Methylphenidate and (lis)dexamfetamine toxicity‐related deaths of adults, Australia, 2000–24: analysis of <scp>NCIS</scp> data

The stimulants methylphenidate, dextroamfetamine, and lisdexamfetamine are prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in adults.1-4 The prescribing of ADHD medications has increased notably since 2000,2 and, while they are considered to have good safety profiles, the number of poisonings in Australia has also increased.3, 4 Few reports on fatal poisonings with these drugs in adults have been published.5-8 We therefore conducted a retrospective observational study of deaths in Australia of people aged 15 years or older in which methylphenidate or (lis)dexamfetamine toxicity was implicated. We searched records in the National Coronial Information System (NCIS), a database of medico-legal death investigation records provided by the coroners’ courts of each Australian jurisdiction; all suspected drug overdose deaths in Australia must be reported to coroners for investigation. We included all closed cases (deaths in which the coronial process had been completed) of deaths during 1 January 2000 – 30 July 2024 in which methylphenidate was listed in the NCIS drug coding fields set as contributing to death. These fields code for external factors that contributed to death according to the coronial investigation. We also searched records for “ADHD”, “dexamphetamine”, “lisdexamphetamine”, and “dextroamphetamine”, as well as for their registered brand names. The Justice Human Research Ethics Committee (M0063) and the University of New South Wales Human Research Ethics Committee (HC220754) approved the study. Our report conforms with STROBE (Supporting Information) guidelines for observational study reports.9 We identified 64 deaths in which ADHD medications were implicated: 41 methylphenidate-related, 23 (lis)dexamfetamine-related. The mean age at death was 38.2 years (standard deviation, 10.7 years); 45 were men. Substance use problems were documented in 45 cases. Evidence from witnesses or the death scene indicated probable injection of the drug as the terminal event in 18 cases. ADHD diagnoses were documented for 37 people, other mental health problems for 44 people. Fifty-one deaths were deemed unintentional. In 49 cases, death was attributed to polysubstance toxicity; the most frequent clinical presentation form was sudden collapse (20 cases) (Box 1). Blood toxicology results that covered all major drug classes were available for 63 of 64 deaths. In no case was there evidence for use of both methylphenidate and (lis)dexamfetamine by an individual. In the cases in which they were detected, the median methylphenidate concentration was 0.06 mg/L (interquartile range [IQR], 0.03–0.20 mg/L; range, 0.01–2.50 mg/L); the median amfetamine concentration was 0.11 mg/L (IQR, 0.03–0.40 mg/L; range 0.01–1.20 mg/L). Other drugs were detected in 57 cases, most frequently sedative–hypnotics (35 cases: 33 benzodiazepines, two Z-class hypnotics) and antidepressants (32 cases) (Box 2). Autopsy reports were available for 47 cases. Cardiomegaly (heart weight exceeding the 95th percentile of normal weight range) was evident in twelve people (eight of 28 methylphenidate-related deaths, four of 19 (lis)dexamfetamine-related deaths) and severe coronary artery disease in 17 (eleven methylphenidate-related deaths, six (lis)dexamfetamine-related deaths). We identified 64 AHDH medication-related deaths in Australia during 2000–24. As methylphenidate was dispensed 1 270 397 times and (lis)dexamfetamine 2 001 934 times during 2023 alone,10 recorded ADHD medication toxicity-related deaths were rare. About 20% of the deaths were intentional, a proportion similar to those in other reports on stimulant poisoning in Australia,3, 4 and mental health or substance use problems were each recorded for about 70% of the people who died. Blood methylphenidate and amfetamine concentrations each ranged across two orders of magnitude. Reported blood concentrations in stimulant-related deaths in other studies ranged between 0.05 and 3 mg/L for methylphenidate and 0.5 to more than 40 mg/L for amfetamine.1, 5, 8 Drugs other than ADHD medications were detected in 49 cases; the concomitant use of other drugs can increase the toxicity risk of ADHD medications.3, 4, 11 The small number of deaths we identified provides reassurance that ADHD medications have a relatively good safety profile. There are, however, people for whom greater caution is warranted, including those with histories of substance misuse or of mental health problems. People who use these medications need to be warned about the risk of polypharmacy. Given that psychostimulants may exacerbate cardiovascular disease, and that evidence of such disease was frequently recorded at autopsy in the cases we reviewed, people with cardiovascular disease may require closer monitoring. Our series did not include deaths for which the coronial process was not yet complete. While all suspected fatal drug overdoses must be reported to coroners for investigation and will be recorded in the NCIS, some deaths may not have been reported. Clinical histories were restricted to details documented in NCIS case files. Blood drug concentrations at the time of death or hospital admission may not be the peak concentrations. Toxicological analysis may not have detected new psychoactive substances. Finally, assessment of intent is difficult in all studies of mortality; classification as self-harm was based upon the NCIS code for “intentional self-harm”. In summary, we identified 64 deaths of adults in which the ingestion of methylphenidate, dextroamfetamine, or lisdexamfetamine was deemed to be a contributory factor; in 20% of cases, the death was judged to be intentional. In 78% of cases, people had ingested more than one drug, and 70% of people had known substance use problems. This study was funded by the National Drug and Alcohol Research Centre at the University of New South Wales. The Centre is funded by the Australian Department of Health and Aged Care. We acknowledge the Victorian Department of Justice and Community Safety as the source organisation for the data we analysed and the National Coronial Information System as the data source. We thank the staff at the National Coronial Information System. Amy Peacock is funded by a National Health and Medical Research Council Investigator Fellowship (1174630). Open access publishing facilitated by the University of New South Wales, as part of the Wiley – University of New South Wales agreement via the Council of Australian University Librarians. Amy Peacock has received untied educational grants from Seqirus and Mundipharma for post-marketing surveillance of pharmaceutical opioids; the organisations had no role in study design, analysis, or reporting, and their funding was for work unrelated to this project. Michael Farrell has received untied educational grants from Seqirus, Mundipharma, and Indivior for post-marketing surveillance of pharmaceutical opioids; the organisations had no role in study design, analysis, or reporting, and their funding was for work unrelated to this project. The data upon which the study is based comprise confidential medico-legal documents. Ethics agreements and legal obligations prevent making these data available for sharing. 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