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Objectives: Identify how the American Headache Society (AHS) membership manages status migrainosus (SM) among outpatients. Background: SM is defined as a debilitating migraine attack lasting more than 72 h. There is no standard of care for SM, including whether a 72‐h duration is required before the attack can be treated as SM. Methods: The Refractory Headache Special Interest Group from AHS developed a four‐question survey distributed to AHS members enquiring (1) whether they treat severe refractory migraine attacks the same as SM regardless of duration, (2) what their first step in SM management is, (3) what the top three medications they use for SM are, and (4) whether they are United Council for Neurologic Subspecialties (UCNS) certified. The survey was conducted in January 2022. Descriptive statistical analyses were performed. Results: Responses were received from 196 of 1859 (10.5%) AHS members; 64.3% were UCNS certified in headache management. Respondents treated 69.4% (136/196) of patients with a severe refractory migraine attack as SM before the 72‐h period had elapsed. Most (76.0%, 149/196) chose "treat remotely using outpatient medications at home" as the first step, 11.2% (22/196) preferred procedures, 6.1% (12/196) favored an infusion center, 6.1% (12/196) sent patients to the emergency department (ED) or urgent care, and 0.5% (1/196) preferred direct hospital admission. The top five preferred medications were as follows: (1) corticosteroids (71.4%, 140/196), (2) nonsteroidal anti‐inflammatory drugs (NSAIDs) (50.1%, 99/196), (3) neuroleptics (46.9%, 92/196), (4) triptans (30.6%, 60/196), and (5) dihydroergotamine (DHE) (21.4%, 42/196). Conclusions: Healthcare professionals with expertise in headache medicine typically treated severe migraine attacks early and did not wait 72 h to fulfill the diagnostic criteria for SM. Outpatient management with one or more medications for home use was preferred by most respondents; few opted for ED referrals. Finally, corticosteroids, NSAIDs, neuroleptics, triptans, and DHE were the top five preferred treatments for home SM management. Plain Language Summary: In this research study, we asked members of the American Headache Society how they treat status migrainosus, a very severe migraine attack lasting more than 3 days. Out of the 196 people who answered the survey, most used stronger treatments before the headache lasted 72 h, and the majority preferred to use home‐based treatments to avoid the hospital. The five most common treatments they use are corticosteroids (like dexamethasone), nonsteroidal anti‐inflammatory drugs (like ketorolac), neuroleptics (like prochlorperazine), triptans (like naratriptan), and dihydroergotamine. [ABSTRACT FROM AUTHOR]

We describe the first total syntheses of tabernanthine and ibogaline. Entry to these iboga alkaloid natural products is enabled by a thermal coupling of indoles and aziridines to furnish the requisite nosyl tryptamine starting materials. This route features a Friedel‐Crafts type alkylation to form the key indole‐isoquinuclidine C−C bond. Finally, a regio‐ and diastereoselective hydroboration‐oxidation enables C−N bond formation to close the isoquinuclidine ring system and deliver tabernanthine and ibogaline in 10 and 14 % yield respectively. Both syntheses were completed in eight steps. [ABSTRACT FROM AUTHOR]

Most of the biogenic amines are naturally found in fermented foods as a consequence of amino acid decarboxylation. Their formation is ascribable to microorganisms (starters, contaminants and autochthonous) present in the food matrix. The concentration of these molecules is important for food security reasons, as they are involved in food poisoning illnesses. The most frequent amines found in foods are histamine, putrescine, cadaverine, tyramine, tryptamine, phenylethylamine, spermine and spermidine. One of the most risk-prone foods are cheeses, mostly ripened ones, which could easily accumulate amines due to their peculiar manufacturing process and ripening. Cheeses represent a pivotal food in our diet, providing for nutrients such as amino acids, calcium, vitamins and others; thus, since they are widely consumed, it is important to evaluate the presence of toxic molecules to avoid consumers' poisoning. This review aimed to gather general information on the role of biogenic amines, their formation, the health issues and the microorganisms and processes that produce/reduce them, with a focus on their content in different types of cheese (from soft to hard cheeses) and the biotic and abiotic factors that influence their formation or reduction and concentration. Finally, a multivariate analysis was performed on the biogenic amine content, derived from data available in the literature, to obtain more information about the factors influencing their presence in cheeses. [ABSTRACT FROM AUTHOR]

The effect of using camel milk on the physiochemical, microbiological and sensory properties, and free amino acid and biogenic amine contents of processed Domiati cheese was investigated during pickling (90 days) at 4°C. The results revealed a decrease in biogenic amines and an increase in free amino acids in cheese made from camel milk compared to cheese made from buffalo milk. Histamine and tryptamine were the most predominant amines in all the treatments (13 and 12 mg/kg), respectively. All samples had lower than the allowable level of biogenic amines, according to the Food and Drug Administration (10 mg/100 g). [ABSTRACT FROM AUTHOR]

Aim: Diet, including foods and beverages, affects migraine. Conversely, the influence of migraine therapies on dietary habits is largely unknown. This study aimed at investigating the effects of triptan intake on foods and drinks consumed by adults with migraine with and/or without aura. Methods: An exploratory questionnaire‐based survey took place online between November 2022 and June 2023. Participants were recruited through advertisements shared on social media accounts (e.g., Facebook and Instagram) and seasonal newsletters of three Danish patient associations. In addition, posters and flyers in headache and pain centers at Danish hospitals and private neurological, pain, and physiotherapeutic clinics were utilized. Results: A total of 314 adults with migraine with and/or without aura completed the survey. Among the respondents, 236 individuals (75.2%) regularly used triptans to treat their migraines. Compared with non‐triptan users, individuals using triptans were characterized by significantly more foods and/or drinks triggering migraine (74.2% vs. 56.4%, p = 0.005). Alcoholic beverages and most specifically red wine were overreported as migraine triggers by triptan users (48.3% vs. 21.8%, p < 0.001). In the week preceding the survey, red wine was significantly less consumed by triptan users than non‐triptan users (92.4% vs. 76.9%, p < 0.001). Conclusions: Patients who regularly consume triptans report red wine most frequently as a migraine trigger. Triptan users are characterized by a lower consumption of red wine than non‐triptan users, suggesting that a regular triptan intake may promote an increased sensitivity to red wine‐induced migraine. [ABSTRACT FROM AUTHOR]

Abstract Probiotics offer a promising prophylactic approach against various pathogens and represent an alternative strategy to combat biofilm-related infections. In this study, we isolated vaginal commensal microbiota from 54 healthy Indian women to investigate their probiotic traits. We primarily explored the ability of cell-free supernatant (CFS) from Lactobacilli to prevent Uropathogenic Escherichia coli (UPEC) colonization and biofilm formation. Our findings revealed that CFS effectively reduced UPEC’s swimming and swarming motility, decreased cell surface hydrophobicity, and hindered matrix production by downregulating specific genes (fimA, fimH, papG, and csgA). Subsequent GC–MS analysis identified Tryptamine, a monoamine compound, as the potent bioactive substance from Lactobacilli CFS, inhibiting UPEC biofilms with an MBIC of 4 µg/ml and an MBEC of 8 µg/ml. Tryptamine induced significant changes in E. coli colony biofilm morphology, transitioning from the Red, Dry, and Rough (RDAR) to the Smooth and White phenotype, indicating reduced extracellular matrix production. Biofilm time-kill assays demonstrated a four-log reduction in UPEC viability when treated with Tryptamine, highlighting its potent antibacterial properties, comparable to CFS treatment. Biofilm ROS assays indicated a significant elevation in ROS generation within UPEC biofilms, suggesting a potential antibacterial mechanism. Gene expression studies with Tryptamine-treated samples showed a reduction in expression of curli gene (csgA), consistent with CFS treatment. This study underscores the potential of Tryptamine from probiotic Lactobacilli CFS as a promising antibiofilm agent against UPEC biofilms.

This article discusses the development of a practical method for Fischer indolization, a commonly used synthetic approach in chemistry. The authors propose the use of bench-stable sodium arylhydrazine sulfonates as a surrogate for arylhydrazine, which eliminates the need for diazotization and reduction steps. The authors demonstrate the effectiveness of this method by synthesizing various tetrahydrocarbazoles and tryptamine-based pharmaceutical molecules. The one-pot reaction conditions are mild and tolerate various functional groups, making this method suitable for the rapid construction of lead-compound libraries. [Extracted from the article]

The total synthesis of alternatamines B and D is outlined. Alternatamine B demonstrates moderate antibacterial activity across a broad spectrum of bacteria. Both alternatamines B and D feature an intriguing 5,6‐dibromoindole skeleton, derived from a four‐step sequence starting with 3,4‐dibromoaniline and achieving a total yield of 48 %. The key steps involve: (a) functional group modifications, including iodination, of 3,4‐dibromoaniline with two bromine substituents to obtain the Sonogashira precursor; (b) indole synthesis through Sonogashira coupling and 5‐endo‐dig cyclization; (c) carbon chain extension and introduction of the nitrogen atom at the C3 of the indole. Subsequently, the tryptamine analogue was coupled with an L‐leucine derivative through amide bond formation after deprotection, yielding alternatamide D. The first total synthesis of alternatamine B was also achieved by selectively introducing a bromine substituent at the C2 of the indole, employing optimal bromination conditions. [ABSTRACT FROM AUTHOR]

The medicinal plant tulsi (Ocimum sanctum L.) is acknowledged for its invigorating and healing properties that enhance resilience to stress in various human and animal models by modulating antioxidant compounds. While extensive research has documented these effects in humans, the adaptogenic potential of tulsi in stressful in vitro plant systems has not been explored. This study aimed to elucidate the adaptogenic properties of tulsi leaf extract on the in vitro regeneration of tobacco leaf explants through an investigation of the indoleamines at different developmental stages. Shoot regeneration from leaf explants on the medium supplemented with tulsi extract (20%) was compared to the control, and the differences in indoleamine compounds were analyzed using ultra-performance liquid chromatography. Treatment of the explants with the extract resulted in an almost two-fold increase in the number of regenerants after four weeks of culture, and 9% of the regenerants resembled somatic embryo-like structures. The occurrence of browning in the extract-treated explants stopped on day 10, shoots began to develop, and a significant concentration of tryptamine and N-acetyl-serotonin accumulated. A comparative analysis of indoleamine compounds in intact and cut tobacco leaves also revealed the pivotal role of melatonin and 2-hydroxymelatonin functioning as antioxidants during stress adaptation. This study demonstrates that tulsi is a potent adaptogen that is capable of modulating plant morphogenesis in vitro, paving the way for further investigations into the role of adaptogens in plant stress biology. [ABSTRACT FROM AUTHOR]

A three component reaction employing readily available starting materials: 2‐(1‐pyrrolyl)benzylamine, arylglyoxal monohydrates and electron‐deficient alkenes in the synthesis of dipyrrolobenzo[1,2‐a : 2′,1′‐c][1,4]diazepines ‐ previously undescribed system and indolo[2,1‐c]pyrrolo[1,2‐a][1,4]benzodiazepine derivatives have been shown. Domino reactions of pyrrolo[1,2‐a][1,4]benzodiazepines with electron‐deficient alkenes has been proposed as another approach. The applicability of the three‐component reaction for the synthesis of indolizino[8,7‐b]indole derivatives from tryptamine has been studied. The in vitro biological activity of title compounds has been tested. [ABSTRACT FROM AUTHOR]

Background: Several studies have focused on the use of triptan and the risk of acute vascular events but the existence of such association is still debated and has never been quantified in patients over 65 years. To assess whether triptan use among older is associated with an increased risk of hospitalization for acute vascular events. Methods: A propensity score-matched cohort study was designed using the French national health insurance database linked to hospital stays. Patients aged ≥ 65 years, newly treated by triptans between 2011 and 2014, were included... The primary event was hospitalization for an acute ischemic vascular event within de 90 days following triptan initiation. Association with triptan exposure was investigated through cox regression model, considering exposure at inclusion, and with exposure as a time-varying variable A case-crossover (CCO) and a self-controlled case series (SCCS) analyses were also conducted to address potential residual confounding. Results: The cohort included 24, 774 triptan users and 99 096 propensity matched controls (mean (SD) age: 71 years (5.9), 74% of women). Within 90 days after cohort entry, 163 events were observed in the triptan group, and 523 in the control group (0.66% vs. 0.53%, adjusted hazard ratio (aHR) exposed/not exposed 1.25 95%CI [1.05–1.49]; aHR time−varying 8.74 [5.21–14.66]). The association was significant (CCO) for all events (adjusted odds ratio (aOR1.63 [1.22–2.19]) with a more consistent association with cerebral events (aOR 2.14 [1.26–3.63]). The relative incidence (RI) for all events was 2.13 [1.76–2.58] in the SCCS, for cardiac (RI: 1.67 [1.23–2.27]) and for cerebral events (RI: 3.20, [2.30–4.45]). Conclusion: The incidence of acute vascular events was low among triptan users. We found that triptan use among older may be associated with a low increased risk for acute vascular events, which may be more marked for cerebral events such as stroke, than for cardiac events. [ABSTRACT FROM AUTHOR]

Tryptamine, a neuromodulator derived from tryptophan, has been shown to significantly impact the host gut homeostasis through its production by the gut microbiota. However, the characterization of tryptamine-producing gut bacteria remains limited, the factors regulating tryptamine production largely unexplored, and its effects on the rest of the gut microbial community unknown. In this study, we screened 13 intestinal strains closely related to known tryptamine producers, characterized their production kinetics, and evaluated whether tryptophan decarboxylation to tryptamine contributes to acid stress tolerance, as shown in other amino acid-dependent acid tolerance systems. We also examined the impact of tryptamine on the composition and function of four healthy human gutmicrobiota by conducting 48-h ex vivo fecal batch fermentations. To complement the ex vivo experiments, we tested the effect of tryptamine exposure (range: 0.5-mM) on the growth of 18 intestinal strains. We identified tryptamine production in five taxa, i.e., Enterocloster asparagiformis, Blautia hansenii, Clostridium nexile, Clostridium sporogenes, and Ruminococcus gnavus,with R. gnavus DSM 108212 accumulating up to 3.4 mM tryptamine after 48 h. An increased tryptophan concentration led to higher tryptamine production. However, tryptamine production was not promoted at low pH andmay not protect cells fromacid-induced cellular damage. Exposing gut microbial communities to 2.4 mM tryptamine caused mild changes in gut microbiota function and composition. All donors showed reduced carbohydrate consumption after 5 h, leading to donor-specific alterations of short-chain fatty acids (SCFAs) (i.e., propionate, acetate, butyrate) and branched-chain fatty acids (BCFAs) (i.e., isobutyrate and isovalerate) after 48 h. Tryptamine also induced a mild change of community structure, with a consistent reduction in the phylum Bacteroidota as well as amplicon sequence variants (ASVs) related to the genera Bacteroides, Blautia, and Faecalibacterium. We confirmed the sensitivity of Bacteroides and Faecalibacterium strains in vitro at concentrations of 2 mM and above. Multiple gut commensals remained unaffected when exposed to 8 mM tryptamine. Taken together, our findings demonstrated that intestinal bacteria-derived tryptamine is a bioactive molecule that not only alters host homeostasis locally but alsomodulates the physiology of gut microbial communities. The specific mechanism through which tryptamine exerts its inhibitory effects on specific gut microbes while leaving others unaffected remains to be elucidated. [ABSTRACT FROM AUTHOR]

Rationale: The 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT, known online as "Moxy") is a new psychedelic tryptamine first identified on Italian national territory in 2014. Its hallucinogen effects are broadly well-known; however, only few information is available regarding its pharmaco-toxicological effects. Objectives: Following the seizure of this new psychoactive substances by the Arm of Carabinieri and the occurrence of a human intoxication case, in the current study we had the aim to characterize the in vivo acute effects of systemic administration of 5-MeO-MiPT (0.01–30 mg/kg i.p.) on sensorimotor (visual, acoustic, and overall tactile) responses, thermoregulation, and stimulated motor activity (drag and accelerod test) in CD-1 male mice. We also evaluated variation on sensory gating (PPI, prepulse inhibition; 0.01–10 mg/kg i.p.) and on cardiorespiratory parameters (MouseOx and BP-2000; 30 mg/kg i.p.). Lastly, we investigated the in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) profile of 5-MeO-MiPT compared to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) and N,N-dimethyltryptamine (DMT). Results: This study demonstrates that 5-MeO-MiPT dose-dependently inhibits sensorimotor and PPI responses and, at high doses, induces impairment of the stimulated motor activity and cardiorespiratory changes in mice. In silico prediction shows that the 5-MeO-MiPT toxicokinetic profile shares similarities with 5-MeO-DIPT and DMT and highlights a cytochrome risk associated with this compound. Conclusions: Consumption of 5-MeO-MiPT can affect the ability to perform activities and pose a risk to human health status, as the correspondence between the effects induced in mice and the symptoms occurred in the intoxication case suggests. However, our findings suggest that 5-MeO-MiPT should not be excluded from research in the psychiatric therapy field. [ABSTRACT FROM AUTHOR]

Background: Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex. Methods: We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex. Results: We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21–51.33) and SSRIs (32.66, 95% CI: 31.33–34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38–76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males. Conclusion: Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans. [ABSTRACT FROM AUTHOR]

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic and entheogenic compound that has been used for centuries by Indigenous Peoples in the Amazon, Caribbean, and more recently in communities in Northern Mexico in ceremonial practices and to connect with nature. In recent years, there has been growing interest in 5-MeO-DMT to treat mental health conditions such as depression, anxiety and post-traumatic stress disorder (PTSD). In response, there has been an increase in scientific research of the efficacy of 5-MeO-DMT in treating such conditions. Little is known about the compound's historical use; this paper will explore and examine the known writings about the origins and original use of 5-MeO-DMT. Additionally, this paper will present the limited data and accounts regarding the use of 5-MeO-DMT and the intersection of those accounts in historical and cultural contexts. [ABSTRACT FROM AUTHOR]

Psychedelic fungi have experienced a surge in interest in recent years. Most notably, the fungal secondary metabolite psilocybin has shown tremendous promise in the treatment of various psychiatric disorders. The mushroom species that produce this molecule are poorly understood. Here we sought to examine for the first time, the response of a psilocybin-producing species Psilocybe cubensis to casing (peat moss and vermiculite) and supplementation with gypsum (calcium sulfate dihydrate), two common practices in commercial mushroom cultivation. Mycelial samples of genetically authenticated P. cubensis were used to inoculate popcorn grain bags. The fully colonized bags of popcorn grain (0.15 kg) were transferred to bins of 0.85 kg pasteurized horse manure, with or without 1 cm thick layer of casing and/or 5 % gypsum. Our results indicate that the use of a casing layer significantly increases the biological efficiency (161.5 %), by approximately four fold, in comparison to control (40.5 %), albeit with a slight delay (∼2 days) for obtaining fruiting bodies and a somewhat reduced total tryptamine content (0.85 %) as gauged by High Performance Liquid Chromatography measurements. Supplementation with both casing and gypsum, however, appears to promote maximal yields (896.6 g/kg of dried substrate), with a biological efficiency of 89.6 %, while also maintaining high total tryptamine expressions (0.95 %). These findings, revealing methods for maximizing yield of harvest and expressions of psychoactive tryptamines, may prove useful for both home growers and commercial cultivators of this species, and ultimately support the growth of a robust industry with high quality natural products. [ABSTRACT FROM AUTHOR]

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). Background: CCH is an excruciating and difficult‐to‐treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. Methods: In this small open‐label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow‐up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. Results: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow‐up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = −0.81), implicating this neural pathway in treatment response. Conclusion: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Two new steroid 3β,21-disulfates (1, 2) and two new steroid 3β,22- and 3α,22-disulfates (3, 4), along with the previously known monoamine alkaloid tryptamine (5) were found in the ethanolic extract of the Far Eastern slime sea star Pteraster marsippus. Their structures were determined on the basis of detailed analysis of one-dimensional and two-dimensional NMR, HRESIMS, and HRESIMS/MS data. Compounds 1 and 2 have a Δ22-21-sulfoxy-24-norcholestane side chain. Compounds 3 and 4 contain a Δ24(28)-22-sulfoxy-24-methylcholestane side chain, which was first discovered in the polar steroids of starfish and brittle stars. The influence of substances 1–4 on cell viability, colony formation, and growth of human breast cancer T-47D, MCF-7, and MDA-MB-231 cells was investigated. It was shown that compounds 1 and 2 possess significant colony-inhibiting activity against T-47D cells, while compounds 3 and 4 were more effective against MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

A series of tryptamine derivatives were transformed into their corresponding 3‐chloro‐2‐oxidation products under simple and mild conditions. This protocol is an operationally simple system that utilizes a single reagent SO2ClF plays a dual role as both oxidant and chloride source and enables the construction of various 3,3‐disubstituted oxindoles with good functional group tolerance. The transformations of the product highlight its potential synthetic applications. [ABSTRACT FROM AUTHOR]

Tryptamine, a neuromodulator derived from tryptophan, has been shown to significantly impact the host gut homeostasis through its production by the gut microbiota. However, the characterization of tryptamine-producing gut bacteria remains limited, the factors regulating tryptamine production largely unexplored, and its effects on the rest of the gut microbial community unknown. In this study, we screened 13 intestinal strains closely related to known tryptamine producers, characterized their production kinetics, and evaluated whether tryptophan decarboxylation to tryptamine contributes to acid stress tolerance, as shown in other amino acid-dependent acid tolerance systems. We also examined the impact of tryptamine on the composition and function of four healthy human gut microbiota by conducting 48-h ex vivo fecal batch fermentations. To complement the ex vivo experiments, we tested the effect of tryptamine exposure (range: 0.5–8 mM) on the growth of 18 intestinal strains. We identified tryptamine production in five taxa, i.e., Enterocloster asparagiformis, Blautia hansenii, Clostridium nexile, Clostridium sporogenes, and Ruminococcus gnavus, with R. gnavus DSM 108212 accumulating up to 3.4 mM tryptamine after 48 h. An increased tryptophan concentration led to higher tryptamine production. However, tryptamine production was not promoted at low pH and may not protect cells from acid-induced cellular damage. Exposing gut microbial communities to 2.4 mM tryptamine caused mild changes in gut microbiota function and composition. All donors showed reduced carbohydrate consumption after 5 h, leading to donor-specific alterations of short-chain fatty acids (SCFAs) (i.e., propionate, acetate, butyrate) and branched-chain fatty acids (BCFAs) (i.e., isobutyrate and isovalerate) after 48 h. Tryptamine also induced a mild change of community structure, with a consistent reduction in the phylum Bacteroidota as well as amplicon sequence variants (ASVs) related to the genera Bacteroides, Blautia, and Faecalibacterium. We confirmed the sensitivity of Bacteroides and Faecalibacterium strains in vitro at concentrations of 2 mM and above. Multiple gut commensals remained unaffected when exposed to 8 mM tryptamine. Taken together, our findings demonstrated that intestinal bacteria-derived tryptamine is a bioactive molecule that not only alters host homeostasis locally but also modulates the physiology of gut microbial communities. The specific mechanism through which tryptamine exerts its inhibitory effects on specific gut microbes while leaving others unaffected remains to be elucidated.

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 μM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer.

Plain Language Summary: A suicidal patient with Short‐lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) whose excruciating condition did not respond to various treatments discovered that ayahuasca, a psychoactive concoction used by indigenous populations of South America, caused his attacks to cease entirely. Inhaled N,N‐dimethyltryptamine (DMT), the principal psychoactive component of ayahuasca, also caused symptoms to disappear temporarily, as did a strong dose of lysergic acid diethylamide (LSD). This case study supports the potential of serotonergic psychedelics for the treatment of SUNCT and related headache disorders. [ABSTRACT FROM AUTHOR]

The article focuses on the integration of psychedelics into mental health care. Topics include the history of psychedelics in medicine and society; the practice of microdosing; the potential benefits and challenges of using psychedelics for mental wellness; the shift in attitudes towards psychedelics; their potential therapeutic effects; the role of technology in enhancing psychedelic treatments; and emphasizing the need for further research and regulation in this emerging field.

Modification of eudesmane-type sesquiterpene lactones and their epoxy derivatives with tryptamines was carried out using the aza-Michael reaction. A series of conjugates was obtained and their inhibitory properties were assessed against the β-secretase activity, which limits the rate of β-amyloid peptide formation and is a promising target for the treatment of Alzheimer's disease. It was found that compounds containing a 5-methoxytryptamine moiety show the greatest activity, reducing protease activity by 65–95% at a concentration of 100 µM and with an IC50 in the range from 15 to 48 µM. This allows us to consider the studied compounds as potential therapeutic agents against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid‐β (Aβ) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N‐methyl‐ d‐aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aβ modulator (e.g., aducanumab). Tryptamine (2‐(1H‐indol‐3‐yl)ethan‐1‐amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aβ aggregation inhibition, antioxidant effects, monoamine‐oxidase inhibition, and neuroprotection. Several tryptamine‐based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in‐depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy. [ABSTRACT FROM AUTHOR]

Tucupi is a broth derived from cassava roots which is produced after the spontaneous fermentation of manipueira (the liquid portion obtained by pressing cassava roots), followed by cooking. This product is widely consumed along with traditional dishes in the Brazilian Amazonia and is already used in different places worldwide. In this study, tucupi obtained from the markets of Belém (Pará, Brazil) and produced using agroindustrial (11 samples) and non-agroindustrial (11 samples) units were investigated to determine their physicochemical characteristics, total and free HCN contents, and free bioactive amine profiles. Most of the samples showed significant variations (p ≤ 0.05) in pH (2.82–4.67), total acidity (0.14–1.36 g lactic acid/100 mL), reducing sugars (up to 2.33 g/100 mL), and total sugars (up to 4.35 g/100 mL). Regarding the amines, four biogenic amines (0.5–4.2 mg/L tyramine, 1.0–23.1 mg/L putrescine, 0.5–66.8 mg/L histamine, and 0.6–2.9 mg/L tryptamine) and one polyamine (0.4–1.7 mg/L spermidine) were identified in the tucupi samples. Even in the tucupi produced using the agroindustrial units, which had quality seals provided by the local regulatory agency, high levels of biogenic amines (4.4–78.2 mg/L) were observed, as well as high dosages of total (8.87–114.66 mg/L) and free (0.80–38.38 mg/L) HCN. These facts highlight the need for better knowledge regarding the product manufacturing process to establish standardization and high-quality conditions for tucupi processing since high contents of biogenic amines and HCN are commonly associated with adverse health effects. [ABSTRACT FROM AUTHOR]

Easy access to divergent products with chemoselectivity is of great importance in organic synthesis. Herein, we have developed a chemoselective copper‐catalyzed carbene insertion protocol onto N−H bonds of tryptamine derivatives. Divergent insertion products are obtained by varying the nucleophilicity of the aliphatic NH of tryptamine with electron‐donating or electron‐withdrawing groups. The reaction provided N−H insertion products with broad substrate scope in good yields. [ABSTRACT FROM AUTHOR]

Biogenic amines (BAs) are biologically active substances found in the cells of microorganisms, plants, and animals. These BAs serve many vital functions in the body. However, an excessive amount can be toxic, especially for individuals taking monoamine oxidase (MAO) and diamine oxidase (DAO) inhibitors. They primarily form in products rich in amino acids, the primary substrates for BA formation. The aim of this study was to determine the formation of BAs and their precursor amino acids in chicken breast and leg muscles stored under chilling conditions. Analyses of BA and AA determinations were conducted on days 1, 3, 5, 7, and 10 of muscle storage. There was a noted increase in BAs with the storage of both muscle types (p < 0.05). Distinct levels of BAs were detected (p < 0.05) in the muscles, except for putrescine (p > 0.05). Interactions emerged between the two factors for various Bas, including histamine (p = 0.001), tyramine (p < 0.001), BAI index (p < 0.001), tryptamine (p < 0.001), agmatine (p = 0.001), spermidine (p < 0.001), TOTAL BA-1 (p < 0.001), and TOTAL BA-2 (p = 0.016). There was no evident interaction between the type of meat and storage time concerning amino acid content (p > 0.05). Correlations in breast muscles were observed for biogenic amine–amino acid pairs such as putrescine–ornithine (r = −0.57) (p < 0.05), spermidine–ornithine (r = −0.73) (p < 0.05), and phenylethylamine–phenylethylalanine (r = −0.50) (p < 0.05). In leg muscles, significant correlations were found for histamine–histidine (r = −0.87) (p < 0.05), putrescine–ornithine (r = −0.96) (p < 0.05), and phenylethylamine–phenylethylalanine (r = −0.65) (p < 0.05). The results obtained can be used in the future to estimate the levels of BAs with knowledge of the levels of individual amino acids and inversely. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to review current literature regarding the epidemiology of vestibular migraine (VM), patient presentation, pathogenesis, and treatment. Recent Findings: VM is becoming an increasingly recognized condition in the United States, currently affecting 2.7% of people. Patients may experience vestibular symptoms, such as vertigo and imbalance, with or without other migrainous symptoms. Recent evidence has also shown that patients with VM are at higher risk for cochlear dysfunction, such as sudden deafness, sensorineural hearing loss, and tinnitus. The heritability and genetics are not well understood, and the pathogenesis may involve calcitonin gene-related peptide, which is also implicated in migraine headaches. A disease-specific patient reported outcome measure, the Vestibular Migraine Patient Assessment Tool and Handicap Inventory, was recently developed and validated. A limited number of controlled trials have assessed various therapies for VM, including triptans and beta-blockers. More data are needed to understand whether or not currently available migraine treatments are effective for VM. Summary: VM is a common etiology of vertigo and dizziness, presenting with a characteristic spectrum of symptoms. Early data suggest that migraine treatments may be helpful in some cases. [ABSTRACT FROM AUTHOR]

Keywords: visible light; 3-methylindole; tryptamine; diphenyl diselenide; diphenyl phosphate EN visible light 3-methylindole tryptamine diphenyl diselenide diphenyl phosphate 3685 3692 8 10/19/23 20231102 NES 231102 Graph The incorporation of selenium into organic scaffolds is not only pivotal for understanding redox processes of biological system, [1] but also plays an important role in pharmaceuticals [5] wherein selenium-containing molecules serve as synthetic intermediates [6] and catalysts for the preparation of various bioactive compounds. When an additive diphenyl phosphate (DPP) was added, formation of desired C-2 Cbz-tryptamine selenide adduct was observed in good yield (entry 2). Transition-metal-catalyzed C2/C3-H activation of indole core (tryptamines) offers robust synthetic strategies to deliver functionalized cores. SP 1 sp H NMR (500 MHz, CDCl SB 3 sb ): = 8.56-8.46 (m, 1 H), 7.69 (d, I J i = 7.9 Hz, 1 H), 7.62 (d, I J i = 7.0 Hz, 1 H), 7.34 (d, I J i = 8.3 Hz, 1 H), 7.27 (s, 1 H), 7.23-7.18 (m, 5 H), 7.16 (s, 1 H), 4.76 (s, 1 H), 4.59 (dt, I J i = 11.6, 6.4 Hz, 2 H), 3.99 (q, I J i = 5.1, 3.1 Hz, 2 H), 3.86 (d, I J i = 4.0 Hz, 2 H), 3.24 (t, I J i = 7.1 Hz, 2 H), 2.32 (d, I J i = 3.6 Hz, 2 H), 2.22 (d, I J i = 4.7 Hz, 2 H), 1.96-1.91 (m, 3 H), 1.82-1.74 (m, 6 H), 1.68-1.66 (m, 2 H), 1.55-1.51 (m, 5 H), 1.30-1.24 (m, 4 H), 1.07 (dd, I J i = 14.4, 3.2 Hz, 2 H), 0.92 (s, 3 H), 0.67 (s, 3 H). [Extracted from the article]

5-hydroxy tryptamine 6, a serotonin receptor has been documented to be involved in epilepsy and is exclusively expressed in central nervous system (eg. cerebral cortex, hippocampus, striatum and olfactory tubercle) that mediate cognition. This study attempted to investigate whether 5-hydroxy tryptamine receptor 6 is involved in cognitive impairment of chronic epileptic rats in vivo magnetic resonance imaging study employing a high field (7T) magnet with T2-weighted imaging sequence and magnetic resonance spectroscopy. Rats were divided into control (n=8) and epileptic group (n=37). Status epilepticus was induced by intraperitoneal injection of lithium chloride-pilocarpine. Spontaneous recurrent seizures rats were divided into dimethyl sulfoxide (SE), SB-271046 (SE+SB), WAY-181187 (SE+WAY) group. Spatial learning and memory were evaluated by Morris-water maze test. Hippocampal volumetric analysis was based on T2-weighted coronal images manually calculated regions of interest. Dentate gyrus data were measured to evaluate metabolite ratios to total creatinine by single voxel point resolved spectroscopy-magnetic resonance spectroscopy. After 4 w of SE, spontaneous recurrent seizures were observed and rats showed poor performance in Morris-Maze. SB-271046 intervention attenuated stages and frequency of spontaneous recurrent seizures and improved performance of Morris-Maze. Lac/total creatine(R) and excitatory neurotransmitters (glutamate, combined resonance of glutamate and glutamine, glutamine, taurine) increased significantly in SE group compared to control group. Volumetric analysis showed hippocampal volume decreased significantly and lateral ventricles became larger in SE group. In SE+SB group, score of N-acetyl aspartate/total creatine+choline(R), volume of hippocampus increased significantly, gap between left and right side of N-acetyl aspartate/total creatine+choline, Lac/total creatine(R) glutamate/total creatine(R), combined resonance of glutamate and glutamine/total creatine(R), glutamine/total creatine(R), taurine/total creatine(R) decreased significantly compared to SE group. N-acetyl aspartate/total creatine+choline(R) was positively correlated with timespent in target quadrant and N-acetyl aspartate/total creatine(L-R) was negatively correlated with timespent in target quadrant and total swimming distance. In conclusion, lateralization of metabolic injury and over-expression of 5-hydroxy tryptamine receptor 6 are characteristics of pilocarpine-induced chronic epilepsy. SB-271046 can attenuate spontaneous recurrent seizures and improve spatial learning and memory by improving hippocampal metabolic injury. [ABSTRACT FROM AUTHOR]

Biogenic amines are a group of metabolites generated in the process of soy sauce brewing, which can result in severe negative impacts on human health at high concentrations. In this study, we innovatively proposed natural extracts (0.1 wt%), of proanthocyanidins, from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves to alternate commercial additives (0.1 wt%), i.e., sodium benzoate and potassium sorbate, for lowering the harmful biogenic amine formation during the fermentation of soy sauce. HPLC results showed that natural extracts from Chinese bayberry leaves could effectively decrease the content of cadaverine, putrescine, histamine, tyramine, phenylethylamine, and agmatine (p < 0.05). In contrast to the inhibitory influence exhibited by commercial sodium benzoate and potassium sorbate, extracts from bayberry leaves can maintain spermidine, spermine, and tryptamine at certain concentrations. Furthermore, both sodium benzoate and potassium sorbate significantly reduced the production of ammonium salt and characteristic components (p < 0.05), like soluble saltless solids, total nitrogen, and amino acid nitrogen, during the 40-day fermentation of soy sauce, whereas proanthocyanidins extracted from Chinese bayberry leaves slightly inhibited the content of ammonium salt. Thus, we can conclude that, while inhibiting the biogenic amine and ammonium salt production, extracts from Chinese bayberry leaves facilitate or maintain the production of characteristic indicators compared to commercial sodium benzoate and potassium sorbate. Taken together, natural extracts from Chinese bayberry leaves can be considered a natural additive to significantly improve the quality of traditional brewing soy sauce. [ABSTRACT FROM AUTHOR]

Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT2A receptors by N,N-dimethyltryptamine (DMT). To reduce first pass metabolism of oral DMT, ayahuasca preparations additionally contain reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation of DMT in brain via systemic MAOA inhibition. Objectives: We measured the pharmacokinetic profile of harmine and/or DMT in rat brain, and tested for pharmacodynamic effects on brain glucose metabolism and DMT occupancy at brain serotonin 5-HT2A receptors. Methods: We first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low sub-cutaneous doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored effects of DMT and/or harmine (1 mg/kg each) on brain glucose metabolism with [18F]FDG-PET. Results: Results confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in brain, while correspondingly increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 μM. We did not observe significant effects of low dose DMT and/or harmine on cerebral [18F]FDG-PET uptake. Conclusion: These preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on serotonin receptor occupancy and cerebral metabolism. [ABSTRACT FROM AUTHOR]

Goat cheese and sheep cheese can offer a range of unique flavors and potential health benefits, making them popular choices among cheese lovers. Both types of cheese contain biogenic amines, which are naturally present in many types of food. The purpose of this study was to assess the levels of the seven most commonly occurring biogenic amines in semi-hard and hard goat and sheep cheeses intended for the Slovak market. The HPLC-DAD method with pre-column derivatization using dansylchloride was employed for the analysis of the hard and semi-hard cheese samples. The presence of biogenic amines was confirmed in all cheese samples, with total levels ranging from 14.4 mg.kg-1 to 1322 mg.kg-1. The most abundant compounds found in the samples were tyramine and tryptamine, followed by 2-phenylethylamine and spermine. Histamine was present in 54.5% of the samples, but its concentration did not exceed 68.7 mg.kg-1. Statistically significant differences in the levels of individual biogenic amines were observed between goat and sheep cheeses, except for spermidine and spermine. [ABSTRACT FROM AUTHOR]

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The medicinal plant tulsi (Ocimum sanctum L.) is acknowledged for its invigorating and healing properties that enhance resilience to stress in various human and animal models by modulating antioxidant compounds. While extensive research has documented these effects in humans, the adaptogenic potential of tulsi in stressful in vitro plant systems has not been explored. This study aimed to elucidate the adaptogenic properties of tulsi leaf extract on the in vitro regeneration of tobacco leaf explants through an investigation of the indoleamines at different developmental stages. Shoot regeneration from leaf explants on the medium supplemented with tulsi extract (20%) was compared to the control, and the differences in indoleamine compounds were analyzed using ultra-performance liquid chromatography. Treatment of the explants with the extract resulted in an almost two-fold increase in the number of regenerants after four weeks of culture, and 9% of the regenerants resembled somatic embryo-like structures. The occurrence of browning in the extract-treated explants stopped on day 10, shoots began to develop, and a significant concentration of tryptamine and N-acetyl-serotonin accumulated. A comparative analysis of indoleamine compounds in intact and cut tobacco leaves also revealed the pivotal role of melatonin and 2-hydroxymelatonin functioning as antioxidants during stress adaptation. This study demonstrates that tulsi is a potent adaptogen that is capable of modulating plant morphogenesis in vitro, paving the way for further investigations into the role of adaptogens in plant stress biology.

The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of essential endogenous metabolites, including kynurenine, kynurenic acid, serotonin, and melatonin, as well as microbiota-derived Trp metabolites like tryptamine, indole propionic acid (IPA), and other indole derivatives. Notably, tryptamine and IPA, among the indole metabolites, exert crucial roles in modulating immune, metabolic, and neuronal responses at both local and distant sites. Additionally, these metabolites demonstrate potent antioxidant and anti-inflammatory activities. The levels of microbiota-derived TRP metabolites are intricately linked to the gut microbiota's health, which, in turn, can be influenced by age-related changes. This review aims to comprehensively summarize the cellular and molecular impacts of tryptamine and IPA on health and aging-related complications. Furthermore, we explore the levels of tryptamine and IPA and their corresponding bacteria in select diseased conditions, shedding light on their potential significance as biomarkers and therapeutic targets.

Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N -methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities. • Microbial metabolite tryptamine is dual agonist of AhR and PXR. • Diverse tryptamine derivatives were synthesized and tested for AhR and PXR activity. • N -methylated tryptamines and tryptamine oleamides were PXR-selective agonists. • Novel PXR agonists were protective in Caco-2 cells exposed to inflammatory cytokines. • Subtle chemical modifications to tryptamine substantially changed AHR/PXR activity. [ABSTRACT FROM AUTHOR]

Aim: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. Findings: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. Conclusion: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache. [ABSTRACT FROM AUTHOR]

Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro‐5‐5‐6‐tricyclic system of these alkaloids was formed through a protecting‐group‐free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next‐generation analgesics. [ABSTRACT FROM AUTHOR]

The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis. Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes capable of metabolizing N‐acetylserotonin (NAS), AADAC was identified as having the ability to convert NAS to serotonin. Both human and rodent recombinant AADAC proteins can deacetylate NAS in vitro, although the human AADAC shows markedly higher activity compared with rodent enzyme. The AADAC‐mediated deacetylation reaction can be potently inhibited by eserine in vitro. In addition to NAS, recombinant hAADAC can deacetylate melatonin (to form 5‐methoxytryptamine) and N‐acetyltryptamine (NAT) (to form tryptamine). In addition to the in vitro deacetylation of NAS by the recombinant AADAC proteins, liver (mouse and human) and brain (human) extracts were able to deacetylate NAS; these activities were sensitive to eserine. Taken together, these results demonstrate a new role for AADAC and suggest a novel pathway for the AADAC‐mediated metabolism of pineal indoles in mammals. [ABSTRACT FROM AUTHOR]

Background: Serotonin receptors 5-HT1B and 5-HT1D in the cerebral arteries are activated by the 5-hydroxytryptophan agonists (triptans) to relieve the discomfort associated with migraines. Even though triptans are often used to treat acute migraines, there is some debate over their effectiveness. Objective: Our systematic review aimed to evaluate the effectiveness of triptans for acute treatment of migraine in young individuals. Methods: Utilizing the databases of Google Scholar, Cochrane Library, and PubMed, a literature search was conducted, and all papers published till July 2022 were included. This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. In addition to the Boolean operators AND, OR, and NOT, the following descriptive terms were also used: "Triptans," "Pediatric Migraine," "Migraine disorders," "Headache," "Children," and "Adolescent." Results: A total of 1047 studies were identified, and 25 articles were finally included in the study. 17 of them were RCTs while the remaining were non-randomized trials. Most studies recruited participants aged between 12–17 years. Among 25 studies, 7 reported sumatriptan use, 3 assessed a combination of sumatriptan and naproxen, 4 were on almotriptan, 1 on eletriptan, 6 on rizatriptan, and 4 on zolmitriptan use. Conclusion: We found that rizatriptan (good tolerability profile with a dose of 5 mg) and sumatriptan (nasal spray, 10 mg and 20 mg) had higher efficiency as compared to other triptans. Regardless of type or dose, all triptans are generally well tolerated by patients, but a few adverse effects such as light-headedness (sumatriptan), nasopharyngitis, and, muscular spasms (sumatriptan/ naproxen), somnolence, and dry mouth (rizatriptan), and dizziness (zolmitriptan group) were reported with the triptans. [ABSTRACT FROM AUTHOR]

Traditional psychedelics are undergoing a transformation from recreational drugs, to promising pharmaceutical drug candidates with the potential to provide an alternative treatment option for individuals struggling with mental illness. Sustainable and economic production methods are thus needed to facilitate enhanced study of these drug candidates to support future clinical efforts. Here, we expand upon current bacterial psilocybin biosynthesis by incorporating the cytochrome P450 monooxygenase, PsiH, to enable the de novo production of psilocybin as well as the biosynthesis of 13 psilocybin derivatives. The substrate promiscuity of the psilocybin biosynthesis pathway was comprehensively probed by using a library of 49 single‐substituted indole derivatives, providing biophysical insights to this understudied metabolic pathway and opening the door to the in vivo biological synthesis of a library of previously unstudied pharmaceutical drug candidates. [ABSTRACT FROM AUTHOR]

Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3rd edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions. [ABSTRACT FROM AUTHOR]