The orexin (hypocretin) system plays a central role in regulating the sleep–wake cycle through two neuropeptides, orexin-A and orexin-B, which act on OX1R and OX2R receptors. Emerging evidence links heightened orexin signaling with the pathophysiology of chronic insomnia. This review outlines the neurobiology of the orexinergic system, compares the pharmacological profile of dual orexin receptor antagonists (DORAs) to traditional GABAergic hypnotics, and evaluates the clinical efficacy and safety of Suvorexant, Lemborexant, and Daridorexant. DORAs function by selectively dampening orexin-driven arousal, thereby facilitating sleep onset and maintenance without disrupting natural sleep architecture. Clinical trials have shown that these agents significantly reduce sleep latency and enhance sleep continuity, with a favorable side effect profile. Overall, DORAs represent a distinct and clinically advantageous option for insomnia treatment, with growing interest in their potential utility across mood, anxiety, and neurodegenerative disorders.

Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep–wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists—melatonin, ramelteon, tasimelteon, and agomelatine—represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep–wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT_2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug’s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep–wake disorders.

Lamotrigine is the drug of choice for the treatment of depressive episodes in bipolar disorder (BD). Despite its generally favorable tolerability profile, lamotrigine use is associated with a risk of Cutaneous Adverse Drug Reactions (cADRs), including Stevens–Johnson Syndrome (SJS) and Lyell’s syndrome, also known as toxic epidermal necrolysis (TEN). Genetic markers HLA and, in particular, HLA-B 15:02 and HLA-A 31:01 are crucial in predicting individuals’ susceptibility to developing the symptoms. The symptoms are triggered by type IV hypersensitivity developing because of CTL and NK cell activation, leading to keratinocyte apoptosis, epidermal necrosis and skin detachment. The exact pharmacotherapy that should be widely utilized in treating affected patients has not yet been established. New therapies including JAK inhibitors or cyclosporine show potential in improving outcomes by reducing mortality and enhancing the period of recovery. Key factors in preventing cADRs may include adequate patient observation, gradual titration of the patient’s dose, and reduction of risk factors through screening for HLA polymorphisms. When the initial symptoms of cADR are identified, it is imperative to make an immediate decision to discontinue treatment, as this can significantly reduce the risk of progression to SJS/TEN and systemic complications. The purpose of this review is to identify a significant correlation between lamotrigine use in BD and the occurrence of SJS by showing the risk factors, neuropharmacological mechanisms, immune response and correctness of pharmacotherapy.

Cognitive enhancement through stimulants such as modafinil is becoming increasingly popular, with many individuals using prescription stimulants for non-medical purposes to improve alertness, attention, and mood. The misuse of such substances has raised concerns, particularly in forensic toxicology. The UHPLC-QqQ-MS/MS method was developed to quantify modafinil in evidentiary samples and biological materials. Additionally, the authors noted the presence of sodium adducts during the analysis of samples with high concentrations of modafinil. The method was validated for accuracy, precision, and linearity, with a concentration range of 0.1–10.0 µg/mL for the evidences and 1.0–100.0 ng/mL for blood. The method successfully detected modafinil as the sole substance in all evidences, with concentrations ranging from 90.7 to 120.8 mg, corresponding to 45.5% to 80.5% of the labeled dose. The method was applied to real post-mortem human cases, where, among others, the concentration of modafinil in blood was 110 ng/mL, whereas, in another case, the concentration of modafinil in the putrefaction fluid exceeded 1000 ng/mL. The developed UHPLC-QqQ-MS/MS method is effective for the quantification of modafinil in evidentiary samples and biological materials, offering a reliable tool for forensic toxicology applications. This method can be used to evaluate modafinil use in both legal and illicit contexts, including cases of overdose or misuse.

The term ‘dementia’ encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient’s independence. Within this group of disorders, Alzheimer’s disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration.

Background: Driving is a coordinated psychomotor activity that involves reaction time, attention, and decision-making. Psychoactive substances such as 2-phenylethylamine (PEA) derivatives and opioids may affect these functions and contribute to traffic safety. This systematic review revealed the effects of the selected PEA derivatives and opioids on psychomotor performance among drivers and potential road safety outcomes. Methods: The review followed PRISMA 2020 standards. Using the PICO method, we conducted a systematic search in Embase, PubMed, and Web of Science (2000–2025). Included studies involved adult participants and quantified the effect of PEA derivatives or opioids on driving-related psychomotor function. Thirty-one articles, such as randomized controlled trials, crossover studies, observational studies, and simulator-based studies, were examined. Risk of bias was evaluated using the RoB2 tool. Results: Evidence indicates therapeutic amphetamine and methylphenidate doses can enhance psychomotor function and safety in patients with ADHD. Recreational or high-dose use of methamphetamine and MDMA is associated with impaired coordination, variable speed, and increased impulsivity. Opioid effects are tolerance- and dose-dependent. Small therapeutic doses of fentanyl in chronically treated patients do not notably impair driving. On the other hand, methadone and tramadol commonly cause somnolence, retardation of reaction, and increased accident risk. Conclusions: The impact of opioids and PEA derivatives on psychomotor function is multifactorial, depending on dose, time, route of administration, and patient status. These substances can either improve or impair driving safety. The findings confirm the need for individual-specific pharmacotherapy treatment. They also highlight the importance of further studies to formulate evidence-based clinical and legislative guidelines.