Cytochrome P450 3A4 (CYP3A4) and 3A7 (CYP3A7) specifically catalyze the 1β- and 5β-hydroxylation of deoxycholic acid (DCA) and glyco-DCA (GDCA). Their oxidation rates in microsomal and recombinant CYP3A4/3A7 conform to the Hill kinetic model at low substrate concentrations of up to 400 and 250 μM for DCA and GDCA, respectively, but decline progressively at submicellar concentrations, culminating in complete enzyme deactivation at or above the critical micelle concentration. We hypothesized that this atypical kinetic behavior originates from the disruption of microsomal vesicles by submicellar assemblies of DCA/GDCA. Transmission electron microscopy revealed that submicellar DCA did not compromise vesicle integrity, whereas membrane disruption became evident at or above 1000 μM. Spectroscopic analyses (UV, NMR, and bilirubin-probed fluorescence) determined the critical micelle concentration of both bile salts at approximately 1000 μM and informed the presence of oligomers below this threshold. Notably, at the concentrations of oligomer formation, DCA/GDCA exhibited no inhibitory effect on cytosolic sulfotransferase; however, they markedly suppressed the membrane-associated activities of CYP1A2 and CYP2D6, as probed by phenacetin and dextromethorphan oxidation, respectively. This differential susceptibility between cytosolic and vesicle-bound enzymes corroborates the proposed vesicle membrane-dependent mechanism. Collectively, our findings strongly suggest that submicellar DCA and GDCA autoinhibit their CYP3A-catalyzed oxidation through a mechanism that involves a vesicle membrane-dependent mechanism, with their self-assembly being intrinsically linked to the observed anomalous kinetics. SIGNIFICANCE STATEMENT: This work demonstrates that submicellar deoxycholate and glycodeoxycholate autoinhibit CYP3A oxidation via membrane perturbation, not substrate sequestration. Spectroscopic detection of bile salt oligomers below the critical micelle concentration correlates with suppression of multiple membrane-bound P450s (CYP1A2/2D6/3A) while sparing cytosolic sulfotransferase, indicating that submicellar bile salts impair electron transfer among P450, P450 reductase, and cytochrome b5. This membrane-dependent mechanism resolves the long-standing atypical kinetics of secondary bile acids and has implications for bile acid-drug interaction assessment, particularly in cholestatic liver disease.

Formerly recognized as an opioid receptor, the sigma-1 receptor (σ1R) is a multifunctional chaperone protein that plays a crucial role in regulating neuronal signaling, neuroprotection, and synaptic plasticity. Increasing evidence highlights a tight functional association between the σ1R and the N-methyl-D-aspartate receptor (NMDAR), a central mediator of excitatory neurotransmission and calcium-dependent neuronal processes. This review summarizes the shared signaling pathways underlying σ1R and NMDAR activity, including calcium homeostasis, calcium/calmodulin-dependent protein kinases (CaMKs), protein kinase C (PKC), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) cascades, as well as transcriptional regulators such as cAMP response element-binding protein (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists-such as ketamine, dextromethorphan, and memantine-also interact with σ1R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the σ1R is a key regulatory element enabling proper NMDAR function and that disruption of this interaction may contribute to excitatory imbalance implicated in the pathophysiology of neuropsychiatric disorders. Recognizing the σ1R-NMDAR crosstalk as an integrated signaling axis may thus inform the development of dual-target therapeutic strategies aimed at improving neuronal resilience and clinical outcomes in psychiatric and neurodegenerative diseases.

Methorphan exists as two optically active enantiomers, levomethorphan (LVM) and dextromethorphan (DXM). DXM is a widely utilized central antitussive, whereas LVM is a strictly regulated controlled substance. This study established a method combining micro-solid-phase extraction with enantioselective high-performance liquid chromatography-mass spectrometry (LC-MS) for the simultaneous determination of LVM and DXM in human urine and nail samples. A spherical porous graphene oxide composite aerogel (GO@CNF/CMC) served as the extraction sorbent. It was synthesized by covalently crosslinking graphene oxide (GO), cellulose nanofibers (CNF), and carboxymethyl chitosan (CMC) via a combined sol-gel and dropwise addition strategy. Aerogels with various GO mass fractions were fabricated for sorption optimization. With a maximum GO loading of 11.2 wt%, the aerogel delivered superior extraction efficiency owing to its large specific surface area and synergistic intermolecular interactions including hydrogen bonding, π-π stacking and electrostatic attraction. The aerogel exhibited excellent mechanical stability and recyclability, with nearly consistent extraction efficiency over 15 extraction cycles. Under optimized extraction conditions, the method exhibited good linearity in the range of 0.05-10 μg/L. The limits of detection were 0.01 μg/L for both LVM and DXM. The spiked recoveries in urine and nail samples ranged from 81.6% to 108.4%, and matrix effects ranged from 83.3% to 105.7%. This method provides a facile, rapid, green and sensitive analytical strategy for the trace analysis of methorphan enantiomers in complex biological matrices.

Pseudobulbar affect is a distressing condition frequently observed in patients with amyotrophic lateral sclerosis (ALS), for which a fixed-dose combination of dextromethorphan and quinidine is approved in the United States. In Europe, no commercial product is available, and compounded capsules or suspensions are used; however, capsules may be unsuitable for patients with dysphagia, and suspensions require shaking before administration. The aim of this study was to develop simple fully water-soluble formulation of dextromethorphan hydrobromide and quinidine sulfate using methyl-β-cyclodextrin as a solubilizing agent and to evaluate its stability under different storage conditions, enabling pharmacies to compound the preparation without complex infrastructure. Preliminary qualitative solubility experiments showed that the dextromethorphan hydrobromide/ quinidine sulfate powder mixture did not dissolve in water without methyl-β-cyclodextrin. Addition of methyl-β-cyclodextrin improved dissolution; however, the initial preparation targeting 20 mg/mL dextromethorphan hydrobromide and 10 mg/mL quinidine sulfate in a final volume of 100 mL remained incompletely dissolved. Increasing the final volume to 250 mL yielded a clear formulation containing nominal concentrations of 8.4 mg/mL dextromethorphan hydrobromide and 4.2 mg/mL quinidine sulfate. Three independently prepared batches were stored in amber PET bottles providing light protection and fitted with child-resistant closure at 2-8°C, 15-25°C, and 40°C and analyzed by HPLC for four weeks. HPLC assay values remained within 10% of the corresponding baseline values at each storage condition, and no visible precipitation was observed. The results support the physical clarity and chemical consistency of the tested methyl-β-cyclodextrin- containing formulation over four weeks under the evaluated storage conditions. Microbiological stability, preservative effectiveness, formal method validation in the author's laboratory, and the extent of cyclodextrin inclusion complexation were not assessed. This formulation may serve as a basis for further pharmaceutical, microbiological, and clinical evaluation of an extemporaneously compounded oral liquid.

Cendakimab is a humanized monoclonal antibody that inhibits interleukin-13 binding to its receptors. Although not expected to share clearance pathways with small molecules, its use in eosinophilic esophagitis, a type 2 inflammatory disease, may indirectly affect cytochrome P450 activity by modulating cytokine signaling affecting certain cytochrome P450 enzymes. This open-label, single-sequence study evaluated the pharmacokinetics of cytochrome P450 substrates in adults with active eosinophilic esophagitis, evidenced by a peak eosinophil count of ≥ 15 per high-power field in esophageal biopsies and clinical symptoms of esophageal dysfunction, before and after 16 weeks of cendakimab treatment. Patients received a cocktail of probe substrates (caffeine 200 mg, warfarin 10 mg + vitamin K 10 mg, omeprazole 40 mg, dextromethorphan 30 mg, midazolam 5 mg) for cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A in two sequential periods, separated by 16 weeks of cendakimab treatment. Blood samples were analyzed to assess pharmacokinetics. Sixteen patients were treated; 15 completed the study. Exposures (AUC and Cmax) of caffeine, S-warfarin, midazolam, and omeprazole were comparable before and after treatment. Dextromethorphan exposure showed no clinically meaningful change, although interpretation is limited by small sample size. Cendakimab was well tolerated. All adverse events were mild to moderate, with no serious adverse events, deaths or discontinuations from adverse events. No clinically relevant changes in laboratory tests, vital signs, or electrocardiograms were observed. Cendakimab had no clinically meaningful effects on cytochrome P450 enzyme activities and was generally safe and well tolerated with or without probe substrates in adults with active eosinophilic esophagitis.

Ayahuasca is a psychoactive botanical brew originating from Amazonian ceremonial traditions, containing monoamine oxidase inhibitors (MAOIs) derived from Banisteriopsis caapi and N,N-dimethyltryptamine from Psychotria viridis or Diplopterys cabrerana. Its use has expanded globally for perceived antidepressant and anti-addictive effects. However, the MAOI content of ayahuasca predisposes users to serotonergic toxicity when combined with other serotonergic agents. We present the case of a 46-year-old man who developed severe serotonin syndrome (SS) complicated by acute respiratory failure after ingesting ayahuasca over three days, followed by over-the-counter dextromethorphan (DXM) and diphenhydramine. He required emergent intubation and intensive care unit (ICU) admission. Management with intravenous benzodiazepines, oral cyproheptadine, and supportive care led to rapid clinical improvement, with extubation on ICU day 2 and discharge on hospital day 3. Severe SS attributable to ayahuasca is rarely documented, and to our knowledge this is the first report of ayahuasca combined with over-the-counter DXM and diphenhydramine producing SS severe enough to cause acute respiratory failure. This case highlights the life-threatening potential of combining ayahuasca with commonly available serotonergic medications and underscores the need for clinician awareness of these interactions.

A large genome-wide association study of parental lifespan was reported in 2019. A later transcriptome-wide association study (TWAS) based on those summary statistics identified a set of transcriptional programs associated with longer genetically predicted survival, including increased brain NAD + salvage, especially NMNAT2, reduced glucose-stimulated insulin secretion, a shift toward synaptic pruning with less broad plasticity, and a glial pattern characterized by relatively greater microglial and lower astrocytic signatures, with only weak pan-tissue senescence signals. Building on those directional findings, this short communication proposes a minimal three-arm oral regimen with unequal evidentiary weight: first, the Cheung Glutamatergic Regimen, consisting of low-dose dextromethorphan potentiated by a CYP2D6 inhibitor together with piracetam and L-glutamine, as an exploratory adjunct aimed at preserving residual functional connectivity; second, daily nicotinamide mononucleotide and N-acetylcysteine with pulsed senolytics for NAD + salvage and senescence modulation; and third, GLP-1 receptor agonism for metabolic reprogramming. The NAD+/senescence arm is the primary mechanistic anchor, GLP-1 receptor agonism provides secondary metabolic support, and the glutamatergic arm is exploratory. Each arm targets a separate node within the pruning-plasticity-metabolic triad. The regimen is fully oral, uses conservative dosing, and draws on prior therapeutic or human-exposure data, although the proposed combination has no established safety profile. Although direct combination data are lacking and the foundational TWAS remains a preprint, the components show plausible but uneven mechanistic alignment with the TWAS signals and may justify carefully designed, safety-focused pilot evaluation.

Treatment-resistant depression (TRD) is commonly operationalized as non-remission after at least two adequately delivered antidepressant trials, but the biological heterogeneity of this population remains substantial. This article presents a translational hypothesis and drug-development framework; it reports no original clinical or laboratory data and is not a systematic review. The central hypothesis is that an oral dextromethorphan-CYP2D6-inhibitor-piracetam regimen could, if pharmacokinetically and clinically validated, initiate glutamatergic plasticity, whereas nicotinamide mononucleotide (NMN) plus N-acetylcysteine (NAC), followed only at a later stage by a candidate senescence-directed agent, could be evaluated for effects on the redox, bioenergetic, inflammatory, and cellular-aging context associated with response durability in a biomarker-enriched subset of unipolar TRD. The core regimen is defined as dextromethorphan, one prespecified CYP2D6 inhibitor, and piracetam. Glutamine is retained only as an optional exploratory component and is not part of the core or augmentation definition used for future testing. Existing evidence is uneven. Human studies establish that CYP2D6 phenotype and inhibition materially alter dextromethorphan exposure; NAC has heterogeneous adjunctive psychiatric evidence; NMN has human NAD-related target-engagement data without established antidepressant efficacy; and senolytics have limited early human data outside TRD. Dasatinib plus quercetin is therefore positioned as a later-stage, specialist-supervised research probe rather than a routine psychiatric augmentation. No clinical role can yet be assigned to any proposed combination, and none should be used outside formal research protocols. The proposed development sequence prioritizes pharmacokinetic characterization, safety, target engagement, biomarker-defined subgroup selection, controlled efficacy testing, and independent replication.