonin neurotransmission by affecting its synthesis and release, as well as modulating the sensitivity and responsiveness of serotonin receptor subtypes in the brain. This could potentially influence the efficacy of psychedelics in females by modifying their therapeutic efficacy across menstrual cycles and developmental stages. Investigating this interaction in the context of psychedelic research could aid in the advancement of therapeutic outcomes, especially for conditions with sex-specific prevalence.

Keywords: cognition; estrogen; learning; psilocybin; psychedelics; serotonin; sex differences.

Figure 1.

Changes observed in preclinical studies using psychedelics based on biological sex. A summary of the behavioral and neurobiological changes observed after psychedelics in rodent studies using either a single sex or both. These studies have used different compounds, doses, strains, and time courses; however, they provide an initial basis from which to explore underlying mechanisms that may be specific for males or females. Upward arrows indicate psychedelics-induced improvements, while downward arrows indicate an effect in the opposite direction. Larger sizes of sex symbols within the Venn diagram overlap represent the sex in which the effect is most pronounced.

Figure 2.

The association between serotonin, estrogen, and psychedelic signaling. The relative peak of estrogen across the estrous cycle in A, rodents, aligns with the highest gene expression of Htr2a (the gene encoding the 5-HT2A receptor) and the lowest gene expression of Htr1a (the gene encoding the 5-HT1A receptor). At the synapse B there are multiple sites of interaction between 5-HT and either estrogen or psilocin that may be responsible for altering the effects of psychedelics based on estrogen availability. Estrogen can bind to either membrane-bound (mER) receptors or permeate the cell membrane to bind to nuclear receptors (ERα/β), to exert its influence on 5-HT transmission. I, Estrogen increases 5-HT levels by enhancing tryptophan hydroxylase (TPH) production, the rate-limiting enzyme that synthesizes 5-HT. II, Inhibition of the transcription of the serotonin reuptake transporter (SERT) gene by estrogen further extends 5-HT availability in the synaptic cleft and interstitial spaces. III, Downstream of this, estrogen also has an inverse effect on levels of the monoamine oxidase A (MAO-A) enzyme targeting the breakdown of 5-HT into its inactive metabolite, 5-HIAA. IV, In combination, this results in alterations in intracellular levels of 5-HT and its transmission across the synaptic cleft. V, Estrogen could also enhance the activity of 5-HT neurons by inhibiting 5-HT1AR signaling, achieved through increased uncoupling of G proteins to 5HT1ARs via activation of the mERs. VI, Estrogen, acting through nuclear receptors (ERα/β) that directly bind to promoter regions at estrogen response element (ERE) sites, enhance 5-HT2A gene transcription and functionally increase neural sensitivity to presynaptic 5-HT. VII, Considering all of these factors and within the framework of psychedelics' mechanisms of action, estrogen plausibly modulates the efficacy of psychedelics by upregulating the expression of 5-HTRs, which in turn increase the plasticity-related gene expression. Figure created with Biorender.com.