The 4th Wave Of Polysubstance Fentanyl Overdose Deaths

Details: Published: Wednesday, 27 September 2023 12:33

One of the consequences of an open Southern Border is the entrance into the U.S. of unprecedented amounts of illicit drugs. Additionally, much of these drugs have been spiked with lethal doses of fentanyl. Fentanyl is the most potent of all narcotics. On a dose:dose basis fentanyl is 50 times stronger than heroin, and 100 times stronger than morphine. What this means is that extremely small doses of fentanyl can cause respiratory depression and death.

INTRODUCTION

The United States (US) overdose crisis has escalated in an exponential fashion for over four decades, yet with a shifting profile of drugs implicated in each successive ‘wave’ of the crisis. The first wave of the overdose crisis is typically argued to have begun in the late 1990s or early 2000s with the rise of deaths involving prescription opioids, the second wave beginning in 2010 driven by a shift to heroin, and the third wave beginning in 2013 driven by illicit fentanyl analogues. Recently, scholars have argued that the ‘fourth wave’ of the US overdose crisis has begun, in recognition of rapidly rising polysubstance overdose deaths involving illicitly manufactured fentanyls, with stimulants playing a key role. Recent studies have highlighted an increasing rate of polysubstance overdose deaths involving fentanyls and stimulants, disproportionately affecting racial/ethnic minority communities. A wide range of polysubstance formulations have been noted in drug checking and overdose mortality data, with myriad substances implicated across numerous drug classes. However, more evidence is needed about exact geographic, temporal, race/ethnicity and demographic trends, as well as which emerging polysubstance formulations are most commonly involved in fatalities.

Findings

The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% (n = 235) in 2010 to 32.3% (34 429) in 2021, with the sharpest rise starting in 2015. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015–2021. Intersectional group analysis reveals particularly high rates for older Black and African American individuals living in the West.

DISCUSSION

The rise of illicitly manufactured fentanyls has ushered in an overdose crisis in the United States of unprecedented magnitude. This has created conditions that have promoted a number of other shifts in the illicit drug supply, leading to rising polysubstance overdose deaths—the so-called ‘fourth wave’ of the crisis, especially involving stimulants and fentanyl co-use starting in 2015. Mixtures of fentanyl analogues and drugs of various drug classes, such as stimulants, benzodiazepines, tranquilizers and other opioids have been noted in distinct geographies.

In 2010, fentanyl was most commonly found alongside prescription medication (opioids and benzodiazepines) and alcohol (i.e. largely products produced in legal markets). Over the past decade this has shifted first to heroin-fentanyl combinations in specific states, and then universally to illicit stimulants. The fraction of all overdose deaths involving both fentanyl and stimulants grew rapidly between 2010 and 2021 and is on track to represent the single largest component of the overdose crisis in the near future. However, this has occurred in a distinct fashion based on geography and time. The northeastern states saw a period of heroin-fentanyl co-involvement, which was also found in some parts of the Midwest and South, but was completely absent from the western states (which transitioned rapidly from black tar heroin to fentanyl with methamphetamine co-involvement). By 2021, cocaine predominated in the Northeast and methamphetamine had become the most common drug found alongside fentanyls in the rest of the country.

There are now two basic archetypes of states in the United States with respect to overdose death rates: (a) states where fentanyl and cocaine co-use predominates; and (b) states where fentanyl and methamphetamine co-use predominates, with surprising little overlap between these two groups. This may reflect the combination of very low-cost, high-purity methamphetamine outcompeting cocaine and other stimulants at the national level, in addition to an enduring, well-entrenched illicit cocaine market in the Northeast and other pockets of the country.

The rise of deaths involving cocaine and methamphetamine must be understood in the context of a shifting illicit opioid drug market increasingly dominated by illicit fentanyls. Recent ethnographic and qualitative research suggests that fentanyls have created conditions that make polysubstance use more sought-after and commonplace. For instance, many individuals report that mixing a small amount of methamphetamine into injected doses of fentanyl subjectively prolongs the onset of withdrawal symptoms, increases euphoria, decreases overdose risk and improves energy levels. These perceived advantages may be particularly important given the short duration of fentanyls, requiring individuals to inject far more frequently than heroin, and the heightened overdose risk from each injection.

Similar findings have been reported in qualitative studies of the veterinary tranquilizer, xylazine, and other drugs commonly added to fentanyls, suggesting possible structural similarities across various emerging polysubstance patterns. Given the increased risk of negative health outcomes such as overdose not fully responsive to naloxone often requiring additional life-saving measures such as airway management.

A critical consideration is the growing prevalence of counterfeit pills, which resemble psychoactive pharmaceuticals such as oxycodone or alprazolam, but contain illicit fentanyls, often mixed with other illicit substances such as stimulants, benzodiazepines, xylazine and other opioids. In recent years, counterfeit pills have grown to represent over a quarter of all illicit fentanyl seizures. Counterfeit pills have the potential to transform overdose risk as they may expand the markets for illicit synthetic drugs to subpopulations, such as adolescents, who may be less likely to consume powder fentanyl products . In the ongoing surveillance of the US overdose crisis, tracking deaths involving counterfeit pills versus other formulations represents an important dimension that is currently difficult within the existing data landscape.

Conclusions

By 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more sought-after and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges.

The information above was gleaned from a soon to be published study by Drs. Friedman and Shover. Addiction. 1-9, 2023

Food Additive Emulsifiers are Deleterious to Health

Details: Published: Friday, 15 September 2023 20:38

A new large prospective cohort study was just released in the British Medical Journal from a research group in France demonstrating that Food Emulsifiers that appear in most processed foods are harmful to health, especially, cardiovascular health. Here are the main points of the study that were summarized in Medscape, 9/15/23:

METHODOLOGY:

Studies have linked high intake of ultraprocessed foods with elevated risks of CVD, possibly because of negative effects of additives used as thickening agents and to improve texture and lengthen shelf life.
Research also suggests food additives such as emulsifiers, which are found in more than half of industrial food or beverage products in France, may have deleterious effects on the gut microbiota and gut inflammation, and impact CVD.
The analysis included 95,442 mostly female volunteer participants in the NutriNet-Santé prospective study, mean age 43.1 years, who did not have CVD at baseline and completed at least 3 days of web-based 24-hour dietary records.
Researchers used various databases to collect information and assess the association between intake of food additives consumed by at least 5% of participants and risks of CVD, coronary heart diseases, and cerebrovascular diseases.

TAKEAWAY:

During a mean follow-up of 7.4 years, there were 1995 incident CVD events, 1044 coronary heart disease events, and 974 cerebrovascular disease events.
After adjusting for sociodemographic, health, and lifestyle factors as well as for intake of food elements possibly affecting CVD risk such as sugar, sodium, saturated fatty acids, fiber, and artificial sweeteners, higher intake of total celluloses was associated with increased risks of CVD (hazard ratio [HR] for an increase of 1 standard deviation, 1.05; 95% CI, 1.02 - 1.09; P = .004) and coronary heart disease (HR, 1.07; 95% CI, 1.02 - 1.12; P = .004).
Higher intakes of total monoglycerides and diglycerides of fatty acids were associated with higher risks of all three outcomes: CVD (HR, 1.07; P < .001), coronary heart disease (HR, 1.08; P = .001), and cerebrovascular disease (HR, 1.07; P = .02).
Trisodium phosphate was associated with higher risks of coronary heart disease (HR, 1.06; P = .03).
Results of multiple sensitivity analyses were consistent with those from the main models, suggesting consistency and robustness of the findings, the researchers say.

IN PRACTICE:

The study may have important public health implications given food additives are used in thousands of commonly consumed ultraprocessed food products, the authors write, adding that the results "will contribute to the reevaluation of regulations around food additive usage in the food industry to protect consumers."

SOURCE:

The study was carried out by Laury Sellem, Université Sorbonne and Université Paris Cité, Center of Research in Epidemiology and Statistics (CRESS), Nutritional Epidemiology Research Team (EREN), Bobigny, France. It was published online September 6 in The British Medical Journal. BMJ.

LIMITATIONS:

The study population was mostly women (79.0%), and participants were better educated and had more healthy behaviors compared with the general French population, which may limit the generalizability of the results. As women tend to have healthier diets with lower emulsifier intakes than men, and a lower absolute risk of CVD, the study is likely to have underestimated the strength of the associations. The study did not capture emulsifier intakes in foods exempt from food labelling (for example, bakery items), and nonadditive emulsifiers occurring naturally in foods such as eggs. Residual confounding in the associations can't be entirely ruled out.

E-Cigarette Liquid Ingestions in Children

Details: Published: Wednesday, 06 September 2023 15:37

An article recently appeared the weekly CDC Morbidity and Mortality Report (MMWR) that addressed eCigarette poisonings reported to Poison Control Centers across the country. One surprising finding from this data is that children less than 5 years old account for almost 2/3 of all poisoning cases. Below is the MMWR report...

E-cigarette–associated cases reported to U.S. poison centers have fluctuated during the past decade, increasing during 2010–2014, and then decreasing during 2015–2017 (1). During 2017–2018, the number of e-cigarette exposure cases increased by 25% (from 2,320 to 2,901), and in 2018 nearly two thirds (63.3%) of cases occurred among children aged <5 years (1). To understand the number and characteristics of e-cigarette exposure cases in the United States, the Food and Drug Administration (FDA) analyzed National Poison Data System (NPDS) data* from the most recently available 12-month period (April 1, 2022–March 31, 2023). NPDS is maintained by U.S. poison centers. FDA’s analyses report a further increase in the number of e-cigarette exposure cases, particularly among children aged <5 years.

NPDS is a repository of cases reported to U.S. poison centers that are recorded by specially trained and certified health care professionals (2). Information on exposure cases (reports or reported incidents by persons who contact poison centers regarding an exposure to a substance) in NPDS is recorded based on generic codes (a required general identification code for a substance or group of products) and product codes (product-specific codes, often by brand; these are not required upon case intake). Cases involving e-cigarettes were identified using generic codes; brands were identified using product codes.^† E-cigarette exposure cases were defined as an exposure to e-cigarettes or e-liquids and were examined by age group, exposure route, level of care provided, medical outcome, and product brand. This study was determined as exempt by the FDA Institutional Review Board for Human Subject Protection.^§

During April 1, 2022–March 31, 2023, a total of 7,043 e-cigarette exposure cases were reported (Table), representing a 32% increase, from 476 in April 2022 to 630 in March 2023. Among all exposures, 6,074 (87.8%) occurred among children aged <5 years. Inhalation or nasal (4,298; 61.0%) and ingestion or oral (2,818; 40.0%) exposure routes were most common. Overall, 43 (0.6%) e-cigarette exposure cases resulted in hospital admission, and 582 (8.3%) required treatment at a health care facility. A major effect^¶was experienced in 12 (0.2%) exposure cases and a moderate effect in 133 (1.9%) cases. One reported case resulted in death (a suspected death by suicide of a person ≥18 years). Approximately one half of reported cases resulted in either a minor effect (27.2%) or no reported effect (19.8%); 50.9% of cases were not followed.** Among 342 (4.9%) cases with brand information, the most commonly reported brand was Elf Bar (60.8%), a disposable e-cigarette available in a variety of flavors; monthly cases involving Elf Bar increased from two in April 2022 to 36 in March 2023. More than 90% of Elf Bar exposures were among children aged <5 years.

NPDS relies on voluntary reporting of poisoning exposure cases; thus, the number of cases is likely underreported (3). In addition, because product codes are not required, only a small proportion of e-cigarette exposure cases included information on the brand associated with the exposure.

The number of reported U.S. e-cigarette exposure cases during this 12-month period is approximately double the number reported in 2018 (1). Most of the cases were among children aged <5 years. Among the 5% of cases for which brand was available, Elf Bar, for which sales in the United States have recently increased (4), was reported more often than all the other reported brands combined, with nearly all Elf Bar cases occurring among children aged <5 years.

Continued surveillance is critical to guiding efforts to prevent poisoning exposure associated with e-cigarettes, particularly among young children. Health care providers; the public health community; e-cigarette manufacturers, distributors, sellers, and marketers; and the public should be aware that e-cigarettes have the potential to cause poisoning exposure and are a continuing public health concern (5). Adult e-cigarette users should store their e-cigarettes and e-liquids safely to prevent access by young children.

Toxicology Case Study: Body Packing of Drugs

Details: Published: Monday, 10 April 2023 14:11

Clinical Toxicology Case Study:

Altered mental status could be due to any number of medical or toxicologic conditions. The following is a case of depressed consciousness in a young man returning to the U.S. from a Third World country. His traveling companions were all well. The case is indicative of an increasingly common phenomenon especially at our southern border. Here is the case:

A 22-year-old man with no significant medical history is transferred from the airport to the emergency department (ED) in a semiconscious state after returning from a 3-week vacation in a malarial zone. According to one of his traveling companions, the patient was at his baseline mental status when boarding the plane for the return trip home. He ate lunch and then took a nap.

After landing, the patient's companion was unable to wake the patient. The companion then called for help, and the patient was rushed to the ED. His other traveling companions, who were also on the same flight, are all asymptomatic.

Physical Examination and Work-up:

The physical examination reveals a physically fit man who is obtunded and minimally arousable. Vital signs reveal an oral temperature of 98.7°F (37°C), pulse of 85 beats/min, blood pressure of 110/70 mm Hg, respiratory rate of 7 breaths/min, and an oxygen saturation of 98% while breathing room air. Diffuse flushing of the skin is noted, without lesions or bruising.

The patient's heart sounds are normal, without any murmurs, rubs, or gallops, and the lungs are clear to auscultation bilaterally. Examination of the head and neck is unremarkable, other than pinpoint pupils. The abdominal examination reveals normal bowel sounds without distention, tenderness to palpation, or organomegaly. Rectal examination shows normal rectal tone, heme-negative stool, and no masses.

The laboratory analysis includes a complete blood cell count (CBC) with differential, a complete metabolic panel, a coagulation profile, a fingerstick blood glucose measurement, and a urine analysis. The CBC reveals a normal white blood cell count without a left shift. The remainder of the laboratory analysis is within normal limits, including a creatinine level of 1.2 mg/dL, glucose of 90 mg/dL, prothrombin time of 12.1 seconds, and a partial thromboplastin time of 28.5 seconds.

The urinalysis is negative for bacteria and has a specific gravity of 1.010. It is noted in the patient's past medical record that he had a negative HIV test approximately 4 months ago.

A routine chest radiograph shows suspicious objects overlying his left diaphragm, which prompts abdominal radiography.

Discussion:

The plain abdominal radiograph (Figure 1) demonstrated heroin-filled condoms in the stomach, small intestine, colon, and rectum. Presumably, the patient swallowed the condoms and one of them ruptured during the flight, thereby causing the patient's drowsiness.

“Body packing” refers to individuals who swallow or pack body orifices with drugs to transport them across borders. Often, this involves the use of rubber or condoms to prevent the packets from rupturing. “Body stuffing” is a term used to describe when an individual swallows drugs in an attempt to avoid prosecution by the police.

The first reported case of body packing was in 1973, when a body packer had developed a small-bowel obstruction nearly 2 weeks after swallowing a condom filled with hashish. The patient underwent surgical removal.^[¹^] Cocaine, heroin, amphetamines, 3,4-methylenedioxymethamphetamine ("ecstasy"), marijuana, and hashish are the drugs that are usually smuggled in this manner.^[²^]

Body packers usually carry about 2.2 lb (1 kg) of drugs, divided into 50-100 packets of 0.29-0.35 oz (8-10 g) each; however, persons carrying more than 200 packets have been reported.^[²^] The packets are usually well-designed and constructed, possibly with the help of machines, so as to make them resistant to rupture.^[³^] The drug is first packed into a balloon or condom, followed by additional layers of latex and, finally, sealed with wax.^[²^] If a packet ruptures, however, it releases a high dose of drug into the gastrointestinal tract that can lead to drastic consequences. The acute drug intoxication that can result is associated with high mortality rates.^[³^]

Body packing should be suspected in anyone exhibiting signs of drug-induced toxic effects after a recent arrival on an international flight, or when there is no history of recreational drug use.^[²^] When a suspected body packer presents to a physician, a detailed history should be obtained, followed by a thorough physical examination. Information should be gathered on the type of drug, the number of packets, the nature of the wrapping, and the presence of any gastrointestinal symptoms.

Assessment of vital signs, mental status, pupil size, bowel sounds, and skin findings can provide useful clues to the nature of the drug. Gentle rectal and vaginal examination should be carried out to disclose the possible presence of packets.^[²^]

Cocaine intoxication manifests with marked anxiety, tachycardia, mydriasis, neuropsychologic symptoms, hyperthermia, seizures, emesis, respiratory depression, dysrhythmia, and myocardial depression.^[³^] Heroin overdose can result in sedation, miosis, and diminished bowel sounds, followed by respiratory depression.^[²^] Body packers may also present with symptoms of intestinal obstruction or other complications, such as gastrointestinal hemorrhage or perforation.^[²^,³^]

Imaging studies should begin with plain radiographs of the abdomen and pelvis; these have a sensitivity of 85%-90%.^[²^] The packets are visualized as multiple round or oval, well-defined, radioopaque objects along the distribution of the intestine. Three different forms of radioopacity have been described, depending on the contents of the packet and purity of the drug: Hashish appears denser than stool; cocaine appears similar to stool; and heroin has a gaseous transparence.^[⁴^] Owing to their method of construction, some types of cocaine packets may exhibit a small radiolucent band around them.^[³^]

Barium and CT studies of the abdomen can be ordered for suspicious cases. Contrast-enhanced CT of the abdomen and pelvis is more sensitive than plain radiography and reveals the presence of foreign bodies surrounded by a small amount of gas. Barium studies identify the packets as filling defects within the contrast medium.^[²^] Urinary toxicology tests are often performed because body packers do not usually provide precise information about the contents of the packets. Positive urine toxicology results were obtained in up to 78% of patients in one study.^[⁵^] However, many toxicologists now have significant questions about the clinical use of these studies due to the rate of false-positives.

Treatment is tailored to the nature of the presentation and the severity of the toxidrome. Asymptomatic body packers may be managed conservatively in an intensive care unit (ICU) while waiting for spontaneous evacuation.^[²^] Medical treatment is mandated in the event of drug-induced toxic effects and in cases presenting with intestinal obstruction or perforation.

For intoxication cases, initial management includes careful attention to the airway, breathing, and circulation (ABCs) and adequate resuscitation measures. Further management is based on the nature of the drug and toxidrome. Opioid poisoning is treated with naloxone. High doses may be necessary because large doses of drug may be released upon gastrointestinal rupture of the packets. Acute lung injury caused by opioid poisoning is treated with supplemental oxygen or intubation as needed.^[²^]

For cocaine poisoning, treatment should be initiated with high doses of benzodiazepines followed by intensive care management.^[⁵^] Ventricular arrhythmia should be managed with lidocaine and hypertonic sodium bicarbonate, and cocaine-induced hypertension should be treated with intravenous sodium nitroprusside or phentolamine.^[²^] In cases of leaking cocaine packets, immediate surgical removal is indicated because no specific antidote is available for cocaine overdose.^[²^]

Management of amphetamine poisoning is similar to that of cocaine poisoning, including prompt surgical removal of leaking packets.^[²^] Marijuana and hashish intoxication is managed with supportive treatment.^[²^]

In the case of bowel obstruction, activated charcoal can be given for cocaine packers at a dose of 1 g per kg of body weight (up to 50 g) every 4 hours for several doses. Oil-based laxatives should be avoided; however, whole-bowel irrigation with polyethylene glycol electrolyte lavage solution can be attempted to aid gentle passage of the packets.^[²^] Ipecac syrup, enemas, and cathartics carry a possibility of packet rupture and must not be used.^[³^] Endoscopic retrieval of packets also entails risk for rupture; therefore, this method is not usually recommended unless carried out in an ICU or operating room.^[²^,³^] Imaging is to be repeated until three packet-negative stools are obtained or according to the count given by the packer to confirm that no packet is left behind.

Prompt surgical management is indicated for packers who present with complications of intestinal obstruction or perforation.^[²^] Enterotomy incisions are made as required, and the intestinal contents are milked toward the incisions or the anus.^[²^] Postoperative imaging (CT or barium study) should be done to ensure the complete removal of packets.^[²^]

In this case, the patient was administered naloxone and was prepared for surgery. Evidence of packet rupture was found, and the packets were successfully removed. The patient survived the surgery and recovered well.

Cases of body packing have been increasing recently because strict border security procedures have made conventional drug smuggling difficult.^[⁶^] Physicians and radiologists should therefore be aware of this potentially fatal form of drug smuggling, its various presentations, and the relevant imaging findings in order to make a prompt diagnosis and begin the appropriate management.

References:

Deitel M, Syed AK. Intestinal obstruction by an unusual foreign body. Can Med Assoc J. 1973;109:211-212. Source
Traub SJ, Hoffman RS, Nelson LS. Body packing--the internal concealment of illicit drugs. N Engl J Med. 2003;349:2519-2526. Source
Pidoto RR, Agliata AM, Bertoline R, Mainini A, Rossi G, Giani G. A new method of packaging cocaine for international traffic and implications for the management of cocaine body-packers. J Emerg Med. 2002;23:149-153. Source
Hergan K, Kofler K, Oser W. Drug smuggling by body packing: what radiologists should know about it. Eur Radiol. 2004;14:736-742. Source
Dueñas-Laita A, Nogué S, Burillo-Putze G. Body packing. N Engl J Med. 2004;350:1260-1261. Source
Cappelletti S, Picacentino D, Ciallella C. Systemic Review of Drug Packaging Methods in Body Packing and Pushing: A Need for New Classification. Am J Forensic Med Pathol. 2019 Mar; 40(1):27-42. Source

Source: Medscape Case Challenge, April 9, 2023

Paxlovid and Rebound COVID Infections

Details: Published: Thursday, 30 March 2023 12:22

A new study just published in Lancet shows that Paxlovid does not increase the incidence of rebound COVID infections. Rebound is defined as an increase in viral load after a short period of recovery from a primary COVID infection. The rebound rates in those who took Paxlovid were not statistically different than rebound rates in those who did not take the drug. The large study involving 4,592 people also found that rebound risk was increased in the 18-65 age group (vs older patients), those with chronic medical conditions, and in those receiving steroid treatment for an unrelated condition. Also, the severity of the rebound infection was no greater in those who took Paxlovid than those who didn't take the medication. The hospitalization and death rates were essentially equivalent. The conclusion of this study is antivirals such as Paxlovid should be prescribed to people who are at high risk of developing severe COVID.

Click the link to read the full study: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00873-8/fulltext

Toxic Chemicals Everyone Regularly Consumes

Details: Published: Friday, 03 March 2023 08:45

Environmental toxins that find their way into our air, food, and water over the past few decades have dramatically increased. Many of these substances have adverse health effects in both humans and animals that may account for the increase of cancer, including an increase in colon cancer in younger age groups. The following article that appeared in a recent issue of Medscape for Physicians summarizes the toxicology and dangers of several of the more common environmental adulterants.

If the pandemic served as a window into our health, what it revealed was a US population that is not only sick but also seemingly only getting sicker. Life expectancy is falling precipitously. Three fourths of Americans are overweight or obese, half have diabetes or prediabetes, and a majority are metabolically unhealthy. Furthermore, the rates of allergic, inflammatory, and autoimmune diseases are rising at rates of 3%-9% per year in the West, far faster than the speed of genetic change in this population.

Of course, diet and lifestyle are major factors behind such trends, but a grossly underappreciated driver in what ails us is the role of environmental toxins and endocrine-disrupting chemicals. In years past, these factors have largely evaded the traditional Western medical establishment; however, mounting evidence now supports their significance in fertility, metabolic health, and cancer.

Although several industrial chemicals and toxins have been identified as carcinogens and have subsequently been regulated, many more remain persistent in the environment and continue to be freely used. It is therefore incumbent upon both the general public and clinicians to be knowledgeable about these exposures. Here, we review some of the most common exposures and the substantial health risks associated with them, along with some general guidance around best practices for how to minimize exposure.

Microplastics

"Microplastics" is a term used to describe small fragments or particles of plastic breakdown or microbeads from household or personal care products, measuring less than 5 mm in length.

Plastic waste is accumulating at alarming and devastating proportions â€” by 2050, it is estimated that by weight, there will be more plastic than fish in the oceans. That translates into hundreds of thousands of tons of microplastics and trillions of these particles in the seas. A recent study demonstrated that microplastics were present in the bloodstream in the majority of 22 otherwise healthy participants.

Since the 1950s, plastic exposure has been shown to promote tumorigenesis in animal studies, and in vitro studies have demonstrated the toxicity of microplastics at the cellular level. However, it is not well known whether the plastic itself is toxic or if it simply serves as a carrier for other environmental toxins to bioaccumulate.

According to Tasha Stoiber, a senior scientist at the Environmental Working Group (EWG), "Microplastics have been widely detected in fish and seafood, as well as other products like bottled water, beer, honey, and tap water." EWG states there are no formal advisories on fish consumption to avoid exposure to microplastics at the moment.

Pressure also is mounting for a ban on microbeads in personal care products.

Until such bans are put in place, it is advised to avoid single-use plastics, favor reusable tote bags for grocery shopping rather than plastic bags, and opt for loose leaf tea or paper tea bags rather than mesh-based alternatives.

Phthalates

Phthalates are chemicals used to make plastics soft and durable, as well as to bind fragrances. They are commonly found in household items such as vinyl (eg, flooring, shower curtains) and fragrances, air fresheners, and perfumes.

Phthalates are known hormone-disrupting chemicals, exposure to which has been associated with abnormal sexual and brain development in children, as well as lower levels of testosterone in men. Exposures are thought to occur via inhalation, ingestion, and skin contact; however, fasting studies demonstrate that a majority of exposure is probably food related.

To avoid phthalate exposures, recommendations include avoiding polyvinyl chloride plastics (particularly food containers, plastic wrap, and children's toys), which is identifiable by the recycle code number 3, as well as air fresheners and fragranced products.

The EWG's Skin Deep database provides an important resource on phthalate-free personal care products.

Despite pressure from consumer advocacy groups, the US Food and Drug Administration has not yet banned phthalates in food packaging.

Bisphenol A (BPA)

BPA is a chemical additive used to make clear and hard polycarbonate plastics, as well as epoxy and thermal papers. BPA is one of the highest-volume chemicals, with roughly 6 billion pounds produced each year. BPA is traditionally found in many clear plastic bottles and sippy cups, as well as in the lining of canned foods.

Structurally, BPA acts as an estrogen mimetic and has been associated with cardiovascular disease, obesity, and male sexual dysfunction. Since 2012, BPA has been banned in sippy cups and baby bottles, but there is some debate as to whether its replacements (bisphenol S and bisphenol F) are any safer; they appear to have similar hormonal effects as BPA.

As with phthalates, the majority of ingestion is thought to be food related. BPA has been found in more than 90% of a representative study population in the United States.

Guidance advises avoiding polycarbonate plastics (identifiable with the recycling code number 7), as well as avoiding handling thermal papers such as tickets and receipts, if possible. Food and beverages should be stored in glass or stainless steel. If plastic must be used, opt for polycarbonate- and polyvinyl chlorideâ€“free plastics, and food and beverage should never be reheated in plastic containers or wrapping. Canned foods should ideally be avoided, particularly canned tunas and condensed soups. If canned products are bought, they should ideally be BPA free.

Dioxins and Polychlorinated Biphenyls (PCBs)

Dioxins are mainly the byproducts of industrial practices; they are released after incineration, trash burning, and fires. PCBs, which are somewhat structurally related to dioxins, were previously found in products such as flame retardants and coolants. Dioxins and PCBs are often grouped in the same category under the umbrella term "persistent organic pollutants" because they break down slowly and remain in the environment even after emissions have been curbed.

Tetrachlorodibenzodioxin, perhaps the best-known dioxin, is a known carcinogen. Dioxins also have been associated with a host of health implications in development, immunity, and reproductive and endocrine systems. Higher levels of PCB exposure have also been associated with an increased risk for mortality from cardiovascular disease.

Notably, dioxin emissions have been reduced by 90% since the 1980s, and the US Environmental Protection Agency (EPA) has banned the use of PCBs in industrial manufacturing since 1979. However, environmental dioxins and PCBs still enter the food chain and accumulate in fat.

The best ways to avoid exposures are through limiting meat, fish, and dairy consumption and trimming the skin and fat from meats. The level of dioxins and PCBs found in meat, eggs, fish, and dairy are approximately 5-10 times higher than they are in plant-based foods. Research has shown that farmed salmon is likely to be the most PCB-contaminated protein source in the US diet; however, newer forms of land-based and sustainable aquaculture probably avoid this exposure.

Pesticides

The growth of modern monoculture agriculture in the United States over the past century has coincided with a dramatic surge in the use of industrial pesticides. In fact, over 90% of the US population have pesticides in their urine and blood, regardless of where they live. Exposures are thought to be food related.

Approximately 1 billion pounds of pesticides are used annually in the United States, including nearly 300 million pounds of glyphosate, which has been identified as a probable carcinogen by European agencies. The EPA has not yet reached this conclusion, although the matter is currently being litigated.

A large European prospective cohort trial demonstrated a lower risk for cancer in those with a greater frequency of self-reported organic food consumption. In addition to cancer risk, relatively elevated blood levels of a pesticide known as beta-hexachlorocyclohexane (B-HCH) are associated with higher all-cause mortality. Also, exposure to DDE â€” a metabolite of DDT, a chlorinated pesticide heavily used in the 1940s-1960s that still persists in the environment today â€” has been shown to increase the risk for Alzheimer's-type dementia as well as overall cognitive decline.

Because these chlorinated pesticides are often fat soluble, they seem to accumulate in animal products. Therefore, people consuming a vegetarian diet have been found to have lower levels of B-HCH. This has led to the recommendation that consumers of produce should favor organic over conventional, if possible. Here too, the EWG provides an important resource to consumers in the form of shopper guides regarding pesticides in produce.

Per- and Polyfluoroalkyl Substances (PFAS)

PFAS are a group of fluorinated compounds discovered in the 1930s. Their chemical composition includes a durable carbon-fluoride bond, giving them a persistence within the environment that has led to their being referred to as "forever chemicals."

PFAS have been detected in the blood of 98% of Americans, and in the rainwater of locations as far afield as Tibet and Antarctica. Even low levels of exposure have been associated with an increased risk for cancer, liver disease, low birthweight, and hormonal disruption.

The properties of PFAS also make them both durable at very high heat and water repellent. Notoriously, the chemical was used by 3M to make Scotchgard for carpets and fabrics and by Dupont to make Teflon for nonstick coating of pots and pans. Although perfluorooctanoic acid (PFOA) was removed from nonstick cookware in 2013, PFAS â€” a family of thousands of synthetic compounds â€” remain common in fast-food packaging, water- and stain-repellent clothing, firefighting foam, and personal care products. PFAS are released into the environment during the breakdown of these consumer and industrial products, as well as from dumping from waste facilities.

Alarmingly, the EWG notes that up to 200 million Americans may be exposed to PFAS in their drinking water. In March 2021, the EPA announced that they will be regulating PFAS in drinking water; however, the regulations have not been finalized. Currently, it is up to individual states to test for its presence in the water. The EWG has compiled a map of all known PFAS contamination sites.

To avoid or prevent exposures from PFAS, recommendations include filtering tap water with either reverse osmosis or activated carbon filters, as well as avoiding fast food and carry-out food, if possible, and consumer products labeled as "water resistant," "stain-resistant," and "nonstick."

In a testament to how harmful these chemicals are, the EPA recently revised their lifetime health advisories for PFAS, such as PFOA, to 0.004 parts per trillion, which is more than 10,000 times smaller than the previous limit of 70 parts per trillion. The EPA also has proposed formally designating certain PFAS chemicals as "hazardous substances."

Inflation Reduction Act Destroys Drug Development

Details: Published: Friday, 04 November 2022 12:59

Recently an article appeared in the Wall Street Journal regarding the Inflation Reduction Act and the effects it will have on the development of new medical and surgical treatments. Those effects are numerous and profound, and also come with a health and safety impact. Thus, toxicologists and other medical safety experts have been paying close attention to developments. I include the WSJ article below for your information.

It may take years before we can fully appreciate the impact of the Inflation Reduction Act on the pharmaceutical industry, but we’re already getting signs of the damage. While Democrats boast that they’ve given Medicare the power to “negotiate” drug prices, the effect has been to saddle manufacturers with a complex and ill-conceived price-setting scheme. In response, many have canceled drug-development programs, resulting in an unfortunate but predictable loss for patients nationwide.

One poorly crafted provision is driving companies away from research into treating rare diseases. In its Oct. 27 earnings statement, Alnylam announced it is suspending development of a treatment for Stargardt disease, a rare eye disorder, because of the company’s need “to evaluate impact of the Inflation Reduction Act.” Alnylam’s decision turns on a provision in the Democrats’ bill that exempts from price-setting negotiations drugs that treat only one rare disease. The company’s drug is currently marketed as treating only amyloidosis, and thus is exempt from Medicare’s price setting. If Alnylam proceeded with research into treating Stargardt, it would lose its exemption.

That disincentive might be most pronounced in cancer treatments. On Tuesday, Eli Lillyannounced it is canceling work on a drug that had been undergoing studies for certain blood cancers. “In light of the Inflation Reduction Act,” the company wrote to Endpoints News, “this program no longer met our threshold for continued investment.”

When pharmaceutical companies develop cancer drugs, they usually first develop them for a single indication. Only after the first approval do they research additional indications. Merck’s Keytruda, which successfully treated President Jimmy Carter, was first approved for advanced melanoma in 2014. Today the company lists 19 approved indications on its website. Genentech’s Herceptin, a critical breast-cancer treatment, gained approval in the adjuvant cancer setting eight years after its original approval in the metastatic setting. Today it also has an indication for treating gastric cancer.

Nearly 60% of oncology medications approved a decade ago received additional approvals in later years. The new law eliminates the incentive to conduct additional research, because its price-setting mechanisms kick in after nine years for small-molecule drugs and 13 years for biologics, regardless of how much research companies conduct after the drug’s initial approval.

In devising their bill this way, Democrats have effectively undone decades of bipartisan policy that promoted research and development by balancing profit incentives with cost concerns. The Orphan Drug Act of 1983, which Alnylam counted on in developing its now-abandoned program, provided a combination of tax credits, grants and market exclusivity to create incentive for investment in rare-disease drugs. Fifty-two Republicans and 118 Democrats co-sponsored the law, which Democratic Rep. Henry Waxman called “an example of government at its finest, demonstrating how Congress applies itself to solve overlooked, but deeply important, problems that affect millions of Americans.”

The next year, Mr. Waxman and Republican Sen. Orrin Hatch led another bipartisan coalition to pass the Hatch-Waxman Act. Their bill granted innovators a temporary market monopoly of five years with potential extensions. In return, innovators would submit to generic competition at the end of their monopoly period. The monopoly-to-commodity-pricing pipeline has been a boon for the generic-drug industry and innovators, as well as patients and their families.

The Hatch-Waxman Act also provided six months of market exclusivity for generic manufacturers that undertook the expense and risk of developing first-on-the-market generic drugs. This allowed generics to recoup costs over those first six months as they gained market share against the innovator. As other generics entered the market, prices would plummet for patients and insurers, such as Medicare. According to the Association for Accessible Medicines, more than 90% of prescriptions in Medicare’s Part D program in 2019 were for generic drugs, which saves more than $96 billion annually for Medicare and billions more for seniors. With the impending price caps, these incentives are lost.

Yet that’s still not all the bipartisan legislation that the Inflation Reduction Act destroys. The Food and Drug Administration Modernization Act (1997) provided six months of market exclusivity to manufacturers that conduct pediatric studies for their drugs. That too was a cross-party success, shepherded by a bipartisan cast of eight senators. Pediatric clinical trials carry a host of challenges: Parents are often reluctant to include their children in them and research ethics boards impose more-stringent protections for kids. These challenges lead companies to test therapies for adult indications first. If these are successful, then they may initiate pediatric trials. The new law undercuts these incentives by mandating drastic Medicare price reductions, reducing resources available for pediatric trials and disrupting entire R&D programs.

The Democrats may have achieved a short-term talking point for the midterm elections, but in the long term this partisan healthcare bill will prevent patients from receiving innovative, lifesaving treatments. A new Congress would serve Americans well by replacing the Inflation Reduction Act with an approach that recognizes the need for economic incentives to bring new treatments to patients.

Inflation Reduction Act Destroys Drug Development

Details: Published: Friday, 04 November 2022 12:59

MDMA Microdosing for Depression and Anxiety

Details: Published: Tuesday, 26 May 2020 21:18

Usually when we think of MDMA, Molly's, Ecstasy, or Methamphetamine in the context of toxicology, we think of poisoning and overdose. This blog is about the opposite, the treatment of depression and anxiety with very low doses of these methamphetamine-derived substances. And the results have been surprising good.

Here's an article that describes the process and the science behind it.

MDMA-Assisted Psychotherapy Provides Lasting Benefit for PTSD

Adding 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, to intensive psychotherapy can significantly mitigate symptoms of posttraumatic stress disorder (PTSD), new research confirms.

One month after MDMA-assisted psychotherapy, 43% of patients no longer met criteria for PTSD, and 12 months after MDMA-assisted psychotherapy, 76% of participants no longer had PTSD, according to results of the US Food and Drug Administration (FDA)—regulated phase 2 clinical trial.

"The long-term results are the most significant finding from this latest trial, the largest ever completed of MDMA-assisted psychotherapy for PTSD," Brad Burge, director of strategic communications for the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which funded the study, told Medscape Medical News.

"The finding that about three quarters of participants no longer had PTSD a full year after receiving their last treatment with MDMA-assisted psychotherapy suggests that the treatment is not just ameliorating symptoms and is instead addressing the root cause of PTSD — specifically, a person's inner relationship with their past traumatic experiences," said Burge.

This treatment has the potential to "greatly improve the lives of people suffering from PTSD, regardless of the source of their trauma," lead investigator Marcela Ot'alora, of Aguazul-Bluewater, Inc, Boulder, Colorado, added in a news release.

"After treatment, a great majority of our participants have reported feeling more connected to themselves and to others, more joy, more compassion, and with new skills for facing life's challenges," Ot'alora noted.

The study was published online October 29 in the Journal of Psychopharmacology.

Durable Effect

The double-blind, placebo-controlled, phase 2 pilot study included 28 patients (nine men, 19 women) with chronic PTSD resulting from military service, sexual assault, and other causes. The study compared two active doses of MDMA (100 and 125 mg) with a low dose of MDMA (40-mg active placebo; control group) as an adjunct to psychotherapy.

The course of double-blind treatment included 13.5 hours of nondrug psychotherapy and 16 hours (two day-long sessions) of either full-dose or low-dose MDMA-assisted psychotherapy.

After completing the initial double-blind portion of the study, patients who initially received active-dose MDMA received a third day-long session with active-dose MDMA and 4.5 additional hours of nondrug psychotherapy. Patients initially assigned to the low-dose control group then received three day-long active-dose MDMA sessions and 18 additional hours of nondrug psychotherapy.

The primary outcome was change in total scores on the the Clinician-Administered PTSD Scale–IV (CAPS-IV) 1 month after the second session of MDMA-assisted psychotherapy.

In the intent-to-treat (ITT) set, the active-dose groups demonstrated the largest reduction in PTSD symptoms at the primary endpoint. The mean changes in CAPS-IV total scores were −26.3 with the 125-mg dose and −24.4 with the 100-mg dose, compared with −11.5 with the 40-mg dose. However, the results did not reach statistical significance.

In the per protocol (PP) set, there was a significant main effect in change of CAPS-IV total scores at the 125-mg dose (−37.0; P = .01) and a trend toward significance with the 100-mg dose (−24.4; P = .10), compared to 40-mg dose (mean change, −4.0).

"Although significant group differences were detected only in the PP set for the primary outcome, over half of participants in the ITT set who received active MDMA doses reached a 30% or greater drop in CAPS-IV total scores compared to 16.7% in the 40 mg group," the investigators note in their report.

After the third MDMA session, both the 100-mg and the 125-mg dose groups showed further reductions in CAPS-IV scores, "providing evidence that an additional session significantly improved PTSD outcomes," they note.

"Importantly," they write, the gains were maintained over 12 months after all groups had received active doses of MDMA, with 76% of patients no longer meeting the criteria for a diagnosis of PTSD.

"I would not say that our treatment is a 'cure.' Not meeting criteria for PTSD means that the symptoms are not severe enough to warrant a diagnosis of PTSD," Ot'alora cautioned in email to Medscape Medical New.

The fact that CAPS-IV scores continued to improve between the 2-month and 12-month follow-up assessments supports the theory that MDMA helps to "catalyze a therapeutic process that continues long after the last drug administration," the investigators write.

The secondary outcome measures of depression, sleep problems, and dissociation all showed significant reduction of symptoms at 12 months compared to baseline.

"These findings are noteworthy," the researchers say, "given that participants had moderate to extreme PTSD and had previously failed to benefit from psychotherapy, including approaches thought to be relatively effective (cognitive behavioral therapy [CBT] and eye movement desensitization reprocessing [EMDR]), and pharmacological treatment, including medications for depression and anxiety."

Safety Confirmed

The study replicated previous studies that showed an acceptable risk profile for MDMA, with no MDMA-related serious adverse events, the researchers say. The most frequent adverse reactions (reported by at least 40%) during treatment sessions were anxiety and jaw clenching/tight jaw, followed by headache, muscle tension, dizziness, fatigue, and low mood.

The most common adverse reactions reported 1 week following treatment included insomnia, low mood, irritability, and ruminations. Most were mild to moderate and decreased in frequency dduring the week following treatment. Temporary elevations in heart rate, systolic blood pressure, and temperature were recorded during MDMA sessions and did not require medical intervention.

This is the first MDMA trial to use multiple therapy teams with newly trained therapists implementing the manualized approach.

"Our study demonstrated that different therapy teams were able to get similarly robust results, further strengthening the case for MDMA-assisted psychotherapy as a promising option for the treatment of PTSD," Ot'alora said in the release.

If approved, "the only people with permission to do this treatment will be clinicians who have gone through MAPS training," Ot'alora told Medscape Medical News.

As reported by Medscape Medical News, the FDA granted breakthrough therapy designation to MDMA-assisted psychotherapy for PTSD in August 2017. The FDA stated that the approach "may demonstrate substantial improvement over existing therapies" and agreed to expedite its development and review.

Pivotal phase 3 clinical trials of MDMA-assisted psychotherapy for PTSD began in September 2018. They will enroll up to 300 patients across 16 sites in the United States, Canada, and Israel. If the phase 3 trials demonstrate significant efficacy and an acceptable safety profile, FDA approval is expected by 2021.

Potential for "Dramatic Improvement"

Reached for comment, Matthew Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, said the results are "very promising" and clearly warrant further, larger-scale research into MDMA in the treatment of PTSD.

"The best treatments we have for PTSD are trauma-based psychotherapies, with the strongest evidence for prolonged exposure therapy and cognitive processing therapy. However, the rates at which patients are able to adhere to these long-term therapies is very low," noted Johnson, who was not involved in the study.

"Some medications have been shown to work better than placebo, but the magnitude of improvement is very small, much smaller than for those who are able to complete trauma-based psychotherapies. The present study results are consistent with previous research on MDMA treatment for PTSD, with long-term results showing that a substantial portion of participants no longer met criteria for having PTSD," Johnson told Medscape Medical News.

As for limitations, he noted that the study was relatively small for a group-comparison study.

"The low-dose group, which served as a comparison group, actually showed substantial improvements of a similar magnitude as the higher-dose groups after blinded MDMA sessions," said Johnson.

"This was stated to be driven by a single participant. It is unknown whether this was a result of placebo (expectation) effect, a result of the interactions during preparation, or a result of even the low dose of 40 mg having efficacy.

"A larger trial would help to address this ambiguity. However, these are understandable limitations of a smaller trial, and the results are consistent with the potential for dramatic improvement of PTSD," he added.

Mayer Bellehsen, PhD, director, Mildred and Frank Feinberg Division of the

Unified Behavioral Health Center for Military Veterans and their Families in Bay Shore, New York, said new treatments for PTSD are needed.

"PTSD can be a disabling condition that affects people from all backgrounds. While first-line treatments such as cognitive-behavior therapies can be effective, a good number of individuals are unable to complete these treatments. It is therefore necessary to develop novel treatments for individuals suffering from PTSD," Bellehsen told Medscape Medical News.

He agreed that further research on a larger scale is needed, but added, "the positive results in this study and from prior studies suggest that MDMA-assisted psychotherapy is gaining attention as a promising new treatment approach."

The Multidisciplinary Association for Psychedelic Studies funded the study. Several authors have financial relationships or are employee of MAPS Public Benefit Corporation. Dr Johnson and Dr Bellehsen have disclosed no relevant financial relationships.

J Psychopharmacol. Published online October 29, 2018. Full text

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Cite this: MDMA-Assisted Psychotherapy Provides Lasting Benefit for PTSD - Medscape - Nov 01, 2018.

Dr. Gustin's Blog

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Inflation Reduction Act Destroys Drug Development

Inflation Reduction Act Destroys Drug Development

MDMA Microdosing for Depression and Anxiety

MDMA-Assisted Psychotherapy Provides Lasting Benefit for PTSD

Durable Effect

Safety Confirmed

Potential for "Dramatic Improvement"