Dr. Gustin's Blog

Kraton Products Cause Illness-Heavy Metal Poisoning

Details: Published: Monday, 25 November 2019 12:49

Final results of tests performed by the US Food and Drug Administration (FDA) on 30 kratom products confirm the presence of heavy metals, including lead and nickel, at concentrations not considered safe for human consumption, the FDA said Wednesday.

The FDA first warned of "disturbingly" high levels of heavy metals, including lead and nickel, last November, as reported by Medscape Medical News. The FDA has posted a list of the kratom products and concentrations of heavy metals found in them on its website. Based on reported patterns of kratom use, heavy kratom users may be exposed to levels of lead and nickel many times greater than the safe daily exposure, the FDA warns in a statement.

Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and increased risk of certain cancers, the agency adds.

"Over the last year, the FDA has issued numerous warnings about the serious risks associated with the use of kratom, including novel risks due to the variability in how kratom products are formulated, sold and used both recreationally and by those who are seeking to self-medicate for pain or to treat opioid withdrawal symptoms," FDA Commissioner Scott Gottlieb, MD, said in the statement.

Gottlieb said the FDA has been "attempting to work" with the companies whose kratom products contain high levels of heavy metals. The agency has released the final laboratory results to the public to "help make sure consumers are fully informed of these risks." "The data from these results support our public warning about the risk of heavy metals in kratom products. The findings of identifying heavy metals in kratom only strengthen our public health warnings around this substance and concern for the health and safety of Americans using it," he added.

No Approved Use Kratom is derived from the leaves of the kratom tree (Mitragyna speciosa), which is native to Thailand, Indonesia, and Papua New Guinea. The botanical's popularity has been increasing in the United States, with manufacturers — and those who take it — claiming it can help treat pain, anxiety, depression, and more recently, opioid withdrawal. Last year, an analysis of kratom by FDA scientists found that its compounds act like prescription-strength opioids. In addition to heavy metal contamination, kratom products have also been found to be contaminated with Salmonella, resulting in numerous illnesses and product recalls. Kratom has been linked to numerous deaths in the United States. There are currently no FDA-approved uses for kratom, and the agency has advised against using kratom or its psychoactive compounds mitragynine and 7-hydroxymitragynine in any form and from any manufacturer.

Health providers are encouraged to report any adverse reactions related to kratom products to MedWatch, the FDA's safety information and adverse event reporting program.

Updates on Illicit Drug Overdose

Details: Published: Sunday, 10 November 2019 18:19

Drug overdose remains a significant concern worldwide, with nearly half a million deaths annually. In the United States, drug overdoses are the leading cause of death for adults younger than 55 years. Drug-related deaths now outnumber those attributed to motor vehicle accidents and homicides. According to information from the Centers for Disease Control and Prevention (CDC), the drugs most commonly involved in overdose deaths include opioids (eg, fentanyl, heroin, oxycodone), cocaine, methamphetamines, and benzodiazepines.

Naloxone has been lifesaving in many scenarios, so the CDC recently issued recommendations regarding its use in patients taking opioids. The CDC recommends that clinicians strongly consider prescribing or coprescribing naloxone and providing education about its use in these types of patients taking opioids:

Those who are receiving opioids at a dosage of 50 morphine milligram equivalents per day or greater
Those who have respiratory conditions such as chronic obstructive pulmonary disease or obstructive sleep apnea (regardless of opioid dose)
Those who have been prescribed benzodiazepines (regardless of opioid dose)
Those who have a nonopioid substance use disorder, report excessive alcohol use, or have a mental health disorder (regardless of opioid dose)

The CDC also recommends naloxone in patients who are at high risk for experiencing or responding to an opioid overdose, including the following:

Those known to use heroin or illicit synthetic opioids or misuse prescription opioids
Those using other illicit drugs such as stimulants, including methamphetamine and cocaine
Those receiving treatment for opioid use disorder, including medication-assisted treatment with methadone, buprenorphine, or naltrexone
Those with a history of opioid misuse who were recently released from incarceration or other controlled settings where tolerance to opioids has been lost

Most of the deaths from synthetic opioids are from fentanyl. Most of the increases in fentanyl deaths in recent years do not involve prescription fentanyl but are related to illicitly made fentanyl mixed with or sold as heroin—with or without the users' knowledge—and increasingly sold as counterfeit pills.

In the event of an overdose, pertinent history may be obtained from bystanders, family, friends, or emergency medical services (EMS) providers. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis of opioid toxicity. Occasionally, a trial of naloxone administered by an EMS provider is helpful to establish the diagnosis in the prehospital setting.

Patients with opioid toxicity characteristically have a depressed level of consciousness. Opioid toxicity should be suspected when the clinical triad of central nervous system (CNS) depression, respiratory depression, and pupillary miosis are present. Clinicians must be aware that opioid exposure does not always result in miosis (pupillary constriction), and that respiratory depression is the most specific sign. Drowsiness, conjunctival injection, and euphoria are frequently seen.

Drug screens are widely available but rarely alter clinical management in patients with uncomplicated overdoses. Drug screens are most sensitive when performed on urine. Positive results are observed up to 36-48 hours postexposure, but wide variations are possible depending on test sensitivity, dose, route of opioid administration, and the patient's metabolism. In patients with moderate to severe toxicity, performing these baseline studies is appropriate:

Complete blood cell (CBC) count
Comprehensive metabolic panel
Creatine kinase (CK) level
Arterial blood gas (ABG) determinations

According to American Heart Association guidelines, clear evidence suggests that cocaine can precipitate acute coronary syndrome, and that trying agents that show efficacy in the management of acute coronary syndrome may be reasonable in patients with severe cardiovascular toxicity. Agents that may be used as needed to control hypertension, tachycardia, and agitation include:

Alpha-blockers (eg, phentolamine)
Benzodiazepines (eg, lorazepam, diazepam)
Calcium channel blockers (verapamil)
Morphine
Sublingual nitroglycerin

The American Heart Association does not recommend any one of these agents over another in the treatment of cardiovascular toxicity due to cocaine; however, benzodiazepines are often used as first-line treatment.

Cardiopulmonary complaints are the most common presenting manifestations of cocaine abuse and include chest pain (frequently observed in long-term use or overdose), MI, arrhythmia, and cardiomyopathy. In individuals with cocaine-associated MI, median times to the onset of chest pain vary with the route or form of cocaine use: 30 minutes for intravenous use, 90 minutes for crack, and 135 minutes for intranasal use.

Temperature dysregulation is also a problem with cocaine intoxication. Hyperthermia is a marker for severe toxicity, and it is associated with numerous complications, including renal failure, disseminated intravascular coagulation, acidosis, hepatic injury, and rhabdomyolysis. Dopamine plays a role in the regulation of core body temperature, so increased dopaminergic neurotransmission may contribute to psychostimulant-induced hyperthermia in cocaine users, including those with excited delirium.

No laboratory studies are indicated if the patient has a clear history of cocaine use and mild symptoms.

If a history of cocaine use is absent or if the patient has moderate to severe toxicity, appropriate laboratory tests may include:

CBC count
Electrolytes, blood urea nitrogen, creatinine, and glucose levels (basic metabolic panel)
Glucose level
Pregnancy test
Calcium level
ABG analysis
CK level
Troponin level (cocaine use does not affect the specificity of troponin assays)
Urinalysis
Toxicology screens

Acute and long-term methamphetamine use may lead to abnormal findings on examination of the following organ systems:

Cardiovascular
CNS
Gastrointestinal
Renal
Skin
Dental

There are specific cardiovascular findings associated with acute and long-term methamphetamine use:

Tachycardia and hypertension is frequently observed
Atrial and ventricular arrhythmias may occur
Chest pain from cardiac ischemia and infarction following methamphetamine use has been reported, and patients are at risk because of accelerated atherosclerosis from chronic use; acute aortic dissection or aneurysm has been associated with methamphetamine abuse
Hypotension may be observed with methamphetamine overdose with profound depletion of catecholamines
Acute and chronic cardiomyopathy results directly from methamphetamine cardiac toxicity and indirectly from chronic hypertension and ischemia; intravenous use may result in endocarditis; patients may have dyspnea, edema, and other signs of acute congestive heart failure exacerbation

The euphoric effects produced by methamphetamine, cocaine, and various designer amphetamines are similar and may be difficult to clinically differentiate. A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than that of cocaine.

Methamphetamine can cause significant CNS and psychiatric activation, so patients who present to emergency departments for acute intoxication often require physical restraint and pharmacologic intervention. Hyperactive or agitated patients can be treated with droperidol or haloperidol, which are butyrophenones that antagonize CNS dopamine receptors and mitigate the excess dopamine produced from methamphetamine toxicity. These medications should be administered intravenously, with doses adjusted based on the symptoms. Droperidol has been subject to a black box warning by the US Food and Drug Administration based on concerns of QT prolongation and the potential for torsades de pointes. As a result, some institutions restrict its use. However, it is important to note that the black box warning specifies dementia-related psychosis and is not supported by the literature for doses below 2.5 mg.

If sedation fails to reduce blood pressure, antihypertensive agents such as beta-blockers and vasodilators are effective in reversing methamphetamine-induced hypertension and tachycardia. With regard to choice of beta-blockers, labetalol is preferred because of its combined anti–alpha-adrenergic and anti–beta-adrenergic effects. Labetalol has been shown to safely lower mean arterial pressure in patients with positive cocaine test results. Carvedilol, like labetalol, is a nonselective beta-blocker with alpha-blocking activity and may also be effective for this indication. Esmolol is advantageous because of its short half-life but must be administered via intravenous drip. Metoprolol has excellent CNS penetration characteristics and may also ameliorate agitation.

Oral benzodiazepine overdoses, without co-ingestion of another drug, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality; however, in mixed-drug overdoses, they can potentiate the effect of alcohol or other sedative-hypnotic agents. Overdose of ultrashort-acting benzodiazepines (eg, triazolam) is also more likely to result in apnea and death than overdose with longer-acting benzodiazepines. Of the individual benzodiazepines, alprazolam is relatively more toxic than others in overdose.

Immunoassay screening techniques are most commonly performed when benzodiazepine overdose is suspected. These tests typically detect benzodiazepines that are metabolized to desmethyldiazepam or oxazepam; thus, a negative screening result does not rule out the presence of a benzodiazepine.

As with any overdose, the first step is an assessment of the patient's airway, breathing, and circulation, and any issues should be addressed rapidly. In any patient with an altered mental status, blood glucose level should be checked immediately. The cornerstone of treatment in benzodiazepine overdoses is good supportive care and monitoring. Single-dose activated charcoal is not routinely recommended because the risks far outweigh the benefit. Altered mental status greatly increases the risk of aspiration following an oral activated charcoal dose.

Flumazenil is a competitive benzodiazepine receptor antagonist and the only available specific antidote for benzodiazepines. Its use in acute benzodiazepine overdose is controversial, however, and its risks usually outweigh any benefit. In long-term benzodiazepine users, flumazenil may precipitate withdrawal and seizures; in patients taking benzodiazepines for a medical condition, flumenazil may result in exacerbation of the condition. Flumazenil should not be used in patients with long-term benzodiazepine use or in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsant, or even a possible ingestion of a proconvulsant.

In general, when it is the sole agent used, the clinical presentation of heroin poisoning and its diagnosis hold little challenge for experienced healthcare practitioners. The diagnosis of heroin poisoning should be suspected in all comatose patients, especially in the presence of respiratory depression and miosis.

Respiratory depression, due to heroin's effect on the brain's respiratory centers, is a hallmark sign of overdose. However, the presence of tachypnea should prompt the search for complications of heroin use, such as pneumonia, acute lung injury, and pneumothorax, or an alternative diagnosis, such as shock, acidosis, or CNS injury. Tachypnea may also be seen in overdoses of pentazocine or meperidine.

Symptoms generally develop within 10 minutes of intravenous heroin injection. Patients who survive heroin poisoning commonly admit to using more than their usual dose, using heroin again after a prolonged period of abstinence, or using a more concentrated street sample. Coma, respiratory depression, and miosis are the hallmarks of opioid overdose.

Mild hypotension and mild bradycardia are commonly observed with heroin use. These are attributable to peripheral vasodilation, reduced peripheral resistance and histamine release, and inhibition of baroreceptor reflexes. In the setting of heroin overdose, hypotension remains mild. The presence of severe hypotension should prompt a search for other causes of hypotension, such as hemorrhage, hypovolemia, sepsis, pulmonary emboli, and other causes of shock.

Gastric lavage in the setting of oral heroin overdose is generally not recommended because it has no documented value. Furthermore, gastric lavage is contraindicated in "body packers" and "body stuffers," who have ingested packages of drugs, because the procedure may rupture a package. Activated charcoal is becoming increasingly controversial because of the risk of aspiration and charcoal pneumonitis. It may be indicated for orally ingested narcotics with large enterohepatic circulation (eg, propoxyphene, diphenoxylate) but is of no value in pure heroin overdose.

Psychelic Drugs Used to Treat Depression and Anxiety-Toxicology

Details: Published: Thursday, 16 May 2019 18:11

A very interesting study has recently been done on the effects of a psychedelic substance in a small mitigated-psychedelic dose in the treatment of resistant depression and anxiety. The following is a synopsis of the key points from a recent Medscape article. Â The relevance of this study to toxicology is that psychelics can have severe side-effects, some even long-lasting or permanent, even in customary doses, as noted below. Practitioners who treat their patients with these substances should be aware of the medicolegal liability and health risks.

Fluorquinolones can kill

Details: Published: Wednesday, 01 May 2019 13:22

New warning from the FDA-- a warning about Aortic Aneurysm Risk With Fluoroquinolones in patients being treated for common infections

The agency is urging healthcare providers to avoid prescribing the powerful antibiotics to patients with or at risk for an aortic aneurysm, such as those with peripheral atherosclerotic vascular disease, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and the elderly. This antibiotic is one of the most commonly prescribed antibiotics for braonchitis, sinusitis, bladder infections, and pneumonia.

"Although the risk of aortic aneurysm or dissection is low, we've observed that patients are twice as likely to experience an aortic aneurysm or dissection when prescribed a fluoroquinolone drug," FDA commissioner Scott Gottlieb, MD, said in the Drug Safety Communication.

"For patients who have an aortic aneurysm or are known to be at risk of an aortic aneurysm, we do not believe the benefits outweigh this risk, and alternative treatment should be considered."

The FDA reviewed adverse event reports and four recently published observational studies showing an increased risk of aortic aneurysm or dissection associated with fluoroquinolone use, which can lead to dangerous bleeding or even death.

The underlying reason for this increased risk cannot be determined, the statement notes. The background risk of aortic aneurysm also can vary depending on the population — from nine events/100,000 people/year in the general population to 300 events/100,000 people/year in the highest-risk individuals.

"For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections, but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use," Gottlieb said.

The FDA has issued several prior safety communications about fluoroquinolone use, including in July 2018 (significant decreases in blood sugar and certain mental health side effects), July 2016 (disabling side effects of the tendons, muscles, joints, nerves, and central nervous system), May 2016 (restrict use for certain uncomplicated infections), August 2013 (peripheral neuropathy), and July 2008 (tendinitis and tendon rupture).

Edible Marijuana is Potentially Dangerous

Details: Published: Wednesday, 10 April 2019 13:42

The number of cannabis-associated emergency department (ED) visits has risen sharply since marijuana was legalized in Colorado. New data show that although inhalable cannabis use accounts for most of these visits, edible cannabis is tied to a disproportionate number of visits, and patients present with different symptoms.

Although less frequent overall, edible cannabis products lead to more acute psychiatric events and cardiovascular symptoms than inhaled exposure. Researchers at the University of Colorado report their findings in an article published online recently in the Annals of Internal Medicine.

Edible cannabis has been considered to be more toxic than inhalable cannabis, particularly in light of accumulating poison center data on its associated adverse events (AEs) and anecdotal reports from adult users. In addition, the only deaths in Colorado that have been conclusively linked to cannabis use have involved edible products.

Nevertheless, the relative potential harms of inhalable and edible cannabis products have been poorly characterized.

With this in mind, Monte and colleagues conducted a study to compare adult ED visits related to edible and inhalable cannabis use. Using chart review, the researchers tracked 9973 ED visits to the University of Colorado Health emergency department from 2012 through 2016 that included an ICD-9 or -10 code for cannabis use. Of those, they found that 2567 (25.7%) of the visits were related to cannabis, with 238 of these (9.3%) linked to edible products.

The most common causes of cannabis-linked ED visits were gastrointestinal symptoms (30.7%), intoxication (29.7%), and psychiatric symptoms (24.7%).

Visits as a result of inhalable cannabis were more likely than those because of edibles to involve gastrointestinal symptoms, the most common of which was cannabinoid hyperemesis syndrome (18% vs 8.4%; mean difference, 9.6 percentage points; 95% confidence interval [CI], 5.7 - 13.5).

In contrast, visits due to edible cannabis more commonly involved acute psychiatric symptoms (18% vs 10.9%; mean difference, 7.1 percentage points; 95% CI, 2.1 - 12.1), intoxication (48.3% vs. 27.8%; mean difference, 20.5 percentage points; 95% CI, 13.9 - 27.1), and cardiovascular symptoms (8% vs 3.1%; mean difference, 4.9 percentage points; 95% CI, 1.4 - 8.4).

For patients using edible cannabis, the ED visits were also more likely to be shorter (2 hours vs 3 hours) and less likely to lead to hospitalization (18.9% vs 32.9%; P < .001) than they were for patients using inhalable cannabis.

The researchers also determined that, although edible cannabis accounted for just 0.32% of the states total cannabis sales (in kilograms of tetrahydrocannabinol [THC]) between 2014 and 2016, it was responsible for 10.7% of cannabis-related ED visits in Colorado during that period.

If inhalable and edible cannabis were equally toxic and resulted in the same number of ED visits, based on the study, 0.3% of cannabis-attributable visits would be due to use of edible products. The observed proportion of cannabis-attributable visits with edible exposure was about 33 times higher than expected (10.7% vs 0.32%) if both routes of exposure were equally toxic.

This data establishes that states considering cannabis legalization shouldÂ take into account the relative toxicity of edible products. It may be best to limit edible products to medical indications in order to minimize pediatric exposures and mitigate the excessive rate of adult ED visits associated with these products. At the very least, users must be educated about the delayed kinetic profile and the increased risk for acute psychiatric and adverse cardiovascular events associated with edible ingestion.

Nora D. Volkow, MD, and Ruben Baler, PhD, from the National Institutes of Health, Bethesda, Maryland, highlight the important clinical and public health implications of these findings. There are several reasons why edible cannabis often leads to worse outcomes than inhalable cannabis. Because orally-ingested THC is absorbed more slowly than inhaled THC, people using the edible products find it harder to titrate the doses required to produce the desired effects. This is compounded by the slower clearance of orally-ingested THC from the body, which can result in accumulation in people who take extra doses in an attempt to achieve the desired drug effect more quickly.

In addition, the relatively harmless appearance of edibles and the variability in their labeling accuracy further contribute to overconsumption of these products.

Acknowledging that the complete range of potential adverse health consequences from cannabis consumption remain incompletely understood, the editorialists suggest that future research into the adverse effects of cannabis should focus on THC and content, route of administration, doses consumed, sex, age, body mass index, and the medical conditions for which it might be used.

The results of this recent study also underscore the urgent need for greater oversight of manufacturing practices, labeling standards, and quality control of cannabis products marketed to the public.

Ann Intern Med. Published online March 25, 2019.

EPA Alert: Methylene Chloride Banned

Details: Published: Wednesday, 10 April 2019 13:08

The Environmental Protection Agency (EPA) says it will issue a rule that bans the sale of methylene chloride to consumers but allows for its continued use in commercial products.

The deadly chemical is found in paint and furniture strippers. Many stores, including Lowe’s and Walmart, had already stopped selling products with methylene chloride. The ban includes the manufacturing, processing, and distribution of the chemical for consumers. Alexandra Dunn, the EPA’s assistant administrator for chemical safety, says in a press release: "This rule answers calls from many affected families to effectively remove these products from retail shelves and retail distribution channels, providing protection for the American public."

Environmental advocates say the rule doesn’t go far enough. "They’ve excluded workers who are the most vulnerable population," says Lindsay McCormick, project manager, chemicals and health, for the Environmental Defense Fund in Washington, DC. "It’s a day late and a dollar short here."

The nonprofit group Safer Chemicals, Healthy Families says at least 64 people have died from exposure to methylene chloride since 1980. Many of those deaths were among workers who were refinishing bathtubs. Bathtub refinishers often work in poorly ventilated spaces. Methylene chloride is heavier than air, so it sinks and collects in low places like bathtubs, right where refinishers hold their heads as they work.

Methylene chloride is metabolized to carbon monoxide and replaces and blocks oxygen in the blood. When inhaled, it can cause headaches, nausea, dizziness, seizures, coma, and death. Over the long term, it increases the risk of cancer, and may alter cognitive function permanently.

The EPA has estimated that as many as 32,000 workers use methylene chloride on the job. Yet the EPA will continue to allow the use of the compound for workers even though they are at risk for adverse health events.

The EPA says it will take public comments for the next 90 days. Those comments will inform a future rule that could establish a training, certification, or limited-access program for methylene chloride for commercial uses.

FENTANYL OVERDOSES AND DEMOGRAPHIC DISPARITIES

Details: Published: Thursday, 28 March 2019 13:54

Fentanyl overdoses are increasing at a dramatic rate in the United States. Visits to Emergency Rooms are far more frequent now than they were just a few years ago. Fentanyl is a synthetic opiate that when blending with heroin becomes a life-threatening toxic cocktail as it is 50-100 times more potent than morphine. Physician in the ER when treating cardiorespiratory complications from an assumed heroin overdose must be mindful of the possibility that Fentanyl may have contaminated the ingested drug. The Narcan reversal agent requirements may be higher for Fentanyl. Here are three recent newspaper articles describing the scourge.

The Washington Post (3/20, Achenbach) reports that “the synthetic opioid fentanyl has been driving up the rate of fatal drug overdoses across racial and social lines in the United States, with the sharpest increase among African Americans, according to a new analysis by the Centers for Disease Control and Prevention.” Data show the African American death rate “from fentanyl-involved drug overdoses rose 141 percent each year, on average, from 2011 to 2016, the study showed.” Meanwhile, the overdose death rate “for Hispanics rose 118 percent in that period every year on average, and 61 percent for non-Hispanic whites.”

The Washington Time (3/20, Healy) reports that during the study period, 2011 to 2016, “more than 36,000 Americans died with fentanyl in their systems” and the “majority of those deaths – 18,335 – occurred in 2016 alone.” The Times adds that “fentanyl was first approved by the Food and Drug Administration back in 1968.”

NPR (3/21, Bebinger) reports that the study also indicates “men are dying after opioid overdoses at nearly three times the rate of women,” and there is “an especially steep rise in the number of young adults ages 25 to 34 whose death certificates include some version of the drug fentanyl.”

Intoxication and Death from Synthetic Cannabinoids-Missed Dx

Details: Published: Tuesday, 05 March 2019 09:43

Nearly half of patients with suspected synthetic-cannabinoid-receptor agonist (SCRA) intoxication test negative for an SCRA, and many test positive for another substance, researchers report. Clinicians caring for patients with reported synthetic-cannabinoid exposures must have a high index of suspicion for other drugs of abuse, trauma, or other medical conditions, and should evaluate and treat accordingly,

Additionally, for patients that are exposed to synthetic cannabinoids, it is essential to look out for new or different symptoms and complications, as the chemical composition of these agents is rapidly evolving.

SCRAs, sometimes referred to as "K2" or "Spice," have become popular recreational drugs due to their easy availability, legal ambiguity, inability to be detected by current drug screens, and the potent high associated with their use. Acute SCRA intoxication presents with a wide range of symptoms and poses significant challenges to emergency medicine clinicians seeking to identify and manage these patients.

Dr. Mazer-Amirshahi and colleagues sought to characterize and confirm the constituents of reported or suspected SCRA exposures presenting to two academic emergency departments in Washington, D.C. Among the 128 unique patients included in the study, only 71 (55.5%) tested positive for an SCRA. Most (40/71) were positive for an SCRA alone, but 31 were positive for an SCRA and another substance. Among those testing positive, 12 were positive for two SCRAs, four were positive for three SCRAs, and two were positive for four SCRAs, the researchers report in the American Journal of Emergency Medicine, online December 24.

Of the 57 patients who tested negative for an SCRA, 28 (21.9% overall) tested positive for another substance, the most common being tetrahydrocannabinol (THC) and phencyclidine (PCP). The rest (22.7% of patients overall) tested negative for SCRAs and toxicology screens.

The most commonly detected SCRAs were AB-fubinaca (39.4%), ADB-fubinaca (21.1%), AB-chminaca 3-methyl-butanoic acid (21.1%), ADB-chminaca (19.7%) and 5-flouro-PB-22 (11.3%). There was a significant shift in the chemical constituents from prior studies, which is a known trend to avoid legal regulation.

Synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS). NPS are unregulated mind-altering substances that have become newly available on the market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity.

Individuals reported acquiring the contaminated synthetic cannabinoid products (i.e., K2, spice, synthetic marijuana, and legal weed) from convenience stores, dealers, and friends, in counties across the state.

Synthetic cannabinoids are human-made, mind-altering chemicals that are either sprayed on dried, shredded plant material so they can be smoked or sold as liquids to be vaporized and inhaled in e-cigarettes and other devices. They are sold for recreational drug use with claims they will provide the user the effects of cannabis. These products are also known as herbal or liquid incense and have brand names such as K2, Spice, Black Mamba, Bombay Blue, Genie, and Zohai, but may be packaged under other brand names also.

These chemicals are called cannabinoids because they are similar to chemicals found in the marijuana plant. Because of this similarity, synthetic cannabinoids are sometimes misleadingly called "synthetic marijuana" (or "fake weed"), and they are often marketed as safe, legal alternatives to that drug. In fact, they are not safe and may affect the brain much more powerfully than marijuana; their actual effects can be unpredictable and, in some cases, more dangerous or even life-threatening.

Deaths from synthetic cannabinoids have occurred from ingesting too much of the drug. Also, deaths from synthetic cannabinoid-related motor vehicle accidents are now widely reported in the news.

SOURCE: https://bit.ly/2RqfTU1

Am J Emerg Med 2018. Intoxication From Synthetic-Cannabinoid-Receptor Agonists Often Missed - Medscape - Jan 15, 2019.

Melatonin is Over-rated as a Sleeping Aid

Details: Published: Wednesday, 27 February 2019 15:22

Experts say that other issues pertaining to poor sleep quality, such as light exposure and certain behaviors, should be tackled ahead of resorting to use of the hormone melatonin to regulate sleep. But if it is used, an individual's daily onset of natural melatonin production should be taken into account before deciding on an appropriate dose to supplement, they say.

Melatonin, which is available over-the-counter in the United States but restricted in other developed countries, is typically recommended acutely for sleep schedules thrown off by, for example, jet lag or chronically for certain circadian rhythm disorders. It has also been touted as something close to a panacea, with some even suggesting it can treat cancer, cognitive dysfunction, and obesity. However, it is the explosion in the use of melatonin to regulate general sleep in otherwise healthy individuals that has led to US consumers reportedly spending more than $400 million on melatonin supplements in 2018.

This has raised concerns over its safety among healthcare professionals and led to questions as to whether the hormone should be taken for jet lag at all and whether its use should be restricted in children. This ongoing debate led the American Chemical Society to recently produce a video produce a video that debunks many of the myths around melatonin and its effects, including the magnitude of its benefits in improving sleep.

Now, José Cipolla-Neto, MD, PhD, Institute of Biomedical Sciences, University of São Paulo, and Fernanda Gaspar do Amaral, PhD, a professor at the Federal University of São Paulo, Brazil, have conducted an in-depth review of the literature on melatonin and its uses. Moreover, they have produced a series of recommendations, published in the December issue of Endocrine Reviews, that set out how best to use the hormone, including advice on the most effective dosage and timing.

But others question whether people should look to melatonin to regulate sleep at all, suggesting that, instead, individuals should be looking at controlling night-time light exposure and even regulating light levels in shops. The sheer amount of research that has been conducted into melatonin in recent years is staggering. Cipolla-Neto and Amaral point out more than 4000 studies have been published in the last 20 years, of which 200 were randomized controlled trials and 195 systematic reviews.

Melatonin has been shown to affect a number of physiological processes, including downstream effects on the cardiovascular, reproductive, immune, respiratory, and endocrine systems, alongside energy metabolism. Melatonin synchronizes our organism's temporal order both daily and on the seasonal time scale. Consequently, multiple modes of action should be taken into account both when performing laboratory experiments and conducting clinical studies into melatonin's use as a treatment.

Melatonin's effects depend not just on the route of administration and concentration but also on the time of administration, among other factors. Additionally, the daily variation in melatonin levels varies between individuals. For example, those who prefer to get up early start daily melatonin production earlier than those who prefer to stay up later, while long sleepers tend to produce the hormone for longer periods than those who sleep less.

A given dose of melatonin may, moreover, result in different plasma levels between individuals, owing to pharmacokinetic differences in the way that it is absorbed, distributed, metabolized, and eliminated. These processes can themselves be affected by an individual's age and clinical condition, the presence of pathological conditions, and the physiological performance of the gastrointestinal tract, liver, and kidneys. If these factors are not adequately considered, they say that the clinical efficacy of melatonin will be altered.

How Should Melatonin Be Best Used?

The first recommendation is to determine the start of melatonin production, known as the dim light melatonin onset (DLMO), and its duration in each patient, and use that to guide prescribing. This is because, without using the DLMO as an indicator of the timing of administration, melatonin could advance, delay, or even have no effect on the timing of endogenous circadian rhythms.

However, is not typically feasible to determine the DLMO in everyday clinical practice. A more practical surrogate is to take the time at which the patient usually goes to sleep at night. Because of bioavaiability, melatonin should be taken around an hour before the usual bedtime at exactly the same time every day.

In terms of the dose, there is no consensus in the literature. What is known is that young people who take approximately 0.1 to 0.3 mg of melatonin will have a plasma concentration in the range of 100 to 200 pg/mL, which is considered to be within the physiological range.

A dose of 1.0 mg would result in a plasma concentration of approximately 500 to 600 pg/mL, which is far higher than the physiological concentration. For example, if the outcome is an acute phase displacing, as it is desired for jet lag treatment, a fast-release pulse correctly timed is perfectly adequate. However, if the desired effect is a sustained phase displacement as, for example, in non-24-hour sleep disorder or circadian dysfunction in totally blind people, the synchronizing effect requires chronic continuous daily intake of melatonin. For this purpose, a slow-release or dual-release formulation is the most appropriate."

Should Melatonin Be Taken at All?

A question nevertheless remains as to whether melatonin should be taken at all by individuals who do not have a recognized clinical condition, or indeed whether it is the most appropriate treatment in those who do.

Satchidananda Panda, PhD, and his colleagues at the Salk Institute for Biological Studies, La Jolla, California, published a study in mice showing how the protein melanopsin in retinal cells continually responds to light. Melanopsin, which is tuned to blue light, is essentially checking whether it's daylight still out there and, if there is daylight, then it will tell the brain to avoid sleeping and stay awake. It does that by two ways, one is increasing the circadian clock, telling that it's still daytime, and the second is it tells the pineal gland to slow down production of melatonin. Melatonin, threfore, has a big impact on sleep and it should not be seen as a panacea, and should be heavily regulated, which it's not. At the present time melatonin is the only hormone produced in the human body that's not heavily regulated.

Not Harmful, But Not That Effective

That said, currently, there isn't any hard evidence to say that taking melatonin on a daily basis is harmful; there aren't large-scale multicenter clinical trials to really test that. Most of the ongoing research is now being focused on reduction of light exposure in the hours prior to bedtime.

Drug Overdose Deaths Increasing in U.S.

Details: Published: Monday, 18 February 2019 18:52

Deaths from drug overdose in the United States increased by 54% from 2011 to 2016 — with opioids, benzodiazepines (benzos), and stimulants the most commonly used drug classes involved, a new report released today by the Centers for Disease Control and Prevention's National Center for Health Statistics (NCHS), shows.

The report notes that there were 41,340 drug overdose deaths in 2011 vs 63,632 such deaths in 2016.

Although the opioid oxycodone was the most cited drug in overdose death records in 2011, heroin took the top spot from 2012 to 2015.

The story around fentanyl may be even more troubling. The rate of overdose deaths involving it or one of its analogs doubled each year from 2013 through 2016, when it finally took the lead in becoming the most mentioned drug. In 2016, 29% of all overdose deaths involved fentanyl (n = 18,335).

In addition, cocaine was the second or third most cited drug in the overdose death records throughout the entire study period.

The CDC's list of the 10 most frequently mentioned drugs also included the opioids, methadone, morphine, and hydrocodone; the benzos, alprazolam and diazepam; and the stimulant methamphetamine.

Of all 10 drugs, only methadone was associated with a decreasing overdose death rate from 2011 to 2016.

"While the ranking changed from year to year, the top 10 drugs involved in overdose deaths remained consistent throughout the 6-year period," note the investigators, led by Holly Hedegaard, MD, NCHS.

"This report identifies patterns in the specific drugs most frequently involved in drug overdose deaths…and highlights the importance of complete and accurate reporting in the literal text on death certificates," they write.

The data were published online in the December 12 issue of the National Vital Statistics Reports.

Rise in Overdose Death Toll

An NCHS report released last year showed the age-adjusted rate of US drug overdose deaths increased dramatically from 1999 (6.1 per 100,000 population) to 2016 (19.8 per 100,000).

Although several previous studies on drug overdoses have used National Vital Statistics System-Mortality (NVSS-M) information, this data is coded using the International Classification of Diseases, Tenth Revision(ICD-10); and these ICD-10 codes focus on broad drug categories rather than on individual drugs, note the investigators.

In answer to this, the NCHS and the US Food and Drug Administration "collaboratively developed methods to search the literal text from death certificates to identify mentions of specific drugs and other substances, and to search contextual terms to identify involvement of the drug(s) or substance(s) in the death," the researchers write.

They defined "literal text" as written information from the medical certifier on cause or circumstances related to a death.

For the current report, they examined NVSS-M data from 2011 through 2016. These data were linked to electronic files containing death certificate information.

In addition to the top 10 drugs involved in overdose deaths, drugs that held the number 11 through number 15 ranking throughout the 6-year study period included diphenhydramine, acetaminophen, citalopram, carisoprodol, oxymorphone, tramadol, amitryptyline, clonazepam, gabapentin, and amphetamine.

Threefold Increase in Heroin Deaths

The involvement of heroin in overdose deaths rose threefold from 4571 deaths in 2011 to 15,961 deaths in 2016. This made it the second-most mentioned drug in 2016, behind fentanyl.

Mentions of cocaine increased from 5892 overdose deaths in 2014 to 11,316 deaths in 2016, giving it that year's number 3 ranking.

The fourth most mentioned drug in overdose deaths in 2016 was methamphetamine. Its 6762 related deaths signified a sharp increase from the 1887 related deaths in 2011.

"An analysis of trends…showed that, for several drugs, the age-adjusted rate of drug overdose deaths increased considerably within a relatively short period," the investigators write.

Heroin, cocaine, and methamphetamine all showed significant increasing trends for age-adjusted rates of drug overdose deaths between 2011 and 2016 (1.5 vs 5.1 per 100,000 population; 1.6 vs 3.6 per 100,000; and 0.6 vs 2.1 per 100,000, respectively; all, P< .05).

Fentanyl showed a significant increasing trend between 2013 and 2016 (0.6 vs 5.9 per 100,000; P< .05).

The only decrease for a specific drug came from methadone, which was mentioned in 4545 overdose deaths in 2011 vs 3493 deaths in 2016 (1.4 vs 1.1 per 100,000). Still, it was the eighth most mentioned drug in 2016.

For the 2016 top 10 drugs, "the proportion of deaths involving both the referent drug and at least one other concomitant drug ranged from 50% for methamphetamine to 96% for alprazolam or diazepam," the researchers report.

Finally, drugs most frequently recorded in unintentional overdose deaths in 2016 were fentanyl, heroin, and cocaine. The most frequently cited drugs in suicide by overdose were oxycodone, diphenhydramine, hydrocodone, and alprazolam.

NCHS National Vital Statistics Reports. Published December 12, 2018. Full text