Clinical and forensic aspects of potassium iodide: Suddenly in high demand across Europe due to fears of radiation poisoning from a nuclear attack in Ukraine.

Potassium iodide has demonstrated several therapeutic applications over time, being the choice for shielding the thyroid during radiation emergencies involving radioiodine release. Amidst the ongoing military conflict between Ukraine and Russia and the growing concern regarding the potential deployment of nuclear weapons, there has been a surge in the demand for potassium iodide across Europe. This work aimed to comprehensively review the current knowledge regarding the pharmacology, physiology, adverse effects, the protective role in reducing the risk of thyroid cancer and recommendations for potassium iodide use during radiation emergencies. Evidence on adverse effects is scarce, as potassium iodide is generally well-tolerated. Guidelines for thyroid blocking with potassium iodide during radiation emergencies suggest that, among populations vulnerable to radioiodine exposure, the benefits of potassium iodide outweigh the risks of adverse effects. Controversial topics surrounding the utilization of potassium iodide in radiation emergencies include the prophylaxis in iodine-deficient regions and following the detonation of dirty bombs, whether granule formulations versus tablets should be used and mental health concerns. Although the rise in demand seems to be a justified security measure, it is essential to recognize that potassium iodide protects the thyroid from radioiodine and does not impact the body's absorption of other radioactive materials or defend against external radiation exposure.

Ovarian cancer ascites proteomic profile reflects metabolic changes during disease progression.

Ovarian cancer (OC) patients develop ascites, an accumulation of ascitic fluid in the peritoneal cavity anda sign of tumour dissemination within the peritoneal cavity. This body fluid is under-researched, mainly regarding the ascites formed during tumour progression that have no diagnostic value and, therefore, are discarded. We performed a discovery proteomics study to identify new biomarkers in the ascites supernatant of OC patients. In this preliminary study, we analyzed a small amount of OC ascites to highlight the importance of not discarding such biological material during treatment, which could be valuable for OC management. Our findings reveal that OC malignant ascitic fluid (MAF) displays a proliferative environment that promotes the growth of OC cells that shift the metabolic pathway using alternative sources of nutrients, such as the cholesterol pathway. Also, OC ascites drained from patients during treatment showed an immunosuppressive environment, with up-regulation of proteins from the signaling pathways of IL-4 and IL-13 and down-regulation from the MHC-II. This preliminary study pinpointed a new protein (Transmembrane Protein 132A) in the OC context that deserves to be better explored in a more extensive cohort of patients' samples. The proteomic profile of MAF from OC patients provides a unique insight into the metabolic kinetics of cancer cells during disease progression, and this information can be used to develop more effective treatment strategies.

Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

Clinical and Forensic Signs Resulting from Exposure to Heavy Metals and Other Chemical Elements of the Periodic Table.

Several heavy metals and other chemical elements are natural components of the Earth's crust and their properties and toxicity have been recognized for thousands of years. Moreover, their use in industries presents a major source of environmental and occupational pollution. Therefore, this ubiquity in daily life may result in several potential exposures coming from natural sources (e.g., through food and water contamination), industrial processes, and commercial products, among others. The toxicity of most chemical elements of the periodic table accrues from their highly reactive nature, resulting in the formation of complexes with intracellular compounds that impair cellular pathways, leading to dysfunction, necrosis, and apoptosis. Nervous, gastrointestinal, hematopoietic, renal, and dermatological systems are the main targets. This manuscript aims to collect the clinical and forensic signs related to poisoning from heavy metals, such as thallium, lead, copper, mercury, iron, cadmium, and bismuth, as well as other chemical elements such as arsenic, selenium, and fluorine. Furthermore, their main sources of occupational and environmental exposure are highlighted in this review. The importance of rapid recognition is related to the fact that, through a high degree of suspicion, the clinician could rapidly initiate treatment even before the toxicological results are available, which can make a huge difference in these patients' outcomes.

Twenty years of real-world data to estimate chronic kidney disease prevalence and staging in an unselected population.

Chronic kidney disease (CKD) represents a global public health burden, but its true prevalence is not fully characterized in the majority of countries. We studied the CKD prevalence in adult users of the primary, secondary and tertiary healthcare units of an integrated health region in northern Portugal (n = 136 993; representing ∼90% of the region's adult population). Of these, 45 983 (33.6%) had at least two estimated glomerular filtration rate (eGFR) assessments and 30 534 (22.2%) had at least two urinary albumin:creatinine ratio (UACR) assessments separated by at least 3 months. CKD was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines as a persistent decrease in eGFR (<60 ml/min/1.73 m2) and/or an increase in UACR (≥30 mg/g). The estimated overall prevalence of CKD was 9.8% and was higher in females (5.5%) than males (4.2%). From these, it was possible to stratify 4.7% according to KDIGO guidelines. The prevalence of CKD was higher in older patients (especially in patients >70 years old) and in patients with comorbidities. This is the first real-world-based study to characterize CKD prevalence in a large, unselected Portuguese population. It probably provides the nearest estimate of the true CKD prevalence and may help healthcare providers to guide CKD-related policies and strategies focused on prevention and on the improvement of cardiovascular disease and other outcomes.

Enhancing Immunotherapy in Ovarian Cancer: The Emerging Role of Metformin and Statins.

Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.

Immune Tumor Microenvironment in Ovarian Cancer Ascites.

Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.

An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava.

Kava (Piper methysticum) has been widely consumed for many years in the South Pacific Islands and displays psychoactive properties, especially soothing and calming effects. This plant has been used in Western countries as a natural anxiolytic in recent decades. Kava has also been used to treat symptoms associated with depression, menopause, insomnia, and convulsions, among others. Along with its putative beneficial health effects, kava has been associated with liver injury and other toxic effects, including skin toxicity in heavy consumers, possibly related to its metabolic profile or interference in the metabolism of other xenobiotics. Kava extracts and kavalactones generally displayed negative results in genetic toxicology assays although there is sufficient evidence for carcinogenicity in experimental animals, most likely through a non-genotoxic mode of action. Nevertheless, the chemotherapeutic/chemopreventive potential of kava against cancer has also been suggested. Both in vitro and in vivo studies have evaluated the effects of flavokavains, kavalactones and/or kava extracts in different cancer models, showing the induction of apoptosis, cell cycle arrest and other antiproliferative effects in several types of cancer, including breast, prostate, bladder, and lung. Overall, in this scoping review, several aspects of kava efficacy and safety are discussed and some pertinent issues related to kava consumption are identified.

Acute liver failure requiring transplantation: A possible link to ulipristal acetate treatment?

The present case describes in detail a 55-year-old woman diagnosed with acute liver injury 3 days after completion of the first treatment course with ulipristal acetate (UPA), 5 mg/day orally for uterine fibroids causing persistent bleeding (treatment duration of 109 days). Liver transplantation was performed approximately 6 weeks after UPA suspension, and a photograph of the explanted liver is presented. Of note, other common causes of acute liver injury, such as history of alcohol or other psychoactive substances abuse, viral hepatitis and autoimmune hepatitis or preexisting liver disease were all excluded. This case was reported to the European Medicines Agency (EMA) and contributed to the final recommendations of the Pharmacovigilance Risk Assessment Committee (PRAC) disclosed in January 2021. The causality assessment considered a probable case of drug-induced liver injury as a consequence of UPA treatment, and the Roussel Uclaf Causality Assessment Method (RUCAM) was scored as unlikely. Although further studies are needed aiming to avoid confounding factors, this case suggests that liver function tests should be monitored during treatment with UPA.

Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity.

Ulipristal acetate is a drug used as emergency contraceptive (30 mg) and for the treatment of moderate to severe symptoms of uterine myomas (5 mg). After commercialization, and although the exact number is unknown, serious cases implying ulipristal acetate 5 mg as a contributing factor of liver injury, some leading to transplantation, were reported. These cases prompted to a restrict use of the drug in January 2021 by the European Medicines Agency. This work aimed to fully review pharmacokinetic aspects, namely focusing in the ulipristal acetate metabolism and other hypothetical toxicological underlying mechanisms that may predispose to drug-induced liver injury (DILI). The high lipophilicity, the extensive hepatic metabolism, the long half-life of the drug and of its major active metabolite, the long-term course of treatment, and possibility due to the formation of epoxide reactive may be contributing factors. Scientific results also points evidence to consider monitorization of liver function during ulipristal acetate treatment.

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats.

Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between µ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson's trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses.

Genetic toxicology and toxicokinetics of arecoline and related areca nut compounds: an updated review.

Areca nut (AN) is consumed by more than 600 million of individuals, particularly in some regions of South Asia, East Africa, and tropical Pacific, being classified as carcinogenic to humans. The most popular way of exposure consists of chewing a mixture of AN with betel leaf, slaked lime, and other ingredients that may also contain tobacco named betel quid (BQ). Arecoline is the principal active compound of AN, and, therefore, has been systematically studied over the years in several in vitro and in vivo genotoxicity endpoints. However, much of this information is dispersed, justifying the interest of an updated and comprehensive review article on this topic. In this sense, it is thus pertinent to describe and integrate the genetic toxicology data available as well as to address key toxicokinetics aspects of arecoline. This review also provides information on the effects induced by arecoline metabolites and related compounds, including other major AN alkaloids and nitrosation derivatives. The complexity of the chemicals involved renders this issue a challenge in genetic toxicology. Overall, positive results in several endpoints have been reported, some of them suggesting a key role for arecoline metabolites. Nevertheless, some negative genotoxicity findings for this alkaloid in short-term assays have also been reported in the literature. Finally, this article also collates information on the potential mechanisms of arecoline-induced genotoxicity, and suggests further approaches to tackle this important toxicological issue.

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats.

Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-ß-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman's spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range.

Suicide by inhalation of butane gas through a homemade adaptation of a continuous positive airway pressure (CPAP) face mask.

Fatal poisoning due to butane inhalation has been described in the clinical and forensic literature. We report the first case of a seventy-year-old obese man with a history of sleep apnea and depression, who was found dead in bed after inhaling butane gas through a homemade adaptation of his own continuous positive airway pressure (CPAP) face mask. The death scene investigation, autopsy findings and toxicological results are described. The cause of death was suspected to be due to asphyxia through butane inhalation.

The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis.

Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.

Clinical and Forensic Aspects of Pharmacobezoars.

BACKGROUND: Pharmacobezoars are specific types of bezoars formed when medicines, such as tablets, suspensions, and/or drug delivery systems, aggregate and may cause death by occluding airways with tenacious material or by eluting drugs resulting in toxic or lethal blood concentrations. OBJECTIVE: This work aims to fully review the state-of-the-art regarding pathophysiology, diagnosis, treatment, and other relevant clinical and forensic features of pharmacobezoars. RESULTS: Patients of a wide range of ages and of both sexes present with signs and symptoms of intoxications or more commonly gastrointestinal obstructions. The exact mechanisms of pharmacobezoar formation are unknown but are likely multifactorial. The diagnosis and treatment depend on the gastrointestinal segment affected and should be personalized to the medication and the underlying factor. A good and complete history, physical examination, image tests, upper endoscopy, and surgery through laparotomy of the lower tract are useful for diagnosis and treatment. CONCLUSION: Pharmacobezoars are rarely seen in clinical and forensic practice. They are related to controlled or immediate-release formulations, liquid, or non-digestible substances, in normal or altered digestive motility/anatomy tract, and in overdoses or therapeutic doses, and should be suspected in the presence of risk factors or patients taking drugs which may form pharmacobezoars.

Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects.

Bupropion is an atypical antidepressant of the aminoketone group, structurally related to cathinone, associated with a wide interindividual variability. An extensive pharmacokinetic and pharmacodynamic review of bupropion was performed, also focusing on chemical, pharmacological, toxicological, clinical and forensic aspects of this drug without a limiting period. Bupropion is a chiral, basic, highly lipophilic drug, clinically used as racemate that undergoes extensive stereoselective metabolism. Its major active metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion reach higher plasma concentrations than bupropion. Bupropion exerts its effects mainly by inhibiting dopamine and norepinephrine reuptake and by blocking several nicotinic receptors. Recent reports highlight recreational use of bupropion via intranasal insufflation and intravenous use. Seizures, insomnia, agitation, headache, dry mouth, and nausea are some of the reported adverse effects. Neurologic effects are major signs of intoxication that should be carefully managed. Finally, the characterization of the polymorphic enzymes involved in the metabolism of bupropion is essential to understand factors that may influence the interindividual and intraindividual variability in bupropion metabolite exposure, including the evaluation of potential drug-drug interactions and pharmacogenetic implications.

Massive gas embolism in a child.

A 16-month-old girl who was hospitalized with pneumonia and treated with antibiotics died after the nurse erroneously connected her intravenous left forearm catheter to the oxygen supply. Autopsy revealed an impressive gas embolism in the left subclavian and brachiocephalic veins, reduced crepitus and enlarged lung volume, and congestion of the meningeal vessels with some areas showing small air bubbles. Dilation of the right atrium and the right ventricle with efflux under pressure of large amounts of air bubbles were observed. The coronary arteries and veins were filled with air bubbles intercalated with segments containing blood. After exclusion of putrefactive artifacts as the source of such a large amount of gas in the body death was considered to be due to a massive air embolism. While embolisms are well recognized in adults, these cases are only infrequently encountered in forensic practice in younger decedents.

Evaluation of progressive hepatic histopathology in long-term tamoxifen therapy.

Tamoxifen (TAM) therapy is the better treatment for breast cancer and the drug use the prophylaxis of this disease in young premenopausal women. Yet, the effects associated with this therapy are unknown. To better understand the extension of this problem, we developed an animal model to mimic this therapy, aiming to evaluate its potential biochemical and histopathological changes in the liver. Young cycling female rats were treated with TAM for one, two and three months and toxicological biomarkers and liver histomorphometry were evaluated. Starting at two months, TAM-treatment prevented the normal age-dependent increase in body weight, without inducing changes in food intake. Serum levels of cholesterol and of the metabolic enzymes creatine kinase and aspartate aminotransferase were reduced in all TAM treatment periods. Serum levels of the metabolic enzymes alkaline phosphatase and lactate dehydrogenase were increased after the first month but returned to control levels upon 3 months of drug exposition. Moderate microvesicular steatosis, classified only at the first month of TAM treatment, was reduced afterwards. Our model showed an adaptive response of liver upon 3 months of treatment, suggesting that at the stated conditions, TAM will not promote hepatotoxicity. In this way, the present model may be useful in the study of possible key endocrine effects of TAM use and the search for better clinical outcomes.

Drugs of abuse from a different toxicological perspective: an updated review of cocaine genotoxicity.

Cocaine is one of the most widely consumed psychoactive substances and has been recognized as a major public health concern for many years. While several aspects of the toxicology of cocaine have been thoroughly described in the literature, namely its effects on different target organs, other toxicological features should not be disregarded. In this perspective, the in vitro and in vivo genotoxic effects of cocaine, along with the genotoxicity data from human exposure, especially in the context of "crack" smoking, were reviewed. Some concerns regarding (1) the chronic abuse and forms of cocaine, (2) the role of metabolism and (3) the mode of action of cocaine were discussed. The major limitations of the experimental and human studies available were also addressed and some research gaps in this field identified. Overall, although the genotoxicity of cocaine is still a matter of discussion, this psychoactive substance exhibits a genotoxic potential that should be further considered.