Stimulant storm - state health department psychostimulant age-adjusted mortality rate correlates with psychostimulant-based Michigan Poison Center case exposures over time.

BACKGROUND: Deaths attributable to psychostimulants with abuse potential have increased in the United States (US) in recent years. Methamphetamine use, in particular, has risen sharply. We evaluated the correlation between amphetamine- and methamphetamine-related case exposures reported to the Michigan Poison Center (MiPC) coinciding with psychostimulant age-adjusted mortality rates from the Michigan Department of Health and Human Services (MDHHS). METHODS: We compared amphetamine and methamphetamine exposures reported to the MiPC from 2012 to 2018, queried from ToxSentry® database, to MDHHS reports on resident death certificates with attributed death due to "overdose, regardless of intent" and related cause of death attributed to psychostimulants with abuse potential. Linear regression assessed goodness-of-fit. Slope with standard error and adjusted R2 were reported. Psychostimulants included methamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), dextroamphetamine, levoamphetamine, and methylphenidate. RESULTS: Psychostimulant deaths reported by MDHHS increased from 17 to 165 between 2012 and 2018. The average age-adjusted rate of psychostimulant-involved overdose deaths per 100,000 state residents rose from 0.2 to 1.8. Linear regression of MiPC amphetamine exposure rates with state health department-reported age-adjusted psychostimulant mortality rates yielded a slope of 1.93, SE 0.5, p value 0.035, and adjusted R2 0.55. Linear regression of MiPC methamphetamine exposure rates with state health department-reported age-adjusted psychostimulant mortality rates yielded a slope of 0.78, SE 0.27, p value 0.012, and adjusted R2 0.70 suggesting a strong correlation. CONCLUSION: Psychostimulant use and associated deaths in the US are increasing, representing an evolving public health threat. Michigan demonstrates consistency with national trends and data from the MiPC correlates strongly with state-reported age-adjusted psychostimulant mortality rates. Strengthening collaboration between poison centers and state health departments is critical for detection and mitigation efforts and can thereby inform resource allocation.

Use of cognitive enhancers: methylphenidate and analogs.

OBJECTIVE: In the last decades, several cognitive-enhancing drugs have been sold onto the drug market. Methylphenidate and analogs represent a sub-class of these new psychoactive substances (NPS). We aimed to review the use and misuse of methylphenidate and analogs, and the risk associated. Moreover, we exhaustively reviewed the scientific data on the most recent methylphenidate analogs (methylphenidate and ethylphenidate excluded). MATERIALS AND METHODS: Literature search was performed on methylphenidate and analogs, using specialized search engines accessing scientific databases. Additional reports were retrieved from international agencies, institutional websites, and drug user forums. RESULTS: Methylphenidate/Ritalin has been used for decades to treat attention deficit disorders and narcolepsy. More recently, it has been used as a cognitive enhancer and a recreational drug. Acute intoxications and fatalities involving methylphenidate were reported. Methylphenidate was scheduled as an illegal drug in many countries, but NPS circumventing the ban and mimicking the psychostimulant effects of methylphenidate started being available: ethylphenidate, 3,4-dichloromethylphenidate, 3,4-dichloroethylphenidate, 4-fluoromethylphenidate, 4-fluoroethylphenidate, methylnaphthidate, ethylnaphthidate, isopropylphenidate, propylphenidate, 4-methylmethylphenidate, and N-benzylethylphenidate have been available in the past few years. Only little data is currently available for these substances. Many intoxications involving methylphenidate analogs were reported. To date, ethylphenidate was involved in 28 fatalities, although it was reportedly directly related to the cause of death in only 7 cases; 3,4-dichloroethylphenidate was involved in 1 death. CONCLUSIONS: The rapid expansion of methylphenidate analogs onto the drug market in the past few years makes likely the occurrence of intoxications and fatalities in the next years. Careful monitoring and systematic control of methylphenidate analogs should be undertaken to reduce the uprising threat, and education efforts should be made among high-risk populations.

New drug controls and reduced hospital presentations due to novel psychoactive substances in Edinburgh.

AIMS: Recreational use of novel psychoactive substance (NPS) has become increasingly common. We aimed to assess the association of national legislation and local trading standards activity with hospital presentations. METHODS: We established observational cohorts of patients with recreational drug toxicity presenting to Edinburgh Royal Infirmary and dying with detectable recreational drugs in Edinburgh. We assessed associations with two temporary class drug-orders (April 2015: methylphenidates, Nov 2015: methiopropamine), the Psychoactive Substances Act (June 2016), and trading standards forfeiture orders (October 2015). RESULTS: The methylphenidate temporary class drug-order was associated with rapid 46.7% (P = 0.002) and 21.0% (P = 0.003) reductions in presentations and admissions, respectively, for NPS drug toxicity, comparing 12 months before with 6 months after. The change was greatest for ethylphenidate toxicity (96.7% reduction in admissions, P < 0.001) that was partly offset by a tripling in synthetic cannabinoid receptor agonist cases (P < 0.001) over the next 6 months. This increase reversed following trading standards activity removing all NPS drugs from local shops in October 2015, associated with 64.3% (P < 0.001) and 83.7% (P < 0.001) reductions in presentations and admissions, respectively, for all NPS drugs over the next 12 months. The effect was sustained and associated with a reduced postmortem detection of stimulant NPS drugs. The two interventions prevented an estimated 557 (95% confidence interval 327-934) NPS admissions during 2016, saving an estimated £303 030 (£177 901-508 133) in hospital costs. CONCLUSIONS: We show here that drug legislation and trading standards activity may be associated with effective and sustained prevention. Widespread adoption of trading standards enforcement, together with focused legislation, may turn the tide against these highly-damaging drugs.

ADHD medication overdose and misuse: the NSW Poisons Information Centre experience, 2004-2014.

OBJECTIVES: To describe Australian trends in overdoses with medications used to treat attention deficit hyperactivity disorder (ADHD). DESIGN, SETTING AND PARTICIPANTS: This was a retrospective observational study of intentional exposures to methylphenidate, dexamphetamine, modafinil and atomoxetine reported to the New South Wales Poisons Information Centre (NSWPIC) from 1 January 2004 to 31 December 2014. The NSWPIC takes calls from New South Wales, Tasmania and the Australian Capital Territory between 6 am and midnight each day, and, as part of a national after-hours roster, from all Australian states between midnight and 6 am on seven nights each fortnight. The target population included Australian residents aged 10-75 years. MAIN OUTCOME MEASURES: Demographic characteristics of the patients, changes in numbers of exposures with time, co-ingestants, route of exposure, and disposition of patients. RESULTS: During the 11-year study period, 1735 intentional exposures to the four medications were reported to NSWPIC. There was a 210% increase in intentional exposures to methylphenidate over this period, whereas the number of dexamphetamine exposures declined by 25%. Illicit use (defined as co-ingestion with alcohol or a street drug) increased by 429% across the study period. At least 93% of overdose patients required hospitalisation. Trends in exposures paralleled trends in the dispensing of these medications, as recorded in Pharmaceutical Benefits Scheme data. CONCLUSIONS: NSWPIC data show a dramatic increase in intentional exposures to ADHD medications between 2004 and 2014, mainly to methylphenidate. Further, the data suggest that illicit use of these substances is increasing. The potential harm related to misuse of prescription stimulants and the close correlation between these exposures and the prescribing of these drugs causes concerns about their diversion, and highlights the importance of the quality use of medicines (ie, ensuring that they are used safely, appropriately and in an evidence-based manner, including considering non-medical or non-stimulant alternatives) and of risk assessment for misuse when prescribing ADHD drugs.

Seven fatalities associated with ethylphenidate.

Ethylphenidate is a stimulant novel psychoactive substance that is an analogue of the prescription drug methylphenidate (Ritalin(®)). Methylphenidate is used commonly for the treatment of attention deficit hyperactivity disorder. Due to its stimulant effects ethylphenidate is being abused. There is a single case report of a death associated with ethylphenidate in Germany, and a case series of 19 deaths in the East of Scotland, but otherwise, the contribution of ethylphenidate to death is poorly documented. We report the analytical results of 7 cases (between February 2013 and January 2015) in which ethylphenidate was detected and quantitated with a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The individuals (all male) ranged in age from 23 to 49 years (median 25 years). The concentration of ethylphenidate in the cases ranged from 0.026mg/L to 2.18mg/L in unpreserved post-mortem femoral blood. Only one case had ethylphenidate present as a sole drug. All other cases had at least 2 other drug classes present (benzodiazepines, heroin, methadone antipsychotics, other new psychoactive compounds). Ethylphenidate toxicity was the sole contribution to the cause of death in one case. Hanging was the cause of death in 2 cases, with the other 4 cases being reported as having occurred due to mixed drug toxicity. These data will further help with the interpretation of post-mortem ethylphenidate levels.

Methylphenidate intoxications in children and adults: exposure circumstances and evidence-based dose threshold for pre-hospital triage.

CONTEXT: Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. OBJECTIVE: We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). METHODS: In a prospective follow-up study, we analysed 364 consecutive methylphenidate exposures that were reported to the Dutch Poisons Information Center. Patients and/or physicians were surveyed by telephone using standardized questionnaires. Three physicians independently scored the observed severity of the intoxication of each patient as 'no/mild' (observation at home) or 'moderate/severe' (hospital referral necessary). RESULTS: Unintentional exposures (40%) mostly occurred at home involving the patients' own medication or those from a family member. Compared to unintentionally exposed patients, intentionally exposed patients were exposed to relatively high methylphenidate doses (3.1 vs 1.6 mg/kg), more often used immediate release methylphenidate formulations (62 vs 34%) and more frequently had concomitant exposures (71 vs 17%). Severe symptoms like convulsions or coma were reported only in patients with concomitant exposures. Following exposure to methylphenidate only (i.e. no concomitant exposures), the most commonly reported symptoms were dry mucosa, headache, agitation, sleepiness and tachycardia. Our results show that the reported methylphenidate dose is predictive of the observed severity of the intoxication and can therefore aid in pre-hospital triage. CONCLUSION: We increased our current dose threshold for hospital referral from 2 to 3 mg/kg. In addition, we will refer patients at lower doses when clinical symptoms indicate the need for hospital referral. Application of this new dose threshold optimizes triage, thereby reducing unnecessary hospital referral and thus costs, without jeopardising patient safety.

Methylphenidate misuse in adult patients and the impact of therapeutic use.

OBJECTIVE: Methylphenidate (MPH) prescription rates for adults increase, but the extent of a parallel rise in toxic exposures and their causes and distribution between different MPH trade names are unexplored. METHOD: We retrospectively analyzed adult MPH exposures reported to the Danish Poison Information Centre from January 2006 to July 2012 and the association with MPH sales and the number of patients prescribed MPH. RESULTS: Of the 394 exposures (57% males, median age 27 years) reported, MPH status was available in 249 of whom 65.5% were prescribed MPH. Exposure was in 54% motivated by suicidal attempt and in 40% by recreational use (based on 375 cases). Exposure was dominated by one trade name and exposure incidence correlated significantly with sales ( p = 0.001) and prevalence of MPH-treated patients ( p = 0.0008). CONCLUSIONS: The increase in MPH exposures parallels the prescription rates (particularly Ritalin(®)/Ritalin(®) Uno). Most exposures were intentional and motivated by suicide attempts or recreational use.

Fatal oral methylphenidate intoxication with postmortem concentrations.

Methylphenidate (MPD) is a widely prescribed stimulant used primarily for the treatment for attention-deficit/hyperactivity disorder (ADHD). Suicide attempts involving MPD ingestion have been well described; however, deaths attributed solely to MPD ingestion have not been reported. A 62-year-old woman was found dead on her floor. The only discrepancy in among her medication quantities was that >three hundred 10 mg MPD tablets were missing. Analysis utilizing gas chromatography-mass spectrometry revealed elevated postmortem MPD peripheral and central blood, liver and vitreous humor concentrations. Considering both the central blood to peripheral blood ratio (0.89) and the liver to peripheral blood ratio (3.3), MPD does not appear subject to significant postmortem redistribution. With no other identifiable cause of death, we report what appears to be the first isolated MPD ingestion associated with a fatality.

Dexmedetomidine in a child with methylphenidate intoxication.

Methylphenidate intoxication, due to accidental ingestion, is a common occurrence in pediatrics. Symptoms of extreme agitation are typically controlled with benzodiazepines or barbiturates. There is, however, a legitimate risk of mechanical ventilation due to respiratory depression with increasing doses of benzodiazepines. The authors describe a case of 7-y-old girl with methylphenidate toxicity where dexmedetomidine was successfully used to manage agitation and cardiovascular stimulation without respiratory compromise.

Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets.

BACKGROUND: Non-medical use of methylphenidate is increasing. Little is known about potential acute medical complications associated with recreational use of methylphenidate. STUDY AIM: To identify medical problems associated with methylphenidate abuse. METHODS: Retrospective case series of methylphenidate abuse cases presenting to an inner city emergency department. RESULTS: We identified 14 cases of methylphenidate abuse between 2003 and 2010. Ten of these patients abused methylphenidate alone while four co-ingested other drugs, mainly alcohol. The route of ingestion was oral in nine patients, nasal in one and intravascular in four. Severe toxicity was exclusively observed in users who injected the drug. Two cases involved accidental intra-arterial injection and resulted in tissue necrosis leading to the amputation of a forearm and of fingertips, respectively. Clinical findings in the non-serious cases included mild to moderate symptoms and signs of sympathetic nervous stimulation such as agitation, tachycardia, hypertension, anxiety, hallucination, headache, tremor and dizziness. Nine of the fourteen patients were taking methylphenidate as a prescribed drug. Eight patients were former or current multiple substance abusers. CONCLUSION: Methylphenidate misuse is not a significant burden for emergency departments in Switzerland. Oral and nasal administration of methylphenidate did not result in severe toxicity. However, injection of crushed methylphenidate pills lead to serious local toxicity. Most patients with methylphenidate abuse had a prescription for the drug indicating deviation from medical use. A history of multiple substance use may be a risk factor for non-medical use of methylphenidate.

Methylphenidate toxicosis in dogs: 128 cases (2001-2008).

OBJECTIVE: To determine clinical signs and outcomes of methylphenidate hydrochloride (MPH) toxicosis in dogs; to assess effects of amount (ie, dose) and formulation (immediate or extended release) of ingested MPH on onset, duration, and severity of clinical signs; and to describe management of MPH intoxication. DESIGN: Retrospective case series. ANIMALS: 128 dogs with MPH toxicosis or exposure. PROCEDURES: Data from an Animal Poison Control Center (APCC) database from November 1, 2001, to November 30, 2008, were reviewed. Records of dogs were searched for APCC classifications of confirmed (n = 71) or suspected (39) MPH toxicosis; dogs (18) that ingested MPH but did not develop clinical signs of toxicosis were also included. Signalment, dose, clinical signs, treatment, and outcome were evaluated. RESULTS: Clinical signs of toxicosis were reported in 107 of 128 (84%) dogs that ingested MPH; these included hyperactivity in 42 (33%), tachycardia in 27 (21%), vomiting in 19 (15%), agitation in 16 (13%), and hyperthermia in 13 (10%). Doses ranged from 0.36 mg/kg (0.164 mg/lb) to 117.0 mg/kg (53.18 mg/lb). Severity of clinical signs was not strongly associated with dose. More severe and prolonged clinical signs were associated with ingestion of extended-release formulations of MPH; 3 dogs that consumed these formulations (doses, 10.2 mg/kg [4.64 mg/lb], 15.4 mg/kg [700 mg/lb], and 31.1 mg/kg [14.14 mg/lb]) died. Favorable outcomes were reported for most (31/34 [91%]) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Ingestion of even small amounts of MPH can cause severe clinical signs in dogs. Monitoring and supportive care are recommended regardless of dose.

Electrocardiographic effects of methylphenidate overdose.

OBJECTIVES: Stimulants used in the management of attention-deficit hyperactivity disorder have been associated with an increased risk of sudden cardiac death. One mechanism could involve drug-induced repolarization delay, reflected as prolongation of the QT interval on the electrocardiogram, which has been described in some recipients of methylphenidate in therapeutic doses. Because QT prolongation is usually dose-related, this study was performed to investigate effects of methylphenidate overdose on the QT interval. METHODS: Adults with methylphenidate overdose identified retrospectively were matched for sex and heart rate with a control subject with overdose of a noncardiotoxic substance, mainly acetaminophen. Notes were reviewed for clinical details and coingestants. Admission 12-lead electrocardiograms were individually calibrated and analyzed using a manual digitizer in a blinded manner by a single investigator. Mean QRS and QT intervals were calculated and differences between groups were analyzed. RESULTS: Twenty-three cases of methylphenidate overdose (median reported dose 120 mg, range 40-1,500 mg) were identified (10 males, 13 females, mean age 27.8 years). There were multiple coingestants. Level of consciousness and mean hemodynamic variables were within normal limits for all cases. Symptoms recorded in cases included anxiety (32%), dilated pupils (20%), abdominal pain (16%), vomiting (12%), palpitations (12%), and chest pain (8%). No arrhythmias were recorded. Mean heart rate was 92.4/min in methylphenidate cases and 93.8/min in the heart rate-matched controls. There were no significant differences between the groups in mean QRS (cases 86.1, controls 86.2, mean difference 0.1, 95% confidence interval = -5.1 to 5.0 ms) or mean QT intervals (cases 354, controls 355, mean difference -0.8, 95% confidence interval = -10.7 to 9.2 ms). CONCLUSIONS: Methylphenidate overdose is unlikely to have substantial effects on the QRS or QT intervals.

A case of suicide attempt with long-acting methylphenidate (Concerta).

The prescribed use of methylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD) is widespread. The intranasal and parenteral abuse of methylphenidate (Ritalin) among teenagers is becoming increasingly more common, and deaths have been reported. Newer medical treatment options of long-acting stimulants offer effective treatment with a lower risk of abuse potential. We describe a case of a 17-year-old girl who had attempted suicide by ingesting 270 mg of Concerta. During the third years of treatment with Concerta, parents of patient reported that the patient had a depressive mood in the last week, and had attempted suicide with five tablets of Concerta 54 mg. She was sent to a local hospital with a diagnosis of long-acting methylphenidate overdose. All of vital and laboratory findings were normal except heart rate, which was 132 beats/min. Since more than 3 h have elapsed after the time of ingestion, activated charcoal administration was not carried out at the hospital. She was only observed for 12 h at the emergency department and later discharged from the hospital. While long-acting stimulants offer lower risk of abuse, their greater availability increases the likelihood of ingestion of this nature. Education of clinicians and families to be aware of this risk should reduce the frequency of this complication of treatment.

Case report: intoxication with high dose of long-acting methylphenidate (Concerta(®)) in a suicidal 14-year-old girl.

A 14-year-old girl with suicidal ideation was presented to the paediatric hospital about 2 h after ingestion of 21 long-acting methylphenidate (MPH) 54-mg tablets (1,134 mg Concerta(®)). At admission signs of sympathomimetic syndrome were observed like agitation, visual hallucinations, slight hypertension, and sinus tachycardia. Treatment included prevention of absorption (30 g activated charcoal orally) and careful observation related to the overstimulation of the sympathic system. Despite the intake of charcoal, the serum concentrations of MPH were 107 and 93 ng/ml 2.5 and 22 h after ingestion of MPH tablets. No support of vital functions was necessary. The girl made a full recovery and was discharged after 3 days of care at the paediatric clinic and referred to the child and adolescent psychiatric department. Exposure to a huge overdose of long-acting MPH exhibited acute sympathomimetic toxicity but no life-threatening symptoms in this patient. Thus this case report suggests that patients intoxicated with high dose long-acting MPH formulations can recover without sequelae when managed properly.

Methylphenidate poisoning: an evidence-based consensus guideline for out-of-hospital management.

A review of US poison center data for 2004 showed over 8,000 ingestions of methylphenidate. A guideline that determines the conditions for emergency department referral and prehospital care could potentially optimize patient outcome, avoid unnecessary emergency department visits, reduce health care costs, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with suspected ingestions of methylphenidate by 1) describing the process by which a specialist in poison information should evaluate an exposure to methylphenidate, 2) identifying the key decision elements in managing cases of methylphenidate ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This review focuses on the ingestion of more than a single therapeutic dose of methylphenidate and the effects of an overdose and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) In patients without evidence of self-harm, abuse, or malicious intent, poison center personnel should elicit additional information including the time of the ingestion, the precise dose ingested, and the presence of coingestants (Grade D). 3) Patients who are chronically taking a monoamine oxidase inhibitor and who have ingested any amount of methylphenidate require referral to an emergency department (Grade D). 4) Patients experiencing any changes in behavior other than mild stimulation or agitation should be referred to an emergency department. Examples of moderate to severe symptoms that warrant referral include moderate-to-severe agitation, hallucinations, abnormal muscle movements, headache, chest pain, loss of consciousness, or convulsions (Grade D). 5) For patients referred to an emergency department, transportation via ambulance should be considered based on several factors including the condition of the patient and the length of time it will take for the patient to arrive at the emergency department (Grade D). 6) If the patient has no symptoms, and more than 3 hours have elapsed between the time of ingestion and the call to the poison center, referral to an emergency department is not recommended (Grade D). 7) Patients with acute or acute-on-chronic ingestions of less than a toxic dose (see recommendations 8, 9, and 10) or chronic exposures to methylphenidate with no or mild symptoms can be observed at home with instructions to call the poison center back if symptoms develop or worsen. For acute-on-chronic ingestions, the caller should be instructed not to administer methylphenidate to the patient for the next 24 hours. The poison center should consider making a follow-up call at approximately 3 hours after ingestion (Grade D). 8) Patients who ingest more than 2 mg/kg or 60 mg, whichever is less, of an immediate-release formulation (or the equivalent amount of a modified-release formulation that has been chewed) should be referred to an emergency department (Grade C). 9) If a patch has been swallowed, consider the entire contents of the patch (not just the labeled dose of the patch) to have been ingested. Patients who ingest more than 2 mg/kg or 60 mg, whichever is less should be referred to an emergency department. If it is known that the patch has been chewed only briefly, and the patch remains intact, significant toxicity is unlikely and emergency department referral is not necessary (Grade D). 10) Patients who ingest more than 4 mg/kg or 120 mg, whichever is less, of an intact modified-release formulation should be referred to an emergency department (Grade D). 11) For oral exposures, do not induce emesis (Grade D). 12) Pre-hospital activated charcoal administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activate charcoal (Grade D). 13) Benzodiazepines can be administered by EMS personnel if agitation, dystonia, or convulsions are present and if authorized by EMS medical direction expressed by written treatment protocol or policy or direct medical oversight (Grade C). 14) Standard advanced cardiac life support (ACLS) measures should be administered by EMS personnel if respiratory arrest, cardiac dysrhythmias, or cardiac arrest are present and if authorized by EMS medical direction expressed by written treatment protocol or policy or direct medical oversight (Grade C).