Biology subjects

Tyler, W. J.

Publications and source records attributed to Tyler, W. J..

2 recordsLinked to original sources

bioRxiv2026

Estimating Cardiac 5-HT2B Safety Margins for Repeated Low-Dose Psilocybin Using an Exposure-Response Model

Repeated low-dose psilocybin is being developed as a scalable outpatient treatment for mood and anxiety disorders, but chronic exposure raises concern because psilocin binds the cardiac serotonin 5-HT2B receptor, whose sustained agonism causes drug-induced valvular heart disease (VHD). We evaluated this risk using an exposure-response model that incorporates functional efficacy and exposure duration rather than binding affinity alone. Plasma psilocin concentrations were converted into the time-integrated increment in 5-HT2B Gq signaling above endogenous serotonergic tone ({Delta}TIA) and calibrated against drugs and conditions with known valvular outcomes. All modeled exposures known to cause human VHD scored {Delta}TIA [≥] +172 %{middle dot}h/day, whereas exposures not associated with VHD scored [≤] +28. A candidate 3 mg daily psilocybin regimen scored {Delta}TIA +3, roughly two orders of magnitude below the weakest valvulopathic exposure. This safety margin arises from psilocins low-efficacy partial agonism at 5-HT2B (Emax {approx}51.8% of serotonin, compared with 96% for norfenfluramine) and its short half-life ({approx} 2.5 h), which prevents accumulation and produces brief daily receptor engagement. In support of the model, rats receiving continuous psilocin for 12 days at plasma concentrations {approx}2.4-fold above the projected human peak for 3 mg daily psilocybin showed no valvular lesions by blinded histopathology. This exposure duration however cannot exclude slowly developing fibrosis. Emerging human data, including serial echocardiography in repeated LSD microdosing and a large observational cohort, are also agreement with the model. Collectively, these findings suggest a favorable safety margin for daily, sub-hallucinogenic psilocybin use in clinical indications. Nevertheless, continued pharmacological and clinical investigations should include prospective echocardiographic monitoring to advance the clinical safety profile of sub-hallucinogenic psilocybin and support its evaluation across a broad array of therapeutic programs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=54 SRC="FIGDIR/small/739440v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@a2d696org.highwire.dtl.DTLVardef@b64fbaorg.highwire.dtl.DTLVardef@12c41d4org.highwire.dtl.DTLVardef@95e9cd_HPS_FORMAT_FIGEXP M_FIG C_FIG Three key determinants of cardiac safety margins for repeated low-dose psilocybin are shown. Psilocin is a low-efficacy partial agonist at 5-HT2B (ceiling {approx}52% vs 96% for norfenfluramine; left). Its short half-life yields a brief daily pulse of receptor engagement rather than a sustained plateau (center). The resulting integrated 5-HT2B signal ({Delta}TIA) at 3 mg daily lies roughly two orders of magnitude below valvulopathic exposures, and continuous in vivo exposure produced no valvulopathy (right).

pharmacology and toxicology↗

bioRxiv2019

The Safety and Efficacy of Transdermal Auricular Vagal Nerve Stimulation Earbud Electrodes for Modulating Autonomic Arousal, Attention, Sensory Gating, and Cortical Brain Plasticity in Humans.

Our work was motivated by the goal of developing a Targeted Neuroplasticity Training (TNT) method for enhancing foreign language learning. To this end, our primary effort was to evaluate new and optimized approaches to noninvasive vagal nerve stimulation (VNS). We considered several Human Factors Dimensions to develop methods that would be amenable to comfortable, everyday use in common training environments or contexts. Several approaches to noninvasive or external vagal nerve stimulation have been described. Transcutaneous modulation of the left cervical branch of the vagus nerve can be uncomfortable for users resulting in a distracting experience, which may not be ideal for augmenting plasticity during training. Transdermal auricular vagal nerve stimulation (taVNS) offers another approach by targeting nerve fibers innervating the external ear. Prior methods have described many different approached using electrode clips on the ear or stainless-steel ball electrodes, which can respectively result in mechanical discomfort and electrical stimulus discomfort due to high current densities. Other approaches use carbon-doped or conductive rubbers, which require wetting. This is problematic since small degrees of dehydration cause significant changes in the electrical impedance of the skin-electrode interface. Detailed human cadaveric studies have shown the external auditory meatus or ear canal is highly innervated by branches of the auricular vagus nerve. Therefore, we designed taVNS electrodes that were fabricated as a biocompatible, hydrogel earbud electrodes for unilateral or bilateral use. We then evaluated the safety and efficacy of these approaches across a range of stimulus frequencies and intensities. We further evaluated the influence of this approach on autonomic physiology by recording heart rate, heart rate variability, skin conductance, skin temperature, and respiration rate. We investigated attention using simultaneous EEG and pupillometry during auditory stimulation tasks. We further studied the effects on sensory gating and plasticity by examining EEG brain activity patterns obtained during auditory mismatch negativity tasks. Finally, we investigated the basic safety and tolerability of the methods and approaches. We found that a simple, dry (hydrogel), earbud electrode design is a safe and effective method for achieving taVNS. Given the safety, preliminary efficacy, and comfort outcomes observed, we conclude taVNS approaches using earbud electrodes warrant further development and investigation as a TNT tool, to mediate human-computer interactions, for brain-computer interfaces, and as medical devices for the treatment of pervasive health disorders.

neuroscience↗