Introduction

Cocaine is one of the psychoactive substances that is used in combination with other drugs. Substance users seek out drug combinations to create a "speedball effect" (1).SAMHSA reported that the number of overdose deaths involving cocaine is increasing in the United States.² Cocaine is a central nervous system (CNS) stimulant drug that affects many systems in the body including cardiovascular, respiratory, central nervous, and renal systems (3). The heart is the most affected organ because of the uncontrolled stimulation of the sympathetic system (4). Although cocaine abuse is not prevalent in Iran due to the high price, studies show that in many other countries, cocaine is a frequently abused substance involved in polydrug abuse (5). There is also evidence that up to 90% of cocaine abusers co-ingest beverages that contain ethanol (6). Polydrug users indicate that cocaine modulates feelings of intoxication and decreases ethanol-induced sedation (7). Both cocaine and ethanol exhibit cardiotoxic effects. Chronic consumption of ethanol leads to progressive cardiomyopathy known as alcoholic heart muscle disease. Cocaine induces cardiovascular abnormalities such as ventricular arrhythmia, ventricular hypertrophy and acute myocardial infarction. Accordingly, co-abuse of ethanol and cocaine produces a toxicokinetic interaction leading to cocaethylene production, which is a toxicologically active metabolite of cocaine formed only in the presence of ethanol (8). This metabolite crosses the blood-brain barrier (BBB) rapidly and shows similar pharmacologic properties to cocaine (9). Considering their individual cardiotoxic effects, it is suggested that cocaine and ethanol are more toxic in combination in comparison to their single drug use.

Polydrug use including especially heroin, cocaine, and methadone, is a prevalent phenomenon in many countries (10). Cocktails of illicit drugs are produced to get desired effects (11). Methadone maintenance treatment (MMT) is widely used as opioid substitution therapy. Many patients undergoing MMT continue to use illicit drugs such as heroin and cocaine in combination with their daily dose of methadone (12). This case report presents a forensic case of polydrug use that was referred to the forensic toxicology department in Tehran, Iran to be investigated from forensic toxicology and pathology points of view. Previous studies on polydrug users have reported toxicity or death due to two or three drugs. However, this case report describes the use of a cocktail of drugs that included at least four substances. Moreover, histopathologic findings of vital organs were inspected in combination with the toxicological investigation.

Case report

An Iranian male subject in his early thirties was found dead in his bed with bleeding around his mouth and nose with no visible injuries. According to his relative's declaration, he participated in a party on the night before his death. Although the subject had received Methadone maintenance treatment (MMT) for two months for heroin cessation, he continued to use heroin in combination with methadone. The daily dose of heroin inhaled by the subject reached about 0.5 g/day and he was also receiving 10 mg/day of methadone syrup. At the scene of death, police found an empty bottle of methadone 25 mg/5 mL beside his bed. The deceased was subsequently transferred to the Department of Forensic Medicine at the Legal Medicine Organization in Tehran for an autopsy to determine the cause of death. Height was 180 cm weight was 114 kg. There were no wounds or injuries. Multiple self-immolation scars were seen on the hands and arms. Sulcus and gyrus of the brain were edematous. Hemorrhage was not observed in the brain parenchyma, stem, and cerebellum. The heart weighed 450 g, and there was thickening of the cardiac walls and moderate to severe atherosclerosis in the left anterior descending artery. Myocardial muscle was reddish and petechial hemorrhages in the myocardium were seen. Pulmonary edema and conjunctival hyperemia were noted. The liver weighed 1600 g, was coarsely granular and showed typical advanced fatty liver. s

Urine, liver, stomach contents and bile samples were prepared using liquid-liquid extraction and dispersive liquid-liquid microextraction (DLLME) prior to analysis. Sample preparation steps were taken using prevalidated methods for systematic toxicological analysis of postmortem specimens (13). Qualitative analyses of postmortem samples were carried out for the detection of alcohol, licit and illicit drugs using gas chromatography/mass spectrometry (GC/MS), headspace gas chromatography/mass spectrometry (HSGC/MS) and headspace gas chromatography (HSGC) (13). Forensic toxicology analysis results are shown in Table 1. Chromatograms and mass spectra of detected analytes are shown in Figures 1-3.

Histologic examination was performed on cardiac, pulmonary and hepatic tissues. Pre-established macroscopic and histological criteria were used for the diagnosis of pathologic features. All tissues were formalin fixed. In order to be stained by hematoxylin and eosin, after fixation, samples were dehydrated in alcohol series and embedded in paraffin wax. All prepared samples were examined under light microscopy for histopathological study based on Kiernan protocol (14). Two pathologists reviewed slides blindly. Any gross and microscopic features of tissues were considered and histologic changes for the case were recorded. The histopathological assessment of heart included the inspection of ventricles, pericardium, endocardium, and coronary arteries. The gross examination of the heart showed a pattern of dilated cardiomyopathy. Cardiovascular pathology was noted in the case. Common histopathologic features were left ventricular hypertrophy, chronic myocardial ischemia, moderate to severe atherosclerosis, acute myocardial infarction, hemorrhagic pulmonary edema, diffuse alveolar collapse, micro-vesicular steatosis, focal hepatocyte necrosis, chronic hepatitis and steatohepatitis.

Discussion

Polysubstance use is a common occurrence among substance abusers and often includes cocaine (15). Side effects of mixing drugs with each other can be severe (16). Cocaine exerts its psychostimulant activity via the inhibition of presynaptic reuptake of noradrenaline, dopamine and serotonin in the mesocorticolimbic "reward" system.⁹ Cocaine is metabolized to benzoylecgonine and ecgonine methyl ester (17). In the presented case, detection of ethanol, cocaine and cocaethylene in postmortem samples indicated that cocaine and ethanol were used simultaneously. Cocaethylene has a pharmacologic action comparable to cocaine (18). In general, alcohol is often co-abused with psychostimulants such as cocaine and amphetamine type stimulants, opioids like heroin, and cannabis derivatives (16). Heroin was one of the substances used in the presented case. Previous studies suggest that alcohol increases the risk of heroin-related deaths due to pharmacodynamics interactions (19). In addition to well-known pharmacodynamics interactions between heroin and ethanol, which lead to respiratory depression and death, a previous study by Thaulow and colleagues showed that heroin has pharmacokinetic interactions with ethanol as well. Heroin converts to 6- monoacetyl morphine (6-MAM) and then morphine in the metabolism pathway. The last metabolite conjugates to glucuronic acid to form morphine-3 glucuronide (M-3 G) and morphine-6 glucuronide (M-6G). Ethanol inhibits the conversion of 6-MAM to morphine and also inhibits the final step to produce M-3 G and M-6 G. Previous studies also supported that heroin and synthetic opioids increase the risk of stimulant-involved deaths (20, 21).

Continued use of illicit drugs during methadone maintenance treatment (MMT) represents a problem and perhaps a failure of MMT. In a three-year study (1996-1998) that was conducted in Switzerland, it was concluded that continued drug abuse by study cases occurred before and during MMT program. Most of the patients had used heroin, cocaine and alcohol simultaneously. The authors stated that becoming chronic alcohol users was more probable in cocaine abusers (12).

In the present case, heart weight was 450 g (standard range for Iranian male population; 359.9 ± 76.6g) (22) and the left ventricle wall was thick. Cardiac complications were noted. Cocaine induced arrhythmia, vasoconstriction, platelet aggregation and acceleration of atherosclerosis have been shown to be potential contributors to cardiac complications (23). Severe cardiotoxic effects of cocaine may be correlated with its short half-life in the body. Its brief effect encourages substance abusers to use multiple doses in a short period of time to enhance the feeling of euphoria. When multiple doses are taken, the heart rate increases significantly. Metabolic detoxification of cocaine is altered in the presence of alcohol and cocaethylene is produced. Takayama et al. reported that cocaine-related sudden death was due to subarachnoid hemorrhage (17).

It is also well known that alcohol is a hepatotoxic agent. Alcohol is likely to increase liver damage when it is used in combination with cocaine due to alcohol-mediated increased activity of cytochrome P-450 and production of hepatotoxic agents such as norcocaine hydrochloride (24). Toxic hepatic manifestations in the present case may be related to the production of norcocaine in the body. Norcocaine is an oxidative metabolite with pharmacologically active properties. Further metabolism of norcocaine converts it to norcocaine nitroxide that exerts hepatotoxic effects in animal models. Combined use of cocaine and alcohol may mediate liver damage due to alcohol mediated activity of cytochrome P-450 (23).Laslo et al. in their review article stated that alveolar hemorrhage has been frequently shown in cocaine abusers. The case in the present study had used heroin. One of the complications in the pulmonary system was pulmonary edema. In line with the results of the present case report Laslo et al. indicated that non-cardiogenic pulmonary edema was categorized as a common manifestation associated with heroin use (24).

Conclusion

Concluding results from the study of this case sustain ethanol and other drugs of abuse-elicited additive exacerbation, its consequences in cocaine-induced cardiac toxicity and the role of poly drug use in inducing death.