Hallucinogens, such as lysergic acid diethylamide, act primarily through the 5-hydroxytryptamine 2A (5-HT2A) receptor, but their regulatory mechanisms remain unclear. G protein-coupled receptor 143 (GPR143), an L-3,4-dihydroxyphenylalanine (L-DOPA) receptor, modulates specific GPCRs. We examined the role of GPR143 in the action of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). DOI-induced hyperlocomotion and c-Fos expression in the nucleus accumbens were enhanced in GPR143 knockout mice. In Chinese hamster ovary cells expressing 5-HT2A receptor, DOI-induced extracellular signal-regulated kinase phosphorylation was suppressed by co-expression of GPR143. These findings suggest that GPR143 negatively regulates 5-HT2A receptor signaling and attenuates behavioral responses to hallucinogens.

Efficient whole-cell biocatalytic synthesis of 2′-deoxy-2′-fluoroadenosine, a key building block for nucleic acid drugs

Tumor intracellular bacteria are a key driving force of epithelial-mesenchymal transition (EMT) in tumor cells, and EMT is a critical process in the metastasis cascade. Eliminating intracellular bacteria is a prospective therapeutic target for metastasis. However, existing targeted antibacterial approaches against intracellular bacteria, such as antibiotics, face challenges including drug resistance, biological barriers, or side effects. Here, we develop a tumor-targeted nanoplatform (HSO-OMDs) loaded with autophagy-induced metformin, docosahexaenoic acid, and chemotherapeutic drug oxaliplatin conjugated to hyaluronic acid, which enhances tumor cell autophagy for the effective elimination of intracellular bacteria. HSO-OMDs enhance autophagy by promoting the maturation of autophagosome, the fusion of autophagosomes and lysosomes, and the acidification of lysosomes in tumor cells. As a result, HSO-OMDs effectively eliminate intracellular bacteria by autophagy for blocking EMT processes and inhibit both primary tumor and metastasis. Collectively, our strategy against intracellular-bacteria-driven EMT by enhancing tumor cell autophagy provides a prospective approach for metastatic cancer treatment.

Small interfering RNAs (siRNAs) represent an emerging class of versatile nucleic acid drugs for a broad spectrum of genetic and metabolic disorders. Since siRNAs can be developed to silence any target gene with relative ease compared to conventional drugs, there is enormous potential in this therapeutic modality for combating a variety of illnesses. However, its application is limited by low biostability, rapid clearance, and poor biodistribution of naked RNA. This is overcome by employing backbone modifications, conjugation of cell-targeting ligands, and the use of nanocarriers. DNA-based nanostructures are well suited to carry siRNA drugs since the use of DNA as a construction material provides the ability to tune the size, shape, and other morphological features of the nanostructure. DNA nanostructures also allow easy loading of multiple siRNA drugs with stoichiometric precision, enable functionalization with various targeting and tracking agents, and can be designed to deliver siRNA cargo in response to various stimuli. In this review, we provide an overview of recent reports on the use of DNA-based nanostructures to achieve targeted delivery of siRNA in vitro and in vivo. We discuss aspects of nanostructure design for various drug-loading and drug-release strategies and pharmacodynamic and pharmacokinetic properties of DNA nanocarriers and provide a survey of various diseases that have been targeted by siRNA-carrying DNA nanostructures. We also highlight the challenges facing these new-generation nanocarriers in achieving their therapeutic potential and clinical applications.

Recent literature suggests potential associations between hallucinogen use and valvular heart disease (VHD) due to prolonged activation of serotonin 5-HT2B receptors, which may lead to valvular fibrosis - a condition also linked to drugs including fenfluramine and pergolide. Despite these concerns, epidemiological studies exploring this association are lacking. This exploratory analysis investigated associations between lifetime hallucinogen use and VHD using cross-sectional data from US adults with linked electronic health record data in the NIH All of Us Research Program who completed the Lifestyle survey. This survey included questions about lifetime hallucinogen use (lysergic acid diethylamide [LSD], mushrooms/psilocybin, 3,4-Methylenedioxymethamphetamine [MDMA]/ecstasy, ketamine, phencyclidine [PCP]). Multivariable logistic regression models examined the association between hallucinogen use and VHD, adjusting for sociodemographic factors and other confounding health conditions. Our sample comprised 286,842 adults (mean age 50.8 [SD 16.7], 61.4% female, 60.6% White). Among them, 13.2% reported lifetime hallucinogen use. Individuals with lifetime hallucinogen use had lower unadjusted VHD prevalence compared to those without lifetime hallucinogen use (3.6% vs. 4.7%, p < .001). However, after adjusting for confounders, models revealed modestly increased VHD odds (aOR = 1.08, 95% CI: 1.01-1.55, p = .017). This exploratory study found that hallucinogen use was associated with modestly increased VHD odds after adjustment, requiring confirmation through longitudinal research.

A pivotal hurdle in traumatic brain injury (TBI) therapy is the self-perpetuating cycle between neuroinflammation and oxidative stress. Concurrent targeting of both pathways offers a promising strategy to overcome the key limitation in current therapy. Herein, a programmed streptavidin-condensed bifunctional nucleic acid nanoplatform (DZ-G4/H NPs) was developed via rolling circle amplification (RCA) to integrate numerous C1qa-cleaving DNAzymes with the peroxidase-like G-quadruplex/hemin (G4/H) complex. The platform ingeniously enhances the stability and drug-loading capacity of nucleic acid structures, enabling improved therapeutic efficacy through disruption of the self-perpetuating inflammation-oxidative stress cycle, which is superior to individual monotherapies. Consequently, it alleviated key pathophysiological hallmarks such as brain edema and cerebral blood flow (CBF) deficits, promoted holistic recovery of motor and cognitive functions, and ultimately improved survival in TBI mice. Beyond its promising application in TBI therapy that consolidates multiple therapeutic advantages, this nanostrategy offers a versatile method for streamlined programmed assembly of multifunctional modules, thereby providing an adaptable technical platform for the design and development of multifunctional nucleic acid drugs.

Abstract Introduction Psychedelic use and interest in its therapeutic potential are rapidly increasing; yet its relationship with insomnia remains poorly understood. This study aims to estimate differences in insomnia severity by type of psychedelic consumed among a cohort of 18-to-35-year olds. Methods Data are from the Herbal Heart Study - Sleep Ancillary (N=100) cannabis consumers. Psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) was self-reported. Insomnia and sleep problems were assessed via the Insomnia Severity Index: no clinical insomnia ( &amp;lt; 7), subthreshold clinical insomnia (8-10), moderate-severity clinical insomnia (15-21), and severe clinical insomnia (&amp;gt; 22). Measures were self-reported via REDCap. Chi-square tests, Fisher’s Exact tests, and independent t-tests were conducted where appropriate. Results Among daily cannabis consumers, 55.6% reported lifetime history of psychedelics, of which 42.9% reported past-year consumption. Psilocybin was the most prevalent (50.0%), followed by LSD (29.3%) and DMT (3.5%). Overall, 33.3% met criteria for subthreshold insomnia; 3.2% for moderate severity clinical insomnia; and 1.6% for severe clinical insomnia. There were differential associations between insomnia and psychedelic types (p&amp;lt; 0.05). LSD: 17.7% had moderate-to-severe-clinical-insomnia vs. 0.0% of non-LSD, p=0.006); DMT: 50.0% had moderate-to-severe-clinical-insomnia vs. 3.6% of non-DMT (p= 0.004); Psilocybin: 10.3% had moderate-to-severe-clinical-insomnia vs. 0.0% of non-psilocybin (p=0.07). Sleep problems interfered with daily functioning more frequently among LSD consumers (16.6%) than non-LSD consumers (2.8%, p=0.01). There were no differences consuming cannabis for sleep (p=0.70), or demographics [age: 26.9y (SD: 4.56) vs. 27.2y (SD: 5.56), p= 0.81, sex: 60.0% vs 60.7% female, p=0.95; or ethnicity: 68.6% vs. 57.1% Hispanic/Latino, p=0.26] by psychedelic use. Conclusion LSD and DMT were associated with clinical insomnia; and LSD consumers reported greater sleep problem interference in daily functioning. Longitudinal studies are warranted to evaluate causal effects and long-term sleep outcomes. Given the high burden of insomnia in this population, understanding psychedelic-specific associations with insomnia is essential for clinical and harm-reduction guidelines. Support (if any) R01HL153467 (Vidot); T37MD008647 (Diggs); T32 DA007292 (Baral).

Neuroplastic white matter changes in patients with major depression following lysergic acid diethylamide treatment.

Exosomes derived from MC3T3-E1 cells (M-Exos) exhibit considerable potential for promoting bone repair and regulating bone metabolism. However, their limited osteogenic efficiency and poor targeting capacity remain major challenges. In this study, we developed a therapeutic system, HAMA + BM-Exo138. This platform encapsulates exosomes loaded with the recombinant nucleic acid drug MSA-anti-138 within bone marrow mesenchymal stem cell membranes (BMs), generating a BM-Exo138 complex with enhanced bone-targeting ability and therapeutic efficacy. Hyaluronic acid methacrylate (HAMA) hydrogel was employed as a bone-filling material to provide a supportive matrix for the sustained release of BM-Exo138, thereby promoting osteogenic differentiation and facilitating bone defect repair both in vitro and in vivo. RNA sequencing analysis indicated that BM-Exo138 exerts its therapeutic effects by activating the TGF-β signaling pathway. These findings highlight an integration strategy for exosome-based therapy and offer a promising approach to overcoming current limitations in bone defect treatment, with substantial potential for clinical translation.

Prevalence and Reasons for Microdosing Cannabis, Psilocybin, LSD, and MDMA Among US Adults.

Reports of resurfaced repressed memories during psychedelic experiences have circulated for decades and still emerge today. However, the veracity of repressed memories remains debated, and the mechanisms through which psychedelics might recover alleged repressed memories are unclear. This scoping review aimed to provide an overview of the literature on repressed memory in the context of psychedelics. It examined how repressed memory was defined, which substances were predominantly discussed, which mechanisms were proposed to explain their effects, and whether these mechanisms were empirically supported. A scoping review was conducted in line with PRISMA-ScR guidelines. Web of Science, PubMed, PsycINFO and Google Scholar were searched for relevant publications. Fifty-three sources met eligibility criteria. Data were charted on study design, psychedelic substance, definitions of repressed memory, results, and proposed mechanisms. Most publications focused on lysergic acid diethylamide (LSD) in relation to repressed memory. Few sources provided a definition of repressed memory. Proposed mechanisms on how psychedelics might influence repressed memory included psychoanalytical reductions of defensive memory blockades and neurobiological alterations of executive control. However, empirical support for these mechanisms was limited. The included literature did not offer a coherent explanation on how psychedelics could recover repressed memories, nor consistent evidence that they did so reliably. Future work should provide clear definitions of repressed memory in the context of psychedelics, test proposed effects of psychedelics on memory and executive control across multiple psychedelic substances, include placebo-controlled designs, and account for the potential occurrence of false memories.

Characterization of Amino Acid–Drug Interactions in Aqueous Tetracycline Hydrochloride Systems Using Volumetric, Acoustic, and Viscometric Approaches

Background/Objectives: Recent studies have shown that the solubilisation of poorly water-soluble drugs can be enhanced by using infant formula as a lipid-based formulation. In those studies, digestion of the triglycerides in infant formula to produce more polar lipids, namely fatty acids and monoglycerides, produced a high-capacity solubilisation environment for weakly basic drugs such as clofazimine, driven mainly by ion-pairing of the fatty acid with the drug. However, digestion of lipid-based formulations is not expected to provide the same effect for nonionised or acidic drugs and in fact may present a reduced solubilisation capacity for weakly acidic drugs. Methods: In this study, a weakly acidic drug, tolfenamic acid, was dispersed in reconstituted infant formula, and the infant formula was digested under in vitro simulated intestinal conditions. The quantity of tolfenamic acid that was solubilised in the infant formula during digestion was determined by high-performance liquid chromatography and small-angle X-ray scattering. Results: Unexpectedly, digestion of the infant formula increased the solubilisation capacity for tolfenamic acid. Reconstituting infant formula at a higher fat content also increased the rate and extent of solubilisation of tolfenamic acid during digestion. The quantity of tolfenamic acid that was solubilised during digestion correlated approximately linearly with the quantity of free fatty acids produced during digestion. Conclusions: These results show that a weakly acidic drug can also exhibit digestion-driven solubilisation in a lipid-based formulation in the absence of ion-pairing and highlights the need to better understand drug response to digestion of lipid-based foods and formulations, and their versatility as a formulation option even for poorly water-soluble acidic drugs.

LSD revisited: Mechanisms of action and therapeutic potential in mental health

Hallucinogenic Therapy in Alzheimer's Disease targeting Mitochondria-Associated Membranes.

Recently, many lysergic acid diethylamide (LSD) analogs have emerged as designer drugs worldwide. In Japan, these compounds are distributed as paper sheet or tablet products and are available online. Even after these compounds were regulated, new compounds with modified structures continued to appear. In the present study, two LSD analogs were identified from tablet or paper sheet products. Gas chromatography-mass spectrometry, liquid chromatography-photodiode array-mass spectrometry, liquid chromatography with hybrid quadrupole time-of-flight mass spectrometry, and nuclear magnetic resonance (NMR) measurement were used to determine the structures of the compounds. Based on these analyses, 4-benzoyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1Bz-LSD) and N,N-diethyl-7-methyl-4-(4-(trimethylsilyl)benzoyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1-TMSBz-LSD) were detected and identified in the tablet and paper sheet products, respectively. This paper is the first to report the detection of 1Bz-LSD and 1-TMSBz-LSD in tablet and paper sheet products in Japan.

A novel macrophage membrane-camouflaged ultra-small copper sulfide and photothermal-responsive nitric oxide donor nanocomposites for enhanced synergistic antitumor therapy.

Advances in chromatography for biomacromolecules and bioparticles (2019-2024): Focus on materials and industrial applications.

Mucus-penetrating lipid nanoparticles overcome lung barriers for pulmonary co-delivery of siGSDMD and pDNA-SAP in idiopathic pulmonary fibrosis.

Nucleic acid drug delivery in ophthalmology: Emerging trends and future perspectives.