Serotonin toxicity involving MDMA (ecstasy) and moclobemide.

The use of MDMA (ecstasy) in Australia is a widespread and growing problem, promoting acute toxicity and disease which can lead to premature death in users. We report four cases of fatal serotonin toxicity caused by the combination of MDMA and moclobemide, a reversible MAO-A inhibitor with potent serotonergic activity. Despite the highly reported toxicity of this drug combination, there are very few reports of fatalities attributed to a MDMA and moclobemide interaction. Pathology and toxicology reports, initial police reports and coroners' findings were examined to determine the circumstances of the deaths. Symptoms of some of the four cases as reported by paramedics and medical staff included hyperthermia, hyperkalemia, profuse sweating, twitching and shaking. Two cases involved moclobemide concentrations consistent with common prescribed doses, while the other two cases involved much higher concentrations often associated with toxicity. Three of these cases presented with some form of heart disease.

Deaths involving MDMA and the concomitant use of pharmaceutical drugs.

The increasing use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and tendency of users to combine MDMA with pharmaceutical agents (especially serotonergic medication) warrants a thorough understanding of MDMA's toxicity profile and potential for drug interactions. This study examined the involvement of MDMA and concurrently administered pharmaceutical drugs in cases reported to the Victorian State Coroner. The National Coroners Information System was used to conduct a comprehensive search and examination of all closed cases between 2002 and 2008 where MDMA was detected. Pathology, toxicology, and Coroners' findings were considered in all cases. In all, 106 fatalities were identified, of which 43 (41%) cases involved the concomitant use of MDMA with other drugs, including pharmaceuticals that were likely to result in an adverse drug reaction or varying risks (4 high-risk cases involved moclobemide and MDMA, in addition to 10 moderate-risk cases, and 5 minor-risk cases). These findings highlight the importance of recognizing and publicizing potential drug interactions between MDMA and pharmaceutical preparations that may result in lethal toxicity, in particular serotonin toxicity.

Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects.

The field of pharmacogenetics contains a wealth of potential for the enhancement of clinical practice by providing a more effective match between patient and drug, consequently reducing the probability of an adverse drug reaction. Although a relatively novel concept in the forensic context, pharmacogenetics has the capability to assist in the interpretation of drug related deaths, particularly in unintentional drug poisonings where the cause of death remains unclear. However, the complex pharmacology of the drugs when subjected to genetic variations in metabolism makes interpretation of the expected response and adverse events difficult. Many possess multiple metabolic pathways, narrow therapeutic indices and active metabolites or enantiomers which may be eliminated via different pathways to the parent drug. A number of these drugs, which are metabolised primarily by the CYP450 system, are also associated with serotonin syndrome, or serotonin toxicity, especially when used concomitantly with other serotonin active drugs which rely on the same metabolic pathways for drug elimination. A comprehensive understanding of polymorphic drug metabolism and its expected outcomes is therefore essential when interpreting the involvement of drugs in adverse reactions. This review examines the genetically variable CYP450-mediated metabolism of a number of serotonin-active drugs that are often implicated in cases of serotonin toxicity, to assess the impact of pharmacogenetics on drug metabolism, response, interactions and adverse effects.

Deaths involving serotonergic drugs.

Serotonin-active drugs are detected relatively frequently in Victorian deaths. During 2002-2008, there were 1123 fatalities where one or more of the serotonin-active drugs tramadol, venlafaxine, fluoxetine, sertraline, citalopram, paroxetine and MDMA, were detected. These deaths were reviewed using pathology, toxicology and police reports, to determine the contribution of these drugs to the cause of death, particularly if serotonin toxicity was the mechanism of death. There were 28 cases of most interest to this research because of the presence of the target drugs and the circumstances suggesting the likelihood of serotonin toxicity involvement in death. There were 5 cases of reported serotonin toxicity and 23 other deaths suspected to have involved this form of toxicity. Tramadol featured most commonly out of the seven target drugs and was frequently detected in combination with serotonergic antidepressants. MDMA was also detected relatively commonly and was associated with moclobemide in 4 cases of confirmed serotonin toxicity. There were an additional 1095 cases where natural disease, external injury or the misuse of other drugs caused death, of which 2 reported the incidental contribution of serotonin toxicity.