Suicide remains a leading cause of premature mortality worldwide. Current treatments are limited by delayed onset, durability, or poor tolerability. This narrative review, informed by a structured literature search, summarises the last decade of evidence on pharmacological and neuromodulation interventions for suicidal ideation (SI) or suicide attempt (SA) that are not approved for these indications. We searched PubMed for studies enrolling adults with SI or SA, including controlled trials and naturalistic/observational studies. Thirty-four studies were included: 22 pharmacological (13 efficacy, nine effectiveness) and 12 using neuromodulation (nine efficacy, three effectiveness). Across controlled trials, SI commonly improved within days to weeks. Some trials reported SI reduction beyond concurrent depression score changes, suggesting partial independence, but evidence remains inconsistent and method-dependent. Encouraging results were reported for NMDA-related drugs (NRX-101 and high-dose d-cycloserine; amantadine in Borna disease virus-1-positive depression), opioid-system modulation (buprenorphine at ultra-low and high doses in distinct populations), ayahuasca in major and treatment-resistant depression, and adjunctive pimavanserin. Smaller effects were observed for vortioxetine augmentation and insomnia-targeted zolpidem. Large observational datasets reported associations between lower suicidality and folic acid, benztropine, testosterone initiation in transgender adults, and non-vitamin K oral anticoagulants versus warfarin, whereas non-medical cannabis use was associated with worse SI trajectories. Neuromodulation evidence implicated accelerated or targeted repetitive transcranial magnetic stimulation, theta-burst stimulation, and magnetic seizure therapy for SI reduction, with longer-term observational support for vagus nerve stimulation. Future trials should prespecify suicide-related outcomes, test independence from mood change, and assess durability and high-risk transition periods to advance suicide-specific treatment development.

Little information is available on the use of zaleplon during breastfeeding. Some expert opinion considers zaleplon to be not recommended during breastfeeding.[1,2] Because of the low levels of zolpidem in breastmilk and its short half-life, amounts ingested by the infant are small and would not be expected to cause any adverse effects in older breastfed infants. Monitor infants for excess sedation, hypotonia, and respiratory depression.

Sex-related differences may influence the disposition and pharmacological effects of psychoactive substances. These differences are potentially relevant to forensic toxicology, where blood and tissue drug concentrations are interpreted in relation to impairment, toxicity, and cause of death in consequential medicolegal settings. However, the existing literature is a hodgepodge of often inconclusive or contradictory findings, and sex-related effects are frequently confounded by body size, age, tolerance, comorbidities, hormonal status, route of administration, drug-drug interactions, and gender-related behavioral or sociocultural factors. This review evaluates evidence for sex-related differences in the pharmacokinetics and pharmacodynamics of major psychoactive drug classes, including ethanol, sedative-hypnotics, cannabinoids, opioids, antidepressants, antipsychotics, and stimulants. Human studies were prioritized, while animal and mechanistic studies were used when human evidence was limited or when they clarified plausible biological mechanisms. Evidence was summarized according to biological mechanisms, drug classes, forensic relevance, and interpretive limitations. Literature supports the conclusion that biological sex may affect drug concentrations, metabolite patterns, adverse effects, and pharmacodynamic responses. The forensic relevance was identified for ethanol distribution, adverse effects of selected sedative-hypnotics such as zolpidem, opioids, QT-prolonging psychotropics, and polydrug fatalities. Nevertheless, current evidence does not support universal sex-specific correction factors for toxicological concentrations or deterministic conclusions about impairment or cause of death. Sex is accordingly best used as a contextual interpretive variable within a case-specific framework that incorporates pertinent other factors including measured concentration, specimen type, intake timing, route, tolerance, concomitant drugs, medical history, autopsy findings, and investigative circumstances.

Considering the wide and increasing utilization of drugs which act upon the central nervous system, a pressing, infrequently investigated question is their potential impact on sleep-associated memory consolidation. Here the influence of approved pharmaceuticals on memory consolidation during sleep in healthy humans, rats, and mice was investigated. A systematic review of the literature was conducted according to PRISMA guidelines. Criteria to be met included healthy subjects, drug application after learning and a comparable placebo condition. Exclusion criteria included but were not limited to repetitive dosing and additional non-pharmacological interventions. A total of 65 studies were included, whereby a limited number of studies lent themselves to a meta-analysis. The risk-of-bias assessment showed a lack of reporting predominantly in animal studies. Meta-analysis was conducted for the influence of zolpidem on consolidation of the word-pair association task in human adults, which showed an improvement in memory consolidation (0.57 (95% confidence interval 0.04-1.10)). Most importantly, for memory consolidation, results point toward a favorable position of second-generation antidepressants compared to their first-generation counterparts. Knowledge of such cognitive effects in healthy subjects should encourage consideration in designing studies with patients and/or in patient care.

Melatonin is widely used for sleep disorders and has been hypothesized to exert neuroprotective effects. However, real-world evidence regarding its long-term association with neurodegenerative outcomes remains limited and may be confounded by prodromal sleep disturbances related to early neurodegenerative disease. We conducted a retrospective target trial emulation using the TriNetX Global Collaborative Network between 2015 and 2024. Adults aged ≥ 50 years with sleep disorders identified using ICD-10-CM diagnostic codes and newly prescribed melatonin, benzodiazepines, or zolpidem were eligible. Medication exposure was defined using prescription records documented in the electronic health record system. Two active-comparator cohorts were constructed: melatonin versus benzodiazepines and melatonin versus zolpidem. Outcomes included incident all-cause dementia (ICD-10-CM F01-F03), vascular dementia (F01), Parkinson's disease (G20), and Alzheimer's disease (G30). Analyses were performed in 1:1 propensity score-matched cohorts adjusted for demographic characteristics, healthcare utilization, body mass index, comorbidities, psychosocial risk factors, and selected comedications. Sensitivity analyses incorporated lag periods, varying follow-up durations, and alternative matching approaches. Among 91,216,302 eligible individuals in the TriNetX Global Collaborative Network, 189,858 matched pairs were included in the melatonin versus benzodiazepine analysis and 190,889 matched pairs in the melatonin versus zolpidem analysis. Median follow-up duration was 1.88 versus 2.88 years in the melatonin versus benzodiazepine cohorts and 2.37 versus 3.70 years in the melatonin versus zolpidem cohorts. Melatonin use was associated with higher observed risk of all-cause dementia compared with benzodiazepines (HR 2.09, 95% CI 2.01-2.16) and zolpidem (HR 1.74, 95% CI 1.67-1.82). Elevated risks were also observed for vascular dementia (HR 2.39, 95% CI 2.21-2.60; HR 1.99, 95% CI 1.81-2.19), Parkinson's disease (HR 1.63, 95% CI 1.51-1.76; HR 1.44, 95% CI 1.33-1.57), and Alzheimer's disease (HR 2.11, 95% CI 1.96-2.26; HR 1.54, 95% CI 1.41-1.67). Across sensitivity analyses, including lag-time analyses up to 4 years, the direction of associations remained consistent. Melatonin initiation was associated with higher observed risks of dementia and Parkinson's disease outcomes compared with benzodiazepine or zolpidem initiation among older adults with sleep disorders. These findings should not be interpreted as evidence of a causal pharmacologic effect of melatonin and may instead reflect residual confounding, confounding by indication, and prodromal neurodegenerative disease.

In recent years, the analysis and identification of benzodiazepines and Z-drugs have presented significant challenges in forensic medicine and pharmaceutical analysis due to their widespread use. Notably, some of these substances are classified as new psychoactive substances (NPS) by the UNODC. Hair was chosen as a biological matrix for monitoring long-term drug intake in this study. We aimed to develop and validate a rapid and sensitive method for simultaneous determination of 40 benzodiazepines and Z-drugs in hair using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). All the analytes were detected within 11 min. The method was validated with linear calibration curves over the range of 5-500 pg mg[-1] (coefficient of determination, r[2] > 0.99). The limits of detection (LOD) were 1-3 pg mg[-1], and the limits of quantification (LOQ) were 5 pg mg[-1]. The method demonstrated acceptable selectivity, accuracy, and precision (< 20%). Matrix effects ranged from -29.8-23.5%, and recoveries ranged from 77.9% to 119.9%. The method was successfully applied to six authentic hair samples, detecting nine substances: Nitrazepam, Temazepam, Lorazepam, 7-Aminoflunitrazepam, Clobazam, Lormetazepam, α-Hydroxyalprazolam, 7-Aminoclonazepam, and Zolpidem. Benzodiazepines concentrations ranged from 5.6 to 436.1 pg mg[-1], while zolpidem concentrations ranged from 11.1 to 113.8 pg mg[-1]. This method provided a reliable tool for detecting benzodiazepines and Z-drugs in hair and addresses the requirements of routine forensic practice.

Hemolacria is a rare condition characterized by bloody tears. Its etiology is often multifactorial, but functional/psychosomatic mechanisms have been proposed when organic causes are excluded. A 48-year-old woman with a history of multiple traumatic brain injuries (coma in 2008, car accident in 2017) presented with refractory generalized anxiety disorder, major depressive disorder, insomnia disorder, and treatment-resistant hypertension. Since 2022, she developed bilateral hemolacria with a baseline frequency of 4-5 episodes daily despite extensive negative ophthalmological, neurological, hematological, and imaging workups. She had been on stable doses of sertraline 100 mg/day, amlodipine 10 mg/day, losartan 100 mg/day, and intermittent zolpidem for at least 6 months. Anodal transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (L-DLPFC; anode F3, cathode Fp2) was administered for 27 sessions over 61 days (1-2 mA, 20 min/session, 5 days/week). No concurrent medication changes were made during or after the intervention. Marked clinical improvement began around session 12. By session 27, standardized scores showed remission of symptoms (HAM-D-17 from 26 to 4, HAM-A from 34 to 6, PSQI from 16 to 5), office blood pressure normalized to 125-135/80-85 mmHg, and hemolacria frequency decreased to one minor episode every 43 days. All improvements were sustained at the 3-month follow-up without further tDCS. This single-case, open-label report describes concurrent reductions in psychiatric, cardiovascular, and hemolacria symptoms that occurred in temporal association with anodal tDCS over the L-DLPFC in a treatment-refractory patient after organic causes had been excluded. Given the uncontrolled design, causality cannot be established; alternative explanations including placebo response, non-specific effects of clinical attention, regression to the mean, or spontaneous remission cannot be excluded. Randomized controlled trials are warranted to investigate the potential efficacy and mechanisms of tDCS in functional hemolacria.