RARE DISEASE
Cocaine intoxication
Cocaine intoxication
Cocaine intoxication
Drug discovery
2
drugs
With orphan designations
Overview
Cocaine intoxication is a stimulant toxidrome characterized by sympathomimetic hyperactivity (tachycardia, hypertension, hyperthermia), CNS excitation (agitation, seizures), and sodium channel blockade effects. Severe cases may progress to life-threatening complications including myocardial infarction, stroke, aortic dissection, rhabdomyolysis, and multi-organ failure [1][3][11]. Immediate management focuses on benzodiazepines for agitation/cardiotoxicity, aggressive cooling for hyperthermia, and alpha-blockers/phentolamine for hypertensive crises while avoiding beta-blockers [3][13][16].
Categories: rare disorders due to toxic effects
Research Papers
312 drug discovery papers about Cocaine intoxication, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
312 drug discovery papers about Cocaine intoxication, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-11 | Anaesthetic and intensive care management of refractory hypotension in a high-risk patient with chronic cocaine use.
Chronic cocaine use is associated with complex cardiovascular changes, including catecholamine depletion and dilated cardiomyopathy, predisposing patients to peri-operative haemodynamic instability. We report a 41-year-old man with chronic cocaine use, severe left ventricular dysfunction (left ventricular ejection fraction 20%), type 2 diabetes mellitus and recent myocardial infarction who underwent emergency surgery for perforated appendicitis. After induction of anaesthesia, he developed profound hypotension refractory to fluids and ephedrine, requiring a noradrenaline infusion. The postoperative course was complicated by septic shock and acute kidney injury requiring continuous renal replacement therapy, followed by gradual stabilisation in intensive care. This case highlights that peri-operative hypotension in patients with chronic cocaine use and advanced cardiac dysfunction may reflect catecholamine depletion rather than acute intoxication. Early use of direct acting vasopressors with planned postoperative intensive care monitoring may be crucial in reducing morbidity and mortality.
2026-06-08 | Length of Stay of Emergency Department Patients with Stimulant Intoxication Receiving Intravenous Fluid.
Intravenous (IV) fluids are routinely administered empirically in the emergency department (ED) for patients presenting with stimulant intoxication (eg, cocaine, methamphetamine, synthetic marijuana), although the literature is sparse regarding the benefits and risks of this practice. Our primary objective in this study was to assess whether empiric administration of IV fluids in the ED is associated with increased discharge length of stay (LOS) among ED patients presenting for stimulant intoxication who were subsequently discharged. This single-center, retrospective cohort study included 100 patients 18-69 years of age who were discharged from the ED with a non-incidental diagnosis related to stimulant intoxication between May 29, 2020-December 31, 2023, based on International Classification of Diseases code and chart review, in addition to a triage heart rate ≥ 90 beats per minute. We excluded patients if the medical decision-making reflected a clear indication for IV fluids or the presence of pre-defined confounding diagnoses or an uncontrolled factor that would have inherently impacted discharge LOS. Our primary outcome measure was discharge LOS. A multiple linear regression model controlled for the potentially confounding secondary outcome measures of age, sex, alcohol involvement, advanced imaging, sedation, and discharge escort. A total of 100 patients were included, including 50 (50%) patients who did not receive IV fluids and 50 (50%) patients who did. Median patient age was 35 (interquartile range [IQR] 29-41) and 73% of patients were male. Patients who received IV fluids had a median LOS of 345 minutes (IQR 260-470) vs 305 minutes (IQR 205-413), with multivariable linear regression showing no statistically significant difference (β = 40.3, 95% CI, -13.6 to 94.2, R2 = 0.162). This study suggests that empiric IV fluid administration in stimulant-intoxicated ED patients was not significantly associated with discharge length of stay. Although the observed difference and confidence interval suggest the possibility of a clinically meaningful increase in discharge LOS with empiric IV fluid, these findings should be interpreted cautiously. Time is an important resource in high-volume ED settings, and this study suggest the need for judicious use of IV fluids in the absence of a clear indication.
2026-06-05 | β-Blockers for ED Presentations with Recent Cocaine Use: A Systematic Review
Abstract Background Cocaine produces cardiovascular toxicity through intense sympathetic stimulation and direct myocardial injury, generating presentations ranging from hypertension and tachycardia to coronary vasospasm, arrhythmia, and myocardial depression. β-blockers are foundational therapies in acute coronary syndromes, yet their use after cocaine exposure remains controversial due to concerns about unopposed α-adrenergic stimulation. Methods A systematic review was conducted in accordance with PRISMA guidelines. PubMed and Google Scholar (2000–2026) were searched for observational studies of adults (≥18 years) presenting to acute care with recent cocaine use that compared outcomes between β-blocker recipients and non-recipients. Eligible studies reported in-hospital mortality, myocardial infarction/troponin rise, clinically significant arrhythmia, or haemodynamic instability. Risk of bias was assessed using the Newcastle–Ottawa Scale, and certainty of evidence using GRADE. Results Four retrospective ED cohorts (n = 1,140) met inclusion criteria; 503 patients received at least one β-blocker dose. Across studies, β-blocker use was not associated with increased in-hospital mortality or malignant arrhythmias. Myocardial infarction was heterogeneous and sensitive to definition and timing. Haemodynamic data showed no hypertensive surge and modest systolic blood pressure reductions. Risk of bias was moderate, and certainty of evidence very low to low. Conclusions In typical ED presentations of recent cocaine use, β-blocker administration does not appear to increase mortality, myocardial infarction, or malignant arrhythmias, and available haemodynamic data do not support a reproducible unopposed-α response. However, mechanistic and preclinical evidence suggests potential harm in severe intoxication or myocardial depression. A selective, phenotype-guided approach is warranted, and prospective mechanistic studies are needed. Key Points Beta-blockers did not increase deaths, heart attacks, or dangerous heart rhythms in adults who came to the emergency department after recent cocaine use. Blood pressure generally decreased after beta-blocker treatment, and no consistent “unopposed alpha” reaction was seen in typical presentations. Caution is still needed in severe intoxication or cases with heart muscle weakness, but for most emergency presentations, beta-blockers appear safe when used appropriately.
2026-06-01 | GLP-1 Receptor Agonists in Addiction: From Observational Signals to Research Priorities
Aims: Recent large registry studies report associations between GLP-1 RA use and reduced substance-related harms. We synthesize this evidence, identify critical knowledge gaps, and define research priorities needed before clinical translation. Methods: A targeted evidence synthesis was conducted across three domains: 1. Large registry studies examining outcomes in people with AUD or opioid use disorder (OUD) prescribed GLP-1 RAs. 2. Real-world cohort studies comparing overdose and hospitalisation rates between GLP-1 RA users and non-users. 3. Neuroscience literature describing GLP-1 receptor activity in reward-related brain regions. Results: Multiple observational studies show associations between GLP-1 RA use and reduced substance-related harms. In a Swedish cohort of 227,866 individuals with AUD, semaglutide was associated with reduced alcohol-related hospitalisations (Lähteenvuo 2024). US data (>500,000 OUD, >800,000 AUD patients) showed lower opioid overdose and alcohol intoxication rates among GLP-1 RA users (Qeadan 2024; Wang 2024). All current human findings are observational, but several human randomised controlled trials are now underway, including trials of semaglutide and exenatide for AUD, semaglutide for cocaine use disorder, and liraglutide for nicotine dependence. The overlap between metabolic and addiction pathways may explain these associations, as GLP-1 signaling modulates reward processing relevant to both food intake and substance use. Preclinical studies demonstrate GLP-1R-mediated reduction in substance self-administration via reward pathway modulation in VTA, NAcc, and PFC. While this provides biological plausibility, observational human data cannot establish causality, and RCT evidence is needed. Conclusion: Observational data suggest potential associations between GLP-1 RA use and reduced substance-related harms, but cannot establish causality due to confounding. Before clinical application, essential research includes: (1) completion of ongoing RCTs with addiction-specific outcomes, (2) safety and tolerability evaluation in actively substance-using populations, including assessment of nausea/vomiting risks and drug interactions with methadone, buprenorphine, and benzodiazepines, (3) adherence and implementation feasibility studies in populations with chaotic substance use, and (4) health economics modeling. Psychiatrists should monitor emerging trial results critically as this evidence base develops in the coming years.
2026-04-19 | Substrate specificity and in vivo efficacy of engineered cocaine esterases toward cocaine and its toxic metabolites.
Cocaine abuse remains a significant global public health challenge, yet no specifically approved pharmacotherapies are currently available. While enzyme-based strategies offer promise, an effective treatment must address not only cocaine but also its major active and/or toxic metabolites-benzoylecgonine, norcocaine, and cocaethylene, several of which exhibit greater toxicity than cocaine itself. Here, we report for the first time that two engineered cocaine esterases, E196-301 and BZEase2, are capable of hydrolyzing cocaine and its three toxic metabolites. By integrating molecular modeling with comprehensive in vitro kinetic analysis and in vivo efficacy studies, we demonstrate that these enzymes possess distinct yet complementary substrate selectivity: E196-301 efficiently catalyzes the hydrolysis and clearance of cocaine, norcocaine, and cocaethylene, whereas BZEase2 preferentially degrades benzoylecgonine. Both enzymes conferred significant therapeutic benefits in rodent models of acute cocaine-metabolite exposure and cocaine-alcohol co-administration, though neither alone achieved complete detoxification against cocaine and its toxic metabolites under the tested conditions. Their complementary substrate profiles suggest combining E196-301 and BZEase2 or engineering next-generation broad-spectrum hydrolases may offer a rational strategy for comprehensive detoxification across the full spectrum of cocaine-related toxins. This work establishes a critical foundation for enzyme-based therapy targeting cocaine's multifaceted toxicology.
2026-07-11 | Anaesthetic and intensive care management of refractory hypotension in a high-risk patient with chronic cocaine use.
Chronic cocaine use is associated with complex cardiovascular changes, including catecholamine depletion and dilated cardiomyopathy, predisposing patients to peri-operative haemodynamic instability. We report a 41-year-old man with chronic cocaine use, severe left ventricular dysfunction (left ventricular ejection fraction 20%), type 2 diabetes mellitus and recent myocardial infarction who underwent emergency surgery for perforated appendicitis. After induction of anaesthesia, he developed profound hypotension refractory to fluids and ephedrine, requiring a noradrenaline infusion. The postoperative course was complicated by septic shock and acute kidney injury requiring continuous renal replacement therapy, followed by gradual stabilisation in intensive care. This case highlights that peri-operative hypotension in patients with chronic cocaine use and advanced cardiac dysfunction may reflect catecholamine depletion rather than acute intoxication. Early use of direct acting vasopressors with planned postoperative intensive care monitoring may be crucial in reducing morbidity and mortality.
2026-06-08 | Length of Stay of Emergency Department Patients with Stimulant Intoxication Receiving Intravenous Fluid.
Intravenous (IV) fluids are routinely administered empirically in the emergency department (ED) for patients presenting with stimulant intoxication (eg, cocaine, methamphetamine, synthetic marijuana), although the literature is sparse regarding the benefits and risks of this practice. Our primary objective in this study was to assess whether empiric administration of IV fluids in the ED is associated with increased discharge length of stay (LOS) among ED patients presenting for stimulant intoxication who were subsequently discharged. This single-center, retrospective cohort study included 100 patients 18-69 years of age who were discharged from the ED with a non-incidental diagnosis related to stimulant intoxication between May 29, 2020-December 31, 2023, based on International Classification of Diseases code and chart review, in addition to a triage heart rate ≥ 90 beats per minute. We excluded patients if the medical decision-making reflected a clear indication for IV fluids or the presence of pre-defined confounding diagnoses or an uncontrolled factor that would have inherently impacted discharge LOS. Our primary outcome measure was discharge LOS. A multiple linear regression model controlled for the potentially confounding secondary outcome measures of age, sex, alcohol involvement, advanced imaging, sedation, and discharge escort. A total of 100 patients were included, including 50 (50%) patients who did not receive IV fluids and 50 (50%) patients who did. Median patient age was 35 (interquartile range [IQR] 29-41) and 73% of patients were male. Patients who received IV fluids had a median LOS of 345 minutes (IQR 260-470) vs 305 minutes (IQR 205-413), with multivariable linear regression showing no statistically significant difference (β = 40.3, 95% CI, -13.6 to 94.2, R2 = 0.162). This study suggests that empiric IV fluid administration in stimulant-intoxicated ED patients was not significantly associated with discharge length of stay. Although the observed difference and confidence interval suggest the possibility of a clinically meaningful increase in discharge LOS with empiric IV fluid, these findings should be interpreted cautiously. Time is an important resource in high-volume ED settings, and this study suggest the need for judicious use of IV fluids in the absence of a clear indication.
2026-06-05 | β-Blockers for ED Presentations with Recent Cocaine Use: A Systematic Review
Abstract Background Cocaine produces cardiovascular toxicity through intense sympathetic stimulation and direct myocardial injury, generating presentations ranging from hypertension and tachycardia to coronary vasospasm, arrhythmia, and myocardial depression. β-blockers are foundational therapies in acute coronary syndromes, yet their use after cocaine exposure remains controversial due to concerns about unopposed α-adrenergic stimulation. Methods A systematic review was conducted in accordance with PRISMA guidelines. PubMed and Google Scholar (2000–2026) were searched for observational studies of adults (≥18 years) presenting to acute care with recent cocaine use that compared outcomes between β-blocker recipients and non-recipients. Eligible studies reported in-hospital mortality, myocardial infarction/troponin rise, clinically significant arrhythmia, or haemodynamic instability. Risk of bias was assessed using the Newcastle–Ottawa Scale, and certainty of evidence using GRADE. Results Four retrospective ED cohorts (n = 1,140) met inclusion criteria; 503 patients received at least one β-blocker dose. Across studies, β-blocker use was not associated with increased in-hospital mortality or malignant arrhythmias. Myocardial infarction was heterogeneous and sensitive to definition and timing. Haemodynamic data showed no hypertensive surge and modest systolic blood pressure reductions. Risk of bias was moderate, and certainty of evidence very low to low. Conclusions In typical ED presentations of recent cocaine use, β-blocker administration does not appear to increase mortality, myocardial infarction, or malignant arrhythmias, and available haemodynamic data do not support a reproducible unopposed-α response. However, mechanistic and preclinical evidence suggests potential harm in severe intoxication or myocardial depression. A selective, phenotype-guided approach is warranted, and prospective mechanistic studies are needed. Key Points Beta-blockers did not increase deaths, heart attacks, or dangerous heart rhythms in adults who came to the emergency department after recent cocaine use. Blood pressure generally decreased after beta-blocker treatment, and no consistent “unopposed alpha” reaction was seen in typical presentations. Caution is still needed in severe intoxication or cases with heart muscle weakness, but for most emergency presentations, beta-blockers appear safe when used appropriately.
2026-06-01 | GLP-1 Receptor Agonists in Addiction: From Observational Signals to Research Priorities
Aims: Recent large registry studies report associations between GLP-1 RA use and reduced substance-related harms. We synthesize this evidence, identify critical knowledge gaps, and define research priorities needed before clinical translation. Methods: A targeted evidence synthesis was conducted across three domains: 1. Large registry studies examining outcomes in people with AUD or opioid use disorder (OUD) prescribed GLP-1 RAs. 2. Real-world cohort studies comparing overdose and hospitalisation rates between GLP-1 RA users and non-users. 3. Neuroscience literature describing GLP-1 receptor activity in reward-related brain regions. Results: Multiple observational studies show associations between GLP-1 RA use and reduced substance-related harms. In a Swedish cohort of 227,866 individuals with AUD, semaglutide was associated with reduced alcohol-related hospitalisations (Lähteenvuo 2024). US data (>500,000 OUD, >800,000 AUD patients) showed lower opioid overdose and alcohol intoxication rates among GLP-1 RA users (Qeadan 2024; Wang 2024). All current human findings are observational, but several human randomised controlled trials are now underway, including trials of semaglutide and exenatide for AUD, semaglutide for cocaine use disorder, and liraglutide for nicotine dependence. The overlap between metabolic and addiction pathways may explain these associations, as GLP-1 signaling modulates reward processing relevant to both food intake and substance use. Preclinical studies demonstrate GLP-1R-mediated reduction in substance self-administration via reward pathway modulation in VTA, NAcc, and PFC. While this provides biological plausibility, observational human data cannot establish causality, and RCT evidence is needed. Conclusion: Observational data suggest potential associations between GLP-1 RA use and reduced substance-related harms, but cannot establish causality due to confounding. Before clinical application, essential research includes: (1) completion of ongoing RCTs with addiction-specific outcomes, (2) safety and tolerability evaluation in actively substance-using populations, including assessment of nausea/vomiting risks and drug interactions with methadone, buprenorphine, and benzodiazepines, (3) adherence and implementation feasibility studies in populations with chaotic substance use, and (4) health economics modeling. Psychiatrists should monitor emerging trial results critically as this evidence base develops in the coming years.
2026-04-19 | Substrate specificity and in vivo efficacy of engineered cocaine esterases toward cocaine and its toxic metabolites.
Cocaine abuse remains a significant global public health challenge, yet no specifically approved pharmacotherapies are currently available. While enzyme-based strategies offer promise, an effective treatment must address not only cocaine but also its major active and/or toxic metabolites-benzoylecgonine, norcocaine, and cocaethylene, several of which exhibit greater toxicity than cocaine itself. Here, we report for the first time that two engineered cocaine esterases, E196-301 and BZEase2, are capable of hydrolyzing cocaine and its three toxic metabolites. By integrating molecular modeling with comprehensive in vitro kinetic analysis and in vivo efficacy studies, we demonstrate that these enzymes possess distinct yet complementary substrate selectivity: E196-301 efficiently catalyzes the hydrolysis and clearance of cocaine, norcocaine, and cocaethylene, whereas BZEase2 preferentially degrades benzoylecgonine. Both enzymes conferred significant therapeutic benefits in rodent models of acute cocaine-metabolite exposure and cocaine-alcohol co-administration, though neither alone achieved complete detoxification against cocaine and its toxic metabolites under the tested conditions. Their complementary substrate profiles suggest combining E196-301 and BZEase2 or engineering next-generation broad-spectrum hydrolases may offer a rational strategy for comprehensive detoxification across the full spectrum of cocaine-related toxins. This work establishes a critical foundation for enzyme-based therapy targeting cocaine's multifaceted toxicology.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Cocaine intoxication.
2 orphan drug designations for Cocaine intoxication.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Alpha-1-acid glycoprotein | proteins | FDA | 2004-03-05 | — | Bio Products Laboratory |
Butyrylcholinesterase | proteins | FDA | 1992-03-25 | — | Shire Laboratories Inc. |
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