A male-derived nonribosomal peptide pheromone controls female schistosome development.

Schistosomes cause morbidity and death throughout the developing world due to the massive numbers of eggs female worms deposit into the blood of their host. Studies dating back to the 1920s show that female schistosomes rely on constant physical contact with a male worm both to become and remain sexually mature; however, the molecular details governing this process remain elusive. Here, we uncover a nonribosomal peptide synthetase that is induced in male worms upon pairing with a female and find that it is essential for the ability of male worms to stimulate female development. We demonstrate that this enzyme generates ß-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic ß-alanyl-tryptamine can replace male worms to stimulate female sexual development and egg laying. These data reveal that peptide-based pheromone signaling controls female schistosome sexual maturation, suggesting avenues for therapeutic intervention and uncovering a role for nonribosomal peptides as metazoan signaling molecules.

Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics.

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.

Rapid effects of tryptamine psychedelics on perceptual distortions and early visual cortical population receptive fields.

N, N-dimethyltryptamine (DMT) is a psychedelic tryptamine acting on 5-HT2A serotonin receptors, which is associated with intense visual hallucinatory phenomena and perceptual changes such as distortions in visual space. The neural underpinnings of these effects remain unknown. We hypothesised that changes in population receptive field (pRF) properties in the primary visual cortex (V1) might underlie visual perceptual experience. We tested this hypothesis using magnetic resonance imaging (MRI) in a within-subject design. We used a technique called pRF mapping, which measures neural population visual response properties and retinotopic maps in early visual areas. We show that in the presence of visual effects, as documented by the Hallucinogen Rating Scale (HRS), the mean pRF sizes in V1 significantly increase in the peripheral visual field for active condition (inhaled DMT) compared to the control. Eye and head movement differences were absent across conditions. This evidence for short-term effects of DMT in pRF may explain perceptual distortions induced by psychedelics such as field blurring, tunnel vision (peripheral vision becoming blurred while central vision remains sharp) and the enlargement of nearby visual space, particularly at the visual locations surrounding the fovea. Our findings are also consistent with a mechanistic framework whereby gain control of ongoing and evoked activity in the visual cortex is controlled by activation of 5-HT2A receptors.

Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids.

We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by our hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso-chimonanthine headcap, we leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a-C7' quaternary stereocenters on a heterodimeric meso-chimonanthine surrogate with full stereochemical control at each quaternary linkage. We developed a new strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by our completely stereoselective total syntheses and expanded characterization data sets, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n + 1] oligocyclotryptamine alkaloids.

Fully Integrated Recognition and Enrichment Electrospray Ionization Source for High-Sensitivity Mass Spectrometry Determination of Bioamine.

The development of a highly specific recognition electrospray ionization source presents a major challenge for achieving rapid ambient mass spectrometry (AMS) detection of trace harmful substances in complex samples. In this study, we constructed a molecular imprinting nanofiber electrospinning membrane-coated steel substrate (MINMCS) based on the electrospinning strategy. This was designed as a highly specific recognition and enrichment electrospray ionization source module for AMS, where the molecular imprinting nanofiber membrane served as an excellent extraction and enrichment layer. The prepared ionization source demonstrated a sufficient loading capacity for three bioamines (BAs): histamine (HIS), tyramine (TYR), and tryptamine (TRY). With simplified sample pretreatment, this ionization source exhibited sensitivity comparable to that of high performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Moreover, the entire analysis process could be completed within 1 min with acceptable recoveries (83.21-101.80%). In brief, this study introduces a new integrated recognition and enrichment electrospray ionization source for the detection of harmful substances such as bioamines, showcasing significant commercial potential for the rapid detection of foodborne harmful compounds.

Buspirone and Zolmitriptan Combination for Dyskinesia: A Randomized, Controlled, Crossover Study.

BACKGROUND: Preclinical evidence suggests that co-administration of the 5-HT1A agonist buspirone and the 5-HT1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone. OBJECTIVES: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. METHODS: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia. RESULTS: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported. CONCLUSIONS: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society.

Cost of illness and labour market disaffiliation among patients with migraine discontinuing triptan treatment: A Danish nationwide register study from 1995 to 2021.

BACKGROUND: Migraine presents significant health and economic challenges. Despite the widespread use of triptans, some patients discontinue them because of insufficient relief or adverse effects. Using national registers, the present study investigates the excess costs and labour market disaffiliation of Danish patients discontinuing triptan treatment. METHODS: The study included all individuals ≥18 years ("patients") who discontinued redemption of triptan prescriptions between 1998 and 2019. They were categorized by number of distinct triptans redeemed before discontinuation: one, two or three or more. A control group was established from the general population without triptan redemptions, three per patient, matched by year of birth, sex and region of residence. We estimated excess direct and indirect costs from 5 years prior ("year -5") to 10 years post ("year 10") the first triptan redemption. RESULTS: We identified 211,026 patients who discontinued triptan redemption, 82% after one, 14% after two and 4% after three or more distinct triptans. Over the period from year -5 to year 10, average excess healthcare costs per patient in these cohorts were EUR 9,554, EUR 10,942 and EUR 12,812 respectively. Over the same period, these patients earned EUR 27,964, EUR 35,920 and EUR 50,076 less than their respective controls, and received higher public transfer payments of EUR 20,181, EUR 23,264 and EUR 26,459. CONCLUSIONS: Triptan discontinuers, who appear to have exhausted all current treatment avenues, face high direct and very high indirect excess costs attributable to migraine, and experience substantial increased labour market disaffiliation.

Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study.

BACKGROUND: Triptans revolutionized the acute treatment of migraine; however, varied responses to triptans, as a result of poor efficacy and tolerability, are reported. A standardized definition of triptan non-response was recently proposed by the European Headache Federation (EHF). There is currently limited data available on the prevalence of triptan non-response. METHODS: We used clinic letters over a two-year duration to evaluate the triptan response and triptan efficacy or tolerability failure, or both, in a London-based tertiary headache service. RESULTS: In total, 419 adult migraine patients (females: 83.8%, age: 46 ± 18 years, chronic migraine: 88.5%) were included in a service evaluation. In line with the EHF definitions, "triptan non-response" was seen in 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF "triptan resistant") and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF "triptan refractory"). Notably, 21.3% of patients (88/414) had failed at least three triptans inclusive and exclusive of subcutaneous triptan use. Advancing age (p < 0.001) and the presence of medication overuse (p = 0.006) increased the probability of triptan response, whereas an increased number of failed preventives (p < 0.001) and the use of calcitonin gene-related peptide monoclonal antibodies (p = 0.022) increased the probability of triptan non-response. The largest proportion of patients responded to eletriptan (49.5%), followed by nasal zolmitriptan (44.4%) and rizatriptan (35.7%). CONCLUSIONS: Our findings highlight an alarming prevalence of triptan non-response among adult migraineurs receiving treatment in a London-based tertiary headache service. It is imperative for clinicians to explore methods to optimize acute medication efficacy, whether this comprises changing to a triptan with a superior response rate, advocating for early intervention or considering alternative acute medication classes, such as gepants or ditans.

Patterns of migraine medication use in Norway: A nationwide registry-based observational study.

OBJECTIVE: The objective of this study was to describe and discuss patterns of migraine medication use in the entire Norwegian population. METHODS: In this nationwide, observational study, all individuals with a migraine-related prescription between 2010 and 2020 were identified using the Norwegian Prescription Database. The outcomes of interest were the incidence and 1-year prevalence of migraine medication users, as well as individuals with triptan overuse. Patterns of medication use were statistically compared between women and men adjusted for age, year of treatment start, comorbidities and county of residence calculating adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: We identified 327,904 migraine medication users. The incidence ranged from 0.39% to 0.46%, and the 1-year prevalence increased from 1.99% to 2.99%. Preventive use increased >50% during the study period. Preventives were significantly more often prescribed to women than to men (39.72% vs. 33.75%; aOR 1.41, 95% CI 1.38 to 1.44). Triptan overuse was significantly more common among women, but women with overuse were more often using preventives, as compared to men (56.64% vs 52.69%; aOR = 1.43, 95% CI 1.37 to 1.49). CONCLUSION: The prevalence of medically treated migraine is low. Overuse of triptans is frequent, especially among women. Clinicians should be encouraged to try out different triptans, recognize triptan overuse, and prescribe preventives when indicated.

Drugs associated with reversible cerebral vasoconstriction syndrome: A pharmacovigilance study in vigiBase®.

BACKGROUND: Data on drug-induced reversible cerebral vasoconstriction syndrome (RCVS) are scarce. We aimed to describe RCVS characteristics with drugs previously identified as associated with RCVS and investigate potential signals related to other drugs. METHODS: VigiBase® was queried for all reports of RCVS until 31 May 2023. A descriptive study was performed on reports concerning drug classes known to precipitate RCVS. To identify new drugs, a disproportionality analysis was conducted. RESULTS: In total, 560 reports were included. RCVS occurred in patients aged between 45-64 years (40%) and 18-44 years (35%), mainly in females (72.5%). Drugs were antidepressants (38.4%), triptans (6.4%), nasal decongestants (3.7%) and immunosupressants (8.7%). In 50 cases, antidepressants were in association with drugs known to precipitate RCVS. The median time to onset was 195 days for antidepressants and much shorter (1-10 days) for triptans, nasal decongestants and immunosuppressants. The outcome was favorable in 87% of cases, and fatal in 4.4%. We found a disproportionality signal with 14 drugs: glucocorticoids, bupropion, varenicline, mycophenolic acid, aripiprazole, trazodone, monoclonal antibodies (erenumab, ustekinumab and tocilizumab), leuprorelin and anastrozole. CONCLUSIONS: The present study confirms the role of vasoconstrictors in the onset of RCVS, particularly when used in combination and found potential signals, which may help clinicians envisage an iatrogenic etiology of RCVS.

Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

Treatment patterns and characteristics of headache in patients in Japan: A retrospective cross-sectional and longitudinal analysis of health insurance claims data.

BACKGROUND: The present study aimed to investigate prescription patterns for patients aged over 17 years with headaches in the REZULT database. METHODS: We conducted a cross-sectional study (Study 1) of the proportion of over-prescription of acute medications (≥30 tablets/90 days for triptans, combination non-steroidal anti-inflammatory drugs (NSAIDs) and multiple types; ≥45 tablets/90 days for single NSAIDs) among patients with headache diagnosed in 2020. We longitudinally studied (Study 2) patients for >2 years from initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache was diagnosed in 200,055 of 3,638,125 (5.5%) patients: 13,651/200,055 (6.8%) received acute medication. Single NSAIDs were prescribed to 12,297/13,651 (90.1%) patients and triptans to 1710/13,651 (12.5%). Over-prescription was found in 2262/13,651 (16.6%) patients and 1200/13,651 (8.8%) patients received prophylactic medication. In Study 2, 408,183/6,840,618 (6.0%) patients were first diagnosed with headaches, which persisted for ≥2 years. Over time, the proportion of patients over-prescribed acute medications increased. Over 2 years, 37,617/408,183 (9.2%) patients were over-prescribed acute medications and 29,313/408,183 (7.2%) patients were prescribed prophylaxis at least once. CONCLUSIONS: According to real-world data, prophylaxis remains poorly prescribed, and both acute and prophylactic treatment rates for headaches have increased over time.

Comparative retention and effectiveness of migraine preventive treatments: A nationwide registry-based cohort study.

BACKGROUND AND PURPOSE: Little is known about the comparative effects of migraine preventive drugs. We aimed to estimate treatment retention and effectiveness of migraine preventive drugs in a nationwide registry-based cohort study in Norway between 2010 and 2020. METHODS: We assessed retention, defined as the number of uninterrupted treatment days, and effectiveness, defined as the reduction in filled triptan prescriptions during four 90-day periods after the first preventive prescription, compared to a 90-day baseline period. We compared retention and efficacy for different drugs against beta blockers. Comparative retention was estimated with hazard ratios (HRs), adjusted for covariates, using Cox regression, and effectiveness as odds ratios (ORs) using logistic regression, with propensity-weighted adjustment for covariates. RESULTS: We identified 104,072 migraine patients, 81,890 of whom were female (78.69%) and whose mean (standard deviation) age was 44.60 (15.61) years. Compared to beta blockers, botulinum toxin (HR 0.43, 95% confidence interval [CI] 0.42-0.44) and calcitonin gene-related peptide pathway antibodies (CGRPabs; HR 0.63, 95% CI 0.59-0.66) were the least likely to be discontinued, while clonidine (HR 2.95, 95% CI 2.88-3.02) and topiramate (HR 1.34, 95% CI 1.31-1.37) were the most likely to be discontinued. Patients on simvastatin, CGRPabs, and amitriptyline were more likely to achieve a clinically significant reduction in triptan use during the first 90 days of treatment, with propensity score-adjusted ORs of 1.28 (95% CI 1.19-1.38), 1.23 (95% CI 0.79-1.90), and 1.13 (95% CI 1.08-1.17), respectively. CONCLUSIONS: We found a favorable effect of CGRPabs, amitriptyline, and simvastatin compared with beta blockers, while topiramate and clonidine were associated with poorer outcomes.

AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs.

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.

Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae.

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

Beneficial effect of 5-HT1b/1d agonist on Parkinson's disease by modulating glutamate and reducing deposition of α-synuclein.

The given investigation examined the neuroprotection role of 5-HT1b/1d agonist in reserpine induced Parkinson's disease (PD) in male Wistar rats. PD was induced in rats by reserpine at 5 mg/kg ip for 3 days and thereafter the rats were provided with the following treatments for 4 days, zolmitriptan (ZLM) group (30 mg/kg ip); STD group (levodopa + carbidopa, 200 + 5 mg/kg ip); ZLM + GA group (zolmitriptan, 30 mg/kg ip and glutamic acid, 1.5 mg/kg); ZLM + DX group (zolmitriptan, 30 mg/kg ip and dextromethorphan, 20 mg/kg ip). All the groups were then assessed for cognitive and motor functions at the end of the protocol. Moreover, oxidative stress parameters and histopathological changes were observed in rats of all treatment groups. Deposition of α-synuclein in the brain tissue was observed by silver staining. Data of this investigation revealed that motor and cognitive functions were improved in the ZLM-treated group compared with the negative control group, which was observed to be reversed in ZLM + GA group. Treatment with ZLM ameliorated oxidative stress and histopathological changes in the brain tissue of PD rats. Further, ZLM reduced the deposition of α-synuclein in PD rats, which reversed in ZLM + GA-treated group. This study concludes by stating that 5-HT1b/1d agonist can prevent neurodegeneration and reduce oxidative stress in PD rats. The probable underlying mechanism of such an effect of 5-HT1b/1d agonist could be by regulating the deposition of α-synuclein and reducing the expression of NMDA receptor.

Precursor-Directed Biosynthesis of Antialgal Fluorinated Bacillamide Derivatives in Bacillus atrophaeus.

The bacillamides are a class of indole alkaloids produced by the Bacillus genus that possess significant antialgal activity. Incorporation of fluorine into the bacillamides was carried out using a precursor-directed biosynthesis approach, with 4-, 5-, and 6-fluorotryptophan added to growing cultures of Bacillus atrophaeus IMG-11. This yielded the corresponding fluorinated analogues of bacillamides A and C, in addition to new derivatives of the related metabolite N-acetyltryptamine, thus demonstrating a degree of plasticity in the bacillamide biosynthetic pathway. The bacillamide derivatives were tested for activity against bloom-forming algae, which revealed that fluorination could improve the antialgal activity of these compounds in a site-specific manner, with fluorination at the 6-position consistently resulting in improved activity.

Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go.

G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of Gs to four different GPCRs have been elucidated1-4, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT1B receptor (5-HT1BR) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the ß2-adrenoceptor (ß2AR) 3 or the adenosine A2A receptor (A2AR) 1 in complex with Gs. In contrast to the complexes with Gs, the gap between the receptor and the Gß-subunit in the Go-5-HT1BR complex precludes molecular contacts, and the interface between the Gα-subunit of Go and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the Go α-subunit. The molecular variations between the interfaces of Go and Gs in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.

Trajectories of sentiment in 11,816 psychoactive narratives.

OBJECTIVE: Can machine learning (ML) enable data-driven discovery of how changes in sentiment correlate with different psychoactive experiences? We investigate by training models directly on text testimonials from a diverse 52-drug pharmacopeia. METHODS: Using large language models (i.e. BERT) and 11,816 publicly-available testimonials, we predicted 28-dimensions of sentiment across each narrative, and then validated these predictions with adjudication by a clinical psychiatrist. BERT was then fine-tuned to predict biochemical and demographic information from these narratives. Lastly, canonical correlation analysis linked the drugs' receptor affinities with word usage, revealing 11 statistically-significant latent receptor-experience factors, each mapped to a 3D cortical Atlas. RESULTS: These methods elucidate a neurobiologically-informed, sequence-sensitive portrait of drug-induced subjective experiences. The models' results converged, revealing a pervasive distinction between the universal psychedelic heights of feeling in contrast to the grim, mundane, and personal experiences of addiction and mental illness. Notably, MDMA was linked to "Love", DMT and 5-MeO-DMT to "Mystical Experiences" and "Entities and Beings", and other tryptamines to "Surprise", "Curiosity" and "Realization". CONCLUSIONS: ML methods can create unified and robust quantifications of subjective experiences with many different psychoactive substances and timescales. The representations learned are evocative and mutually confirmatory, indicating great potential for ML in characterizing psychoactivity.

Acute treatment of migraine: quantifying the unmet need through real-world data in Italy.

OBJECTIVE: This study is describing subjects with migraine interrupting or not receiving triptans for acute treatment and providing a national-level estimate of people who might benefit from different therapeutic approaches. METHODS: This is a retrospective analysis using IQVIA Longitudinal Patient Database. Starting from 18 + years old individuals with migraine, we selected two cohorts: subjects with triptans prescriptions before and no triptans prescriptions after Index Date (triptan withdraw) and subjects without triptans prescriptions both before and after Index Date (no triptan prescriptions). Index Date was the first record of a health encounter for migraine in 2019. Individuals with cardiovascular disease (CVD) within no triptan prescriptions group were also quantified. RESULTS: Triptan withdraw and no triptan prescriptions cohorts numbered 605 and 3270, respectively, 5% and 29% of subjects with migraine. Mean age was 47 and 51 years respectively; women were more represented (~ 80%). Hypertension and thyroid disease were most frequent comorbidities; non-steroidal anti-inflammatory drugs were among most frequently recorded treatments. Subjects with CVD within no triptan prescriptions cohort were 621 and with triptan withdraw cohort subjects represented the basis to estimate those who might benefit from alternative options for the acute treatment of migraine, who were around 60,000 and accounted for 11% of subjects seeking primary care due to migraine. CONCLUSIONS: This analysis provides a real-word estimate of Italian people that might benefit from different therapeutic approaches as an alternative to triptans, which sometimes might be not effective and/or poorly tolerated. Such estimate should be intended as the lower limit of a wider range due to strict criteria adopted.