Imipramine is a tricyclic antidepressant used in the treatment of several psychiatric disorders including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment in the management of panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting) (1). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, α1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, also a tricyclic antidepressant. Further metabolism is catalyzed by CYP2D6. Individuals who are “CYP2D6 ultrarapid metabolizers” carry more than two normal function alleles (i.e., multiple copies) (Table 1, 2), whereas individuals who are “CYP2C19 ultrarapid metabolizers” carry two increased function alleles (Table 3, 4). Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for imipramine states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. Their recommendations include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6 (1). In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes. Amitriptyline and nortriptyline were used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, it may be reasonable to apply the recommendations to other tricyclics, including imipramine (2). For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., imipramine) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects (2).

Despite its established efficacy, the long-term safety profile of amitriptyline among broad patient populations remains insufficiently characterized. We thoroughly characterized the real-world safety profile of amitriptyline through a systematic analysis of the FDA Adverse Event Reporting System (FAERS). Adverse events were collected from Q1 2004 to Q1 2026, and four disproportionality algorithms-reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS)-were employed to identify safety signals. Weibull distribution modeling was used to assess temporal trends, with subgroup analyses stratified by age and sex. Among 5301 amitriptyline-related cases involving 20,451 adverse events, risk signals were identified for psychiatric, nervous system, and cardiac disorders. Analysis confirmed recognized risks, including somnolence, confusional state, drug interaction, and xerostomia. Additional risk signals were identified for potential drug abuse or misuse and for serious adverse events not currently listed on package insert, like aspiration pneumonia, cardiorespiratory arrest, and specific congenital anomalies (e.g., syndactyly, polydactyly, and adactyly). Temporal analysis revealed 52.84% of events occurred within 30 days, whereas 26.14% occurred beyond six months. Subgroup analyses revealed distinct susceptibility patterns: cardiovascular events were more common in females, neuropsychiatric events (e.g., migraine, nightmares) in males; fetal exposure was concerning in pediatric populations, suicide and overdose predominant among adults, and confusion and drug interactions prominent in elderly patients. This pharmacovigilance study confirmed amitriptyline's established adverse reactions and highlighted previously under-characterized risks. These findings recommended implementing integrated risk management in clinical practice to improve patient safety.

Fibromyalgia (FM) is a chronic nociplastic pain syndrome characterized by widespread pain, nonrestorative sleep, fatigue, and cognitive dysfunction, affecting approximately 2-6% of U.S. adults. Although oral cyclobenzaprine has been used off label for decades, its clinical utility has been limited by a narrow benefit-to-harm ratio, with the number needed to treat for symptomatic improvement approximating the number needed to harm for at least one adverse event at conventional doses. This review examines the mechanistic, pharmacokinetic, and clinical evidence supporting the August 2025 FDA approval of sublingual cyclobenzaprine (TNX-102 SL; Tonmya), the first new pharmacologic treatment approved for FM in more than 15 years.

Use of non-prescription cannabidiol (CBD) has increased in recent years, with dose recommendations ranging from ~10 to 70 mg/day. To investigate this trend, many studies have utilized low-dose CBD paradigms in healthy volunteers and patient populations. Here, we review the pharmacokinetics (PK), pharmacodynamics (PDs), and safety of low-dose CBD (≤2.5 mg/kg or ≤175 mg/day). PK studies using low-dose, oral CBD (all included PK studies ≤150 mg) showed that peak (Cmax) and total exposure (area under the curve [AUC]) were 5- to 100-fold lower than a typical 20 mg/kg dose of Epidiolex. PD studies showed very little evidence of physical or neurological effects of low-dose CBD in healthy volunteers. Drug-drug interactions (DDIs) with Δ9-tetrahydrocannabinol, amitriptyline, and hydromorphone were observed at low doses (10, 30, 50, 60, 100 mg), which may have implications for patients who are co-administering non-prescription CBD with other medications. In randomized controlled trials, there was no evidence that low-dose CBD ameliorated any of the endpoints measured in patients with Parkinson's, Crohn's, pain, fibromyalgia, stress, ocular hypertension or psoriasis. In sleep disorders (sleep duration, 160 mg), alcohol use disorder (alcohol craving and impaired control, 150 mg/day CBD + 0.41 mg/day THC) and multiple sclerosis (timed walk test and pain, 80 mg/day), CBD improved a small selection of endpoints, but consistent changes were not observed across related endpoints and trials. No studies reported serious adverse events associated with low-dose CBD, which was well tolerated. In conclusion, low doses of CBD show very little evidence of any biological effect or therapeutic value.

Tricyclic drugs such as chlorpromazine (CPZ), amitriptyline (AmiT), and imipramine (ImiP) have demonstrated antitumorigenic potential, yet their relative potency and selectivity for different tumors remain unclear. Here, we conducted a comparative study of the antitumorigenic effects of these drugs on three major cancer types: breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and melanoma (A375).

Introduction: Pain is one of the most common reasons why patients seek medical care, and chronic pain is now recognized as a major health problem worldwide. Better understanding of pain mechanisms has shown the importance of distinguishing nociceptive, neuropathic, and nociplastic pain in order to choose the most effective treatment. In recent years, topical analgesics have gained increasing attention because they can provide pain relief directly at the site of application while reducing systemic exposure and the risk of adverse effects. This is especially important in older adults, patients with multiple diseases, and those exposed to polypharmacy. Methods: This narrative review presents the current knowledge on the pharmacology, efficacy, and safety of topical drugs used in pain treatment. Particular attention is given to topical non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, menthol, and camphor. The review also discusses newer and less established therapies used mainly in neuropathic pain, including topical ketamine, amitriptyline, phenytoin, gabapentin, and clonidine. A structured, non-systematic literature search was conducted using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases to identify studies evaluating the efficacy and safety of topical analgesic therapies. Results: Current evidence supports topical NSAIDs as first-line therapy for localized musculoskeletal pain and osteoarthritis, while lidocaine and high-concentration capsaicin patches are effective options in focal neuropathic pain. Although several newer topical therapies show promising results, more high-quality clinical studies are still needed. Overall, topical analgesia is an important part of multimodal pain management because it combines analgesic efficacy with a better safety profile compared with many systemic therapies. Conclusions: Taking the aspects discussed in this paper into account, it seems justified to search for new drug combinations that would contribute to effective pain therapy with topical agents. It is recognized that a multimodal approach to pain management, which utilizes drugs with different mechanisms of action, can increase efficacy and reduce the systemic adverse events of the drugs used. The effective and safe treatment of patients with pain, especially neuropathic pain, despite emerging new clinical trials, remains a challenge for clinicians.