Introduction: The use of Δ8-tetrahydrocannabinol (Δ8-THC) has become increasingly prevalent in the United States, but its metabolic pathways remain poorly characterized. This study aimed to identify the key enzymes responsible for the 11'-hydroxylation of Δ8-THC, its primary metabolic pathway, and assess the effect of metabolizing enzyme genotype on this activity. Results: The intrinsic clearance of recombinant (r) CYP2C9 was >6200-fold higher than that observed for rCYP2C19, the only other tested CYP450 with detectable activity against Δ8-THC. The Km,u of rCYP2C9 (0.013 ± 0.0032 µM) was comparable to that observed in human intestinal microsomes (0.0076 ± 0.00067 µM), but it was substantially lower than that observed for human liver microsomes (0.73 ± 0.065 µM). Inhibition of 11-OH-Δ8-THC formation in rCYP-overexpressing microsomes was observed when using CYP probe inhibitors (sulfaphenazole for CYP2C9 and tranylcypromine for CYP2C19). The intrinsic clearance was markedly reduced in CYP2C9 variant microsomes, with 20- to 60-fold decreases observed for CYP2C9*2 (59 ± 7.9 µL·min[-1]·mg[-1] protein), CYP2C9*3 (34 ± 3.6 µL·min[-1]·mg[-1] protein), CYP2C9*8 (96 ± 13 µL·min[-1]·mg[-1] protein), and CYP2C9*9 (34 ± 11 µL·min[-1]·mg[-1] protein) as compared to wild-type CYP2C9*1 (6028 ± 266 µL·min[-1]·mg[-1] protein). Conclusions: Given that the expression of CYP2C9 is much higher than that of CYP2C19 in both human intestine and liver, these data suggest that CYP2C9 is the primary enzyme responsible for intestinal 11'-hydroxylation of Δ8-THC and that other untested CYPs may be important in hepatic Δ8-THC hydroxylation. In addition, the reduced 11-OH-Δ8-THC formation activity observed with CYP2C9 variants (*2, *3, *8, *9) suggests interindividual variability in Δ8-THC disposition.

Immune checkpoint inhibitors (ICIs) have demonstrated significant potential in cancer therapy. However, the immunosuppressive nature of the tumor microenvironment (TME) and ICI remains a major challenge in clinical treatment. Recently, epigenetic regulators, such as the histone demethylase Lysine (K)-Specific Demethylase 1 A(KDM1A/LSD1), have participated in tumor progression and immune evasion by reshaping the epigenetic state of tumor cells and the immune microenvironment. This study systematically reviewed the dual role of KDM1A in colorectal cancer (CRC). On one hand, KDM1A can promote tumor cell proliferation and aberrant differentiation by regulating signaling pathways, such as Wnt/β-catenin and Notch. On the other hand, it can also modulate the functions of T cells, B cells, macrophages, and Natural Killer (NK)cells through epigenetic modifications, thus inhibiting antitumor immune responses and creating an immunosuppressive microenvironment. Notably, KDM1A can reduce the immunogenicity of CRC by downregulating tumor antigen presentation or pro-inflammatory cytokine secretion, thus enhancing the tumor's resistance to ICI. Clinically, small-molecule inhibitors targeting KDM1A, such as Tranylcypromine (TCP) and Iadademstat, could enhance the efficacy of ICIs by reversing the immunosuppressive microenvironment, especially in mismatch repair proficient (pMMR) CRC. Future studies should further elucidate the molecular networks of KDM1A regulating immunogenicity and explore the synergistic mechanisms of its inhibitors with other epigenetic drugs or immunotherapies in order to provide new strategies for overcoming CRC resistance to immunotherapies.

Lung cancer remains a major global health challenge, and the oncogenic function of KDM1B (Lysine-specific Demethylase 1B) is still poorly characterized. This study employed integrated bioinformatics and experimental approaches to investigate KDM1B's function in lung cancer. Pan-cancer analysis using databases such as TIMER revealed notably elevated KDM1B mRNA expression in LUAD datasets, suggesting its potential as a diagnostic biomarker. A strong association was also found between increased KDM1B levels and immune cell infiltration in LUAD datasets. Protein interaction networks constructed using STRING and Cytoscape revealed close associations between KDM1B and key regulatory genes in NSCLC. KEGG enrichment analysis linked KDM1B to the mTOR signaling, which is critical for cell proliferation and survival. RT-PCR and western blotting for experimental validation showed KDM1B expression was significantly increased in A549 and NCI-H460 lung cancer cells. The deletion of KDM1B inhibits cell growth, induces G0/G1 phase cell cycle arrest, and promotes apoptosis in A54 cells. Moreover, cell proliferation was significantly inhibited by the KDM1B inhibitor, tranylcypromine, and induced G0/G1 phase cell cycle arrest, increased apoptosis, ROS, and glycolytic activity in A549 cells. Collectively, these findings highlight KDM1B as a valuable therapeutic target in lung adenocarcinoma and emphasize its key role in lung cancer development.

LSD1 is a key epigenetic eraser that demethylates the histone proteins and regulates transcription. Overexpression of LSD1 drives the development of multiple cancers, such as prostate, breast, gastric, lung, colorectal cancers, and acute myeloid leukemia. Although several LSD1 inhibitors have shown promise for cancer therapy, monotherapy faces challenges such as low selectivity, high toxicity, and drug resistance. To overcome these drawbacks and achieve synergistic anticancer effects, researchers have focused on dual inhibitors that target LSD1 along with other oncogenic partners, including HDAC, EGFR, EZH2, tubulin, ERα, G9a, JmjC, DCN1, and SMOX. This review aims to provide recent design strategies and SAR for LSD1-based dual inhibitors, emphasizing the fusion of different LSD1 pharmacophore (tranylcypromine, pargyline, pyridine, 5-cyano-3-phenylindole, indole, benzyl/aryl piperazine, triazole-dithiocarbamate and substituted triazole scaffold) with various heterocyclic and zinc-binding cores such as hydroxamic acids, bipyridine, hydroxy quinoline to generate hybrids capable of inducing apoptosis, blocking cell-cycle, differentiation. This review explores the pharmacological role of LSD1 in oncogenesis and offers structural and SAR insights to guide the design of LSD1-based dual inhibitors.

The use of Δ8-tetrahydrocannabinol (Δ8-THC) has become increasingly prevalent in the United States but its metabolic pathways remain poorly characterized. This study aimed to identify the key enzymes responsible for the 11'-hydroxylation of Δ8-THC, its primary metabolic pathway, and assess the effect of metabolizing enzyme genotype on this activity. The intrinsic clearance of recombinant (r) CYP2C9 was >6,200-fold higher than that observed for rCYP2C19, the only other tested CYP450 with detectable activity against Δ8-THC. The K m , u of rCYP2C9 (0.013 ± 0.0032 μM) was comparable to that observed in human intestinal microsomes (0.0076 ± 0.00067 μM) but it was substantially lower than that observed for human liver microsomes (0.73 ± 0.065 μM). Inhibition of 11-OH-Δ8-THC formation in rCYP overexpressing microsomes was observed when using CYP probe inhibitors (sulfaphenazole for CYP2C9 and tranylcypromine for CYP2C19). The intrinsic clearance was markedly reduced in CYP2C9 variant microsomes, with 20- to 60-fold decreases observed for CYP2C9*2 (59 ± 7.9 μL·min[-1]·mg[-1] protein), CYP2C9*3 (34 ± 3.6 μL·min[-1]·mg[-1] protein), CYP2C9*8 (96 ± 13 μL·min[-1]·mg[-1] protein), and CYP2C9*9 (34 ± 11 μL·min[-1]·mg[-1] protein) as compared to wild-type CYP2C9*1 (6,028 ± 266 μL·min[-1]·mg[-1] protein). Given that the expression of CYP2C9 is much higher that CYP2C19 in both human intestine and liver, these data suggest that CYP2C9 is the primary enzyme responsible for intestinal 11'-hydroxylation of Δ8-THC and that other untested CYPs may be important in hepatic Δ8-THC hydroxylation. In addition, the reduced 11-OH-Δ8-THC formation activity observed with CYP2C9 variants (*2, *3, *8, *9) suggests interindividual variability in Δ8-THC disposition.

We report a homologous Horner-Wadsworth-Emmons-type reaction of an imine-substituted phosphine oxide with epoxides, enabling a formal O-to-C(NH2) atom swap to access structurally important cyclopropylamines. This transformation proceeds with high stereochemical fidelity, translating the chirality of epoxides into cyclopropylamines with ≥ 98% enantiospecificity, and accommodating a wide range of mono-, 2,2-, and 2,3-disubstituted epoxides. The strategy's robustness is demonstrated by the efficient, scalable synthesis of the core scaffolds of bioactive molecules such as ticagrelor and tranylcypromine. DFT calculations elucidate the role of the imino group in facilitating the reaction and illustrate the origin of diastereoselectivity through a rigid, chelated transition state model.

Sleep is an important biological function. This article considers practical matters related to the prescription of sedative-hypnotic drugs to patients with insomnia. This article also presents practical suggestions for the management of excessive sedation in patients who need pharmacologic treatments with sedating adverse effects when dose reduction is not an option. Issues examined include the choice of drug for sleep-onset insomnia and for sleep-maintenance insomnia; the choice of drug for insomnia in patients with psychiatric disorders; sedative-hypnotic dosing in contexts such as perturbation of multiple neurotransmitter systems; metabolic drug interactions with sedative-hypnotic drugs; gastrointestinal absorption of hypnotic drugs and time to onset of drowsiness; the effect of food on absorption and time to onset of drowsiness; the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) drugs on absorption and time to onset of drowsiness; the importance of half-life for the duration of action of the sedative-hypnotic drug; strategies to address oversedation with sedating psychotropic drugs; treating insomnia with classical monoamine oxidase inhibitors, especially tranylcypromine; optimization of sedative-hypnotic therapy; provision of patient guidance; and related matters. Readers are also reminded that sleep hygiene and cognitive-behavioral approaches should routinely be combined with sedative-hypnotic drug therapy to optimize insomnia care and improve treatment outcomes.

Lysine-specific demethylase 1 (LSD1), a key epigenetic regulator mediating histone modification, has been a potential therapeutic target for acute myeloid leukemia (AML) due to its critical role in disease pathogenesis. In this work, we designed and synthesized novel LSD1 inhibitors with the scaffold of tranylcypromine-pyrimidine. The representative compound 7a was a highly effective LSD1 inhibitor (IC50 = 7.87 nM) with excellent selectivity over MAO-A and MAO-B (>127-fold over MAO-A and > 1270-fold over MAO-B). Meanwhile, compound 7a also showed effective inhibitory activity against MV-4-11 with IC50 values of 0.36 μM. Mechanistic studies demonstrated that 7a could directly targeted LSD1, thereby promoting a significant increase of H3K4me1/2 histone methylation levels in MV-4-11 cells. 7a induced apoptosis while upregulating the differentiation marker CD86 and downregulating the stem cell-associated proteins SOX2 and CD44. Collectively, these findings establish compound 7a, a tranylcypromine-pyrimidine derivative, provides the structural foundation for the development of LSD1 inhibitors for the treatment of AML.

Leishmaniases remain a major global health challenge due to limited and often toxic therapeutic options. Recent advances in artificial intelligence have enabled the identification of novel antileishmanial candidates through drug repurposing approaches. Among these, our team has previously predicted in silico the monoamine oxidase inhibitor Tranylcypromine as a potential drug candidate against Leishmaniases. In this study, we provided the first experimental evidence supporting its efficacy against Leishmania major using both promastigote and intracellular amastigote models. Tranylcypromine markedly decreased parasite viability in a concentration-dependent manner, displaying IC50 values of 83.6 and 31.6 μg/ml against promastigotes and amastigotes, respectively. Mechanistic investigations revealed that at concentrations ranging from 50 to 200 μg/ml, it induced an apoptotic death of L. major promastigotes leading to necrosis at higher concentrations. Viability and cytotoxicity assays on THP-1-derived macrophages highlighted that the compound, at the selected concentrations, was safe and did not induce a toxic effect on host cells with CC50 values exceeding 280 μg/ml. Altogether, these findings revealed Tranylcypromine as a selective and promising antileishmanial drug candidate, supporting the relevance of AI-assisted drug repurposing strategies to accelerate drug discovery of safe and affordable therapies for neglected tropical diseases.

Monoamine oxidase inhibitors (MAOIs) remain an important option for patients with treatment-resistant depression (TRD) and other psychiatric conditions, despite potentially serious drug-drug interactions and associated dietary tyramine restrictions. However, they are rarely prescribed in patients with comorbid substance use disorders (SUDs) due to concerns about potential drug interactions and limited research in these populations. This narrative review investigates the use of MAOIs in patients who use psychoactive substances, exploring potential interactions while summarizing the relatively scant literature on using MAOIs as treatments for SUDs. It synthesizes data from 219 peer-reviewed publications investigating MAOI/psychoactive substance interactions or the use of MAOIs to treat SUDs or psychiatric conditions in patients with comorbid SUDs, including 20 randomized controlled trials, 18 non-randomized interventional trials, 32 observational studies/case series, 56 case reports, 85 preclinical studies, and 8 reviews, with publication years spanning from 1955 to 2025. Data from 28 non-peer-reviewed user-submitted reports from drug use/harm reduction forums are also included. Suspected cases of serotonin toxicity have been reported for MAOIs in combination with amphetamine, dextromethorphan, 3,4-methylenedioxymethamphetamine (MDMA), meperidine (pethidine), methadone, and tramadol. Hypertensive urgency/emergency has been reported for MAOIs in combination with alcohol (varieties containing significant amounts of tyramine), amphetamine, cocaine, dextroamphetamine, khat, methamphetamine, and psilocybin mushrooms. Other notable adverse events associated with MAOIs in combination with psychoactive substances include agitation (4-bromo-2,5-dimethoxyphenethylamine [2C-B] 5-methoxy-N,N-dimethyltryptamine [5-Meo-DMT]), N,N-dimethyltryptamine [DMT]), delirium/confusion (DMT, propoxyphene, and tramadol), edema (chlordiazepoxide), intracranial hemorrhage (amphetamine, khat, and methamphetamine), mania/psychosis (DMT), rhabdomyolysis (5-MeO-DMT, DMT, and propoxyphene), and sedation/stupor/loss of consciousness (amobarbital, amphetamine, cocaine, dextroamphetamine, and propoxyphene). Fatalities have been reported for MAOIs in combination with 5-MeO-DMT, amphetamine, dextroamphetamine, dextromethorphan (in overdose), MDMA, methamphetamine, meperidine, and tramadol (in overdose). Based on our findings, some substances, such as alcoholic beverages containing significant tyramine quantities (uncommon today), amphetamines, opioids with significant serotonergic reuptake inhibition, and some hallucinogens such as the empathogen/entactogen MDMA, can pose potentially fatal risks in combination with MAOIs. However, MAOI treatment of patients who use alcoholic beverages low in tyramine, caffeine, cannabis, nicotine, sedatives, some (primarily classic) hallucinogens, and some other substances can likely be appropriately managed with careful monitoring, although psychoactive substance dose and route of administration are important safety considerations. While there was initially hope MAOIs might effectively treat some SUDs, there are no robust human data to support their efficacy in this context. Given growing levels of substance use and an increasing number of novel illicit compounds being produced, more research on MAOI safety in patients with psychiatric conditions and comorbid psychoactive substance use/misuse is essential to determining their appropriateness in this complex patient population.

Despite the availability of US Food and Drug Administration-approved pharmacotherapies, smoking continues to be a significant public health problem, with long-term cessation rates often falling below 20%. The cytochrome P450 2A6 (CYP2A6) enzyme plays a critical role in nicotine metabolism, and individuals with genetically reduced CYP2A6 activity exhibit slower nicotine clearance, lower cigarette consumption, and greater cessation success. This observation has led researchers to explore pharmacological inhibition of CYP2A6 as a strategy to aid in smoking cessation. In this review, we discuss 4 CYP2A6 inhibitors, methoxsalen, tranylcypromine, 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine, and cannabidiol, describing their potency, translational potential, and safety considerations. Methoxsalen, a mechanism-based inactivator, inhibits nicotine metabolism in both animals and humans, but there are concerns about its phototoxicity and off-target effects. Tranylcypromine, although a competitive inhibitor of CYP2A6, may also increase nicotine consumption via monoaminergic effects, thereby limiting its practical use in cessation therapies. 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine is a novel synthetic inhibitor with unprecedented potency and specificity in vitro, but lacks clinical validation to support this claim. Cannabidiol is a promising dual-action candidate because it inhibits CYP2A6 in vitro and reduces nicotine intake in rodents, as well as reduces cigarette use and cue reactivity in early human trials. Although these findings emphasize the therapeutic potential of targeting CYP2A6 in smoking cessation efforts, additional validation is required for clinical translation. These include the need for robust human pharmacokinetic studies, long-term safety evaluations, and assessment across genetically diverse populations. With additional research, CYP2A6 inhibition could become a practical and personalized way to improve smoking cessation outcomes. SIGNIFICANCE STATEMENT: This study highlights the clinical significance of inhibiting CYP2A6-mediated nicotine metabolism as a novel smoking cessation strategy by reviewing in vitro, preclinical, and clinical data of agents that mimic the slow CYP2A6 metabolizer phenotype and improve smoking cessation outcomes.

Monoamine oxidase inhibitors (MAOIs) are a separate class from other antidepressants, treating different forms of depression and other nervous system disorders such as panic disorder, social phobia, and depression with atypical features. Even though MAOIs were the first antidepressants introduced, they are not the first choice in treating mental health disorders due to several dietary restrictions, side effects, and safety concerns. MAOIs are only a treatment option when all other medications are unsuccessful. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of MAOIs, pertinent for members of the interprofessional team in treating patients with conditions where this drug class has a therapeutic purpose.

By using the FAERS database, we aim to identify and assess risk signals of adverse drug events (ADEs) potentially causing hypertensive crisis, to inform clinical drug management and promote rational drug use. All statistics were extracted from FAERS by four disproportional methods, which were reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). These four methods were performed to identify hypertensive crisis-related adverse events (AEs) from FAERS. The Weibull shape parameter test was employed to perform a time to onset (TTO) analysis. From the first quarter of 2004 to the second quarter of 2025, a total of 10,281 drug-related hypertensive crisis reports were recorded. A total of 916 drugs were identified as having potential risk signals. The highest incidence of populations related to hypertensive crisis AEs was 37.9% in the 18-65 age group. Among the top 5 drugs with the highest number of reported drug-associated hypertensive crisis events, amlodipine (288 cases) ranked first. Ramipril (282 cases) and valsartan (192 cases) ranked as the second and third medications, respectively. The top 5 drugs associated with the risk of hypertensive crisis under the ROR algorithm were amlodipine perindopril (ROR = 136.64), methyl aminolevulinate (ROR = 122.78), tranylcypromine (ROR = 105.15), rifapentine (ROR = 39.46), and amiloride hydrochlorothiazide (ROR = 39.36). Additionally, the timing of AEs related to hypertensive crisis revealed that the highest incidence (30.69%) was observed within 3 days. The median TTO and interquartile range (IQR) for the top three positive drugs with the highest reported number were as follows: amlodipine 362 (48, 721); ramipril 320 (51, 572); and valsartan 89 (7, 468). These drugs exhibited an early failure type. Our study showed that numerous medications carry potential risks for drug-associated hypertensive crisis. Further investigation is required to establish causality and inform clinical decision-making.

The NLRP3 inflammasome, a key component of the innate immune system, has emerged as a central mediator of inflammation-driven sensorineural hearing loss (SNHL). This review synthesizes current evidence on its involvement across a wide spectrum of auditory pathologies, including genetic syndromes such as CAPS and autosomal dominant deafness (DFNA) 34, as well as noise-induced, age-related, drug-induced, and viral hearing loss. Dysregulated activation of NLRP3 in the cochlea leads to the release of proinflammatory cytokines (IL-1B and IL-18) and pyroptotic cell death, contributing to irreversible cochlear damage. Experimental studies have demonstrated that pharmacological inhibition of NLRP3 via agents such as MCC950, oridonin and tranylcypromine can preserve auditory function. Gain-of-function mutations in the NLRP3 gene are frequently associated with both syndromic and nonsyndromic hearing loss, and animal models expressing these mutations replicate cochlear inflammation and hearing deficits, validating their pathogenic role. Clinically, IL-1B signaling blockers such as anakinra and canakinumab have shown efficacy in CAPS patients, stabilizing or improving hearing outcomes. Emerging selective NLRP3 inhibitors, including dapansutrilo and MCC950, are progressing through early-phase clinical trials. Additionally, natural compounds such as piceatannol and oridonin have demonstrated otoprotective effects in preclinical models of noise- and drug-induced hearing loss. Collectively, these findings position the NLRP3 inflammasome as a promising therapeutic target for SNHL. Future translational research should focus on validating NLRP3-targeting compounds in human trials, identifying biomarkers for early diagnosis, and exploring combination therapies that integrate anti-inflammatory, antioxidant, and regenerative strategies. Targeting NLRP3 may ultimately redefine treatment paradigms for preventing or halting progressive hearing loss.