Addiction Medicine

More teenagers in the United States reported cannabis use with vaping in 2019, compared with 2017, while cannabis use without vaping declined, based on annual survey data from more than 50,000 teens.

“With vaping prevalence rising so quickly among teens, getting a clearer picture of how cannabis use is shifting helps inform prevention and cessation efforts,” corresponding author Noah T. Kreski, MPH, of Columbia University, New York, said in an interview.

“In just 2 years, the most common cannabis use pattern changed from ‘occasional use without vaping’ to ‘frequent use with vaping,’ said Mx. Kreski, who uses the honorific Mx. and the pronouns they/them. “Knowing that, as well as the high overlap of cannabis vaping with nicotine use and binge drinking, adds to the urgency of reducing adolescent vaping.”

To quantify the trends in cannabis vaping, the researchers reviewed data from Monitoring the Future, an annual survey of high school students across the United States. The study population included 51,052 individuals; approximately 49% were male and 49% were non-Hispanic White. The researchers examined frequency of cannabis use, trends across demographic groups, and concurrent use of cannabis and other substances such as alcohol and tobacco. The findings were published in the journal Addiction.

Frequent cannabis use was defined as six or more times in the past 30 days; occasional use was defined as one to five times in the past 30 days.

Frequent cannabis use with vaping increased from 2.1% in 2017 to 5.4% in 2019. Occasional cannabis use with vaping also increased, though less dramatically, from less than 2% in 2017 to approximately 3.5% in 2019.

By contrast, both frequent and occasional cannabis use without vaping declined from 2017 to 2019 (from 3.8% to 2.1% and from 6.9% to 4.4%, respectively).

Overall, the prevalence of any level of cannabis use increased from 13.9% in 2017 to 15.4% in 2019. Both males and females showed a similar increase in reported frequent cannabis use with vaping of approximately 3%.

The results document that vaping cannabis has become more common than smoking alone among U.S. teens across almost all demographic groups, and across sex, race, urbanicity, and level of parent education; however, the increased was especially marked among Hispanic/Latinx teens and those of lower socioeconomic status, the researchers wrote.

The researchers also examined the associations between cannabis use with and without vaping and concurrent nicotine and alcohol use. Overall, the strongest association was between smoking or vaping nicotine and vaping cannabis; teens who smoked or vaped nicotine were 42 times more likely than nonnicotine users to report vaping cannabis in the past 30 days (adjusted odds ratio, 42.28). In addition, more occasions of binge drinking were more strongly associated with cannabis use with vaping (up to 10 times more likely), compared with cannabis use without vaping, (aORs, 4.48-10.09).

The study findings were limited by several factors, including the lack of questions on tetrahydrocannabinol (THC) or cannabidiol content of the cannabis products used, although evidence suggests that the potency of cannabis products in the United States is increasing, the researchers noted. Other limitations included the cross-sectional design, which prevents making associations about causality, and lack of data on the quantity of cannabis used; only data on frequency of use were recorded.

However, the results reflect a rise in cannabis use with vaping among teens in the United States, along with an increased risk of tobacco use, e-cigarette use, and binge drinking, the researchers said.

As cannabis legalization expands across the United States, policies are needed to deter use among adolescents, the researchers wrote. “These policies should be crafted to reduce an emphasis on criminalization in preference for public health promotion given the history of unequal application of punitive consequences of drug use for racialized minorities in the United States. As products, delivery systems, potency, and marketing proliferate within a for-profit industry, increased attention to youth trends, including investment in sustained and evidence-based prevention and intervention, is increasingly necessary.”

The take-home message for clinicians is to ask whether your patients are vaping, because the prevalence is not only up, but fairly universal, Mx. Kreski said. “Have a discussion that covers a broad range of substance use topics and informs teens of the potential risks of vaping, while avoiding stigma.”

The message for parents is “to talk to your kids about the risks of vaping,” said Mx. Kreski. “Prioritize open communication rather than punishment, and work together with your teens to prevent or reduce vaping.” The message for teens: “Understand that vaping has risks. You should feel empowered to talk to your parents or doctor about those risks. While it may seem like everyone’s vaping, the majority don’t. Keeping communication open between parents/caregivers, teens, and health care providers is one of the best ways to address these trends in vaping.”
 

Beware more powerful cannabis products

“While drug use in general is declining in adolescents, marijuana use remains very common,” Kelly A. Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“There is growing evidence that marijuana is now the first drug used by adolescents – replacing alcohol and nicotine – and frequent use can lead to substance abuse,” said Dr. Curran, who specializes in adolescent medicine but was involved in the study. “Cannabis use patterns have evolved over time. As I frequently tell my patients and their families, new strains and hybrids of marijuana have higher potencies of THC. Many adolescents are eschewing smoking and in its place using marijuana concentrates (wax, oil, shatter) via vape, dab pen, or rig. Use of these methods puts adolescents at high risk of social and health complications such as [e-cigarette or vaping use-associated lung injury], cannabis hyperemesis syndrome, and psychosis – and understanding these patterns and associated drug use helps health care professionals and parents keep adolescents safe.”

The take-home message for clinicians is that marijuana use via vaping continues to rise and to become more common than “traditional” marijuana smoking, Dr. Curran said. “This increase is across genders, in nearly all race/ethnicities (especially in Latinx youth), and in youth from lower socioeconomic status.” Vaping marijuana is associated with other substance abuse, so health care professionals should include questions about different forms of marijuana use, such as vape, dab pen, or rig, when working with patients, and counsel patients and families about the risks associated with use of any of these products.

The study was supported by the National Center for Injury Prevention and Control and by the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
 

More teenagers in the United States reported cannabis use with vaping in 2019, compared with 2017, while cannabis use without vaping declined, based on annual survey data from more than 50,000 teens.

“With vaping prevalence rising so quickly among teens, getting a clearer picture of how cannabis use is shifting helps inform prevention and cessation efforts,” corresponding author Noah T. Kreski, MPH, of Columbia University, New York, said in an interview.

“In just 2 years, the most common cannabis use pattern changed from ‘occasional use without vaping’ to ‘frequent use with vaping,’ said Mx. Kreski, who uses the honorific Mx. and the pronouns they/them. “Knowing that, as well as the high overlap of cannabis vaping with nicotine use and binge drinking, adds to the urgency of reducing adolescent vaping.”

To quantify the trends in cannabis vaping, the researchers reviewed data from Monitoring the Future, an annual survey of high school students across the United States. The study population included 51,052 individuals; approximately 49% were male and 49% were non-Hispanic White. The researchers examined frequency of cannabis use, trends across demographic groups, and concurrent use of cannabis and other substances such as alcohol and tobacco. The findings were published in the journal Addiction.

Frequent cannabis use was defined as six or more times in the past 30 days; occasional use was defined as one to five times in the past 30 days.

Frequent cannabis use with vaping increased from 2.1% in 2017 to 5.4% in 2019. Occasional cannabis use with vaping also increased, though less dramatically, from less than 2% in 2017 to approximately 3.5% in 2019.

By contrast, both frequent and occasional cannabis use without vaping declined from 2017 to 2019 (from 3.8% to 2.1% and from 6.9% to 4.4%, respectively).

Overall, the prevalence of any level of cannabis use increased from 13.9% in 2017 to 15.4% in 2019. Both males and females showed a similar increase in reported frequent cannabis use with vaping of approximately 3%.

The results document that vaping cannabis has become more common than smoking alone among U.S. teens across almost all demographic groups, and across sex, race, urbanicity, and level of parent education; however, the increased was especially marked among Hispanic/Latinx teens and those of lower socioeconomic status, the researchers wrote.

The researchers also examined the associations between cannabis use with and without vaping and concurrent nicotine and alcohol use. Overall, the strongest association was between smoking or vaping nicotine and vaping cannabis; teens who smoked or vaped nicotine were 42 times more likely than nonnicotine users to report vaping cannabis in the past 30 days (adjusted odds ratio, 42.28). In addition, more occasions of binge drinking were more strongly associated with cannabis use with vaping (up to 10 times more likely), compared with cannabis use without vaping, (aORs, 4.48-10.09).

The study findings were limited by several factors, including the lack of questions on tetrahydrocannabinol (THC) or cannabidiol content of the cannabis products used, although evidence suggests that the potency of cannabis products in the United States is increasing, the researchers noted. Other limitations included the cross-sectional design, which prevents making associations about causality, and lack of data on the quantity of cannabis used; only data on frequency of use were recorded.

However, the results reflect a rise in cannabis use with vaping among teens in the United States, along with an increased risk of tobacco use, e-cigarette use, and binge drinking, the researchers said.

As cannabis legalization expands across the United States, policies are needed to deter use among adolescents, the researchers wrote. “These policies should be crafted to reduce an emphasis on criminalization in preference for public health promotion given the history of unequal application of punitive consequences of drug use for racialized minorities in the United States. As products, delivery systems, potency, and marketing proliferate within a for-profit industry, increased attention to youth trends, including investment in sustained and evidence-based prevention and intervention, is increasingly necessary.”

The take-home message for clinicians is to ask whether your patients are vaping, because the prevalence is not only up, but fairly universal, Mx. Kreski said. “Have a discussion that covers a broad range of substance use topics and informs teens of the potential risks of vaping, while avoiding stigma.”

The message for parents is “to talk to your kids about the risks of vaping,” said Mx. Kreski. “Prioritize open communication rather than punishment, and work together with your teens to prevent or reduce vaping.” The message for teens: “Understand that vaping has risks. You should feel empowered to talk to your parents or doctor about those risks. While it may seem like everyone’s vaping, the majority don’t. Keeping communication open between parents/caregivers, teens, and health care providers is one of the best ways to address these trends in vaping.”
 

Beware more powerful cannabis products

“While drug use in general is declining in adolescents, marijuana use remains very common,” Kelly A. Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“There is growing evidence that marijuana is now the first drug used by adolescents – replacing alcohol and nicotine – and frequent use can lead to substance abuse,” said Dr. Curran, who specializes in adolescent medicine but was involved in the study. “Cannabis use patterns have evolved over time. As I frequently tell my patients and their families, new strains and hybrids of marijuana have higher potencies of THC. Many adolescents are eschewing smoking and in its place using marijuana concentrates (wax, oil, shatter) via vape, dab pen, or rig. Use of these methods puts adolescents at high risk of social and health complications such as [e-cigarette or vaping use-associated lung injury], cannabis hyperemesis syndrome, and psychosis – and understanding these patterns and associated drug use helps health care professionals and parents keep adolescents safe.”

The take-home message for clinicians is that marijuana use via vaping continues to rise and to become more common than “traditional” marijuana smoking, Dr. Curran said. “This increase is across genders, in nearly all race/ethnicities (especially in Latinx youth), and in youth from lower socioeconomic status.” Vaping marijuana is associated with other substance abuse, so health care professionals should include questions about different forms of marijuana use, such as vape, dab pen, or rig, when working with patients, and counsel patients and families about the risks associated with use of any of these products.

The study was supported by the National Center for Injury Prevention and Control and by the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
 

More teenagers in the United States reported cannabis use with vaping in 2019, compared with 2017, while cannabis use without vaping declined, based on annual survey data from more than 50,000 teens.

“With vaping prevalence rising so quickly among teens, getting a clearer picture of how cannabis use is shifting helps inform prevention and cessation efforts,” corresponding author Noah T. Kreski, MPH, of Columbia University, New York, said in an interview.

“In just 2 years, the most common cannabis use pattern changed from ‘occasional use without vaping’ to ‘frequent use with vaping,’ said Mx. Kreski, who uses the honorific Mx. and the pronouns they/them. “Knowing that, as well as the high overlap of cannabis vaping with nicotine use and binge drinking, adds to the urgency of reducing adolescent vaping.”

To quantify the trends in cannabis vaping, the researchers reviewed data from Monitoring the Future, an annual survey of high school students across the United States. The study population included 51,052 individuals; approximately 49% were male and 49% were non-Hispanic White. The researchers examined frequency of cannabis use, trends across demographic groups, and concurrent use of cannabis and other substances such as alcohol and tobacco. The findings were published in the journal Addiction.

Frequent cannabis use was defined as six or more times in the past 30 days; occasional use was defined as one to five times in the past 30 days.

Frequent cannabis use with vaping increased from 2.1% in 2017 to 5.4% in 2019. Occasional cannabis use with vaping also increased, though less dramatically, from less than 2% in 2017 to approximately 3.5% in 2019.

By contrast, both frequent and occasional cannabis use without vaping declined from 2017 to 2019 (from 3.8% to 2.1% and from 6.9% to 4.4%, respectively).

Overall, the prevalence of any level of cannabis use increased from 13.9% in 2017 to 15.4% in 2019. Both males and females showed a similar increase in reported frequent cannabis use with vaping of approximately 3%.

The results document that vaping cannabis has become more common than smoking alone among U.S. teens across almost all demographic groups, and across sex, race, urbanicity, and level of parent education; however, the increased was especially marked among Hispanic/Latinx teens and those of lower socioeconomic status, the researchers wrote.

The researchers also examined the associations between cannabis use with and without vaping and concurrent nicotine and alcohol use. Overall, the strongest association was between smoking or vaping nicotine and vaping cannabis; teens who smoked or vaped nicotine were 42 times more likely than nonnicotine users to report vaping cannabis in the past 30 days (adjusted odds ratio, 42.28). In addition, more occasions of binge drinking were more strongly associated with cannabis use with vaping (up to 10 times more likely), compared with cannabis use without vaping, (aORs, 4.48-10.09).

The study findings were limited by several factors, including the lack of questions on tetrahydrocannabinol (THC) or cannabidiol content of the cannabis products used, although evidence suggests that the potency of cannabis products in the United States is increasing, the researchers noted. Other limitations included the cross-sectional design, which prevents making associations about causality, and lack of data on the quantity of cannabis used; only data on frequency of use were recorded.

However, the results reflect a rise in cannabis use with vaping among teens in the United States, along with an increased risk of tobacco use, e-cigarette use, and binge drinking, the researchers said.

As cannabis legalization expands across the United States, policies are needed to deter use among adolescents, the researchers wrote. “These policies should be crafted to reduce an emphasis on criminalization in preference for public health promotion given the history of unequal application of punitive consequences of drug use for racialized minorities in the United States. As products, delivery systems, potency, and marketing proliferate within a for-profit industry, increased attention to youth trends, including investment in sustained and evidence-based prevention and intervention, is increasingly necessary.”

The take-home message for clinicians is to ask whether your patients are vaping, because the prevalence is not only up, but fairly universal, Mx. Kreski said. “Have a discussion that covers a broad range of substance use topics and informs teens of the potential risks of vaping, while avoiding stigma.”

The message for parents is “to talk to your kids about the risks of vaping,” said Mx. Kreski. “Prioritize open communication rather than punishment, and work together with your teens to prevent or reduce vaping.” The message for teens: “Understand that vaping has risks. You should feel empowered to talk to your parents or doctor about those risks. While it may seem like everyone’s vaping, the majority don’t. Keeping communication open between parents/caregivers, teens, and health care providers is one of the best ways to address these trends in vaping.”
 

Beware more powerful cannabis products

“While drug use in general is declining in adolescents, marijuana use remains very common,” Kelly A. Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“There is growing evidence that marijuana is now the first drug used by adolescents – replacing alcohol and nicotine – and frequent use can lead to substance abuse,” said Dr. Curran, who specializes in adolescent medicine but was involved in the study. “Cannabis use patterns have evolved over time. As I frequently tell my patients and their families, new strains and hybrids of marijuana have higher potencies of THC. Many adolescents are eschewing smoking and in its place using marijuana concentrates (wax, oil, shatter) via vape, dab pen, or rig. Use of these methods puts adolescents at high risk of social and health complications such as [e-cigarette or vaping use-associated lung injury], cannabis hyperemesis syndrome, and psychosis – and understanding these patterns and associated drug use helps health care professionals and parents keep adolescents safe.”

The take-home message for clinicians is that marijuana use via vaping continues to rise and to become more common than “traditional” marijuana smoking, Dr. Curran said. “This increase is across genders, in nearly all race/ethnicities (especially in Latinx youth), and in youth from lower socioeconomic status.” Vaping marijuana is associated with other substance abuse, so health care professionals should include questions about different forms of marijuana use, such as vape, dab pen, or rig, when working with patients, and counsel patients and families about the risks associated with use of any of these products.

The study was supported by the National Center for Injury Prevention and Control and by the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
 

As older adults turn to cannabis to relieve chronic symptoms, or for fun, an increasing number are winding up in emergency departments with side effects from the drug.

Researchers in California found an 18-fold increase in the rate of cannabis-related trips to the ED visits among adults over age 65 in the state from 2005 to 2019.

Addressing potential harms of cannabis use among older adults, who face heightened risk for adverse reactions to the substance, “is urgently required,” the researchers reported at the annual meeting of the American Geriatrics Society.

The researchers advised doctors to discuss cannabis use with older patients and screen older adults for cannabis use. Those living with multiple chronic conditions and taking multiple medications are especially likely to be at risk for harm, coinvestigator Benjamin Han, MD, MPH, a geriatrician at the University of California, San Diego, said in an interview.

Dr. Han added that “very little” is understood about the risks and benefits of cannabis use in the elderly, and more studies are needed “so that clinicians can have data-informed discussions with their patients.”

California legalized medical marijuana in 1996 and recreational marijuana in 2016.

The researchers used diagnostic code data from California’s nonmilitary acute care hospitals, collected by the state’s Department of Healthcare Access and Information, to calculate annual rates of cannabis-related visits per 10,000 ED visits.
 

ED trips up sharply among older adults

Rates of cannabis-related visits increased significantly for all older adult age ranges (P < .001), according to the researchers. Among those aged 65-74 years, the rate increased about 15-fold, from 44.9 per 10,000 visits in 2005 to 714.5 per 100,000 in 2019; for ages 75-84, the rate increased about 22-fold, from 8.4 to 193.9 per 10,000; and for those 85 and older the rate jumped nearly 18-fold, from 2.1 to 39.2 per 10,000.

The greatest increase occurred in visits categorized in diagnostic codes as cannabis abuse and unspecified use. Cannabis dependence and cannabis poisoning accounted for only a small fraction of cases, the investigators found.

The researchers did not have data on specific reasons for a visit, or whether patients had smoked or ingested marijuana products. They also could not discern whether patients had used delta-9-tetrahydrocannabinol, which has psychoactive properties, or cannabidiol, which typically does not have the same mind-altering effects.

Dr. Han said the data may not present a full picture of marijuana-related ED visits. “It is important to recognize that older adults have lived through the very putative language around drug use – including cannabis – as part of the racist war on drugs,” which could lead them to omit having used drugs during the intake process.

A 2017 study linked cannabis use among older adults with more injuries, which in turn led to greater emergency department use. Brian Kaskie, PhD, associate professor in health management and policy at the University of Iowa, Iowa City, said in an interview that the new findings show a state-specific, but alarming trend, and that more research is needed.

“Were these first-time users who were not familiar with anxiety-inducing aspects of cannabis use and took high potency products? Did they complete any education about how to use cannabis?” said Dr. Kaskie, who was not involved in the new study. “Were the ER visits for relatively benign, nonemergent reasons or were these ... visits an outcome of a tragic, harmful event like a car accident or overdose?”

Dr. Han and Dr. Kaskie disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

As older adults turn to cannabis to relieve chronic symptoms, or for fun, an increasing number are winding up in emergency departments with side effects from the drug.

Researchers in California found an 18-fold increase in the rate of cannabis-related trips to the ED visits among adults over age 65 in the state from 2005 to 2019.

Addressing potential harms of cannabis use among older adults, who face heightened risk for adverse reactions to the substance, “is urgently required,” the researchers reported at the annual meeting of the American Geriatrics Society.

The researchers advised doctors to discuss cannabis use with older patients and screen older adults for cannabis use. Those living with multiple chronic conditions and taking multiple medications are especially likely to be at risk for harm, coinvestigator Benjamin Han, MD, MPH, a geriatrician at the University of California, San Diego, said in an interview.

Dr. Han added that “very little” is understood about the risks and benefits of cannabis use in the elderly, and more studies are needed “so that clinicians can have data-informed discussions with their patients.”

California legalized medical marijuana in 1996 and recreational marijuana in 2016.

The researchers used diagnostic code data from California’s nonmilitary acute care hospitals, collected by the state’s Department of Healthcare Access and Information, to calculate annual rates of cannabis-related visits per 10,000 ED visits.
 

ED trips up sharply among older adults

Rates of cannabis-related visits increased significantly for all older adult age ranges (P < .001), according to the researchers. Among those aged 65-74 years, the rate increased about 15-fold, from 44.9 per 10,000 visits in 2005 to 714.5 per 100,000 in 2019; for ages 75-84, the rate increased about 22-fold, from 8.4 to 193.9 per 10,000; and for those 85 and older the rate jumped nearly 18-fold, from 2.1 to 39.2 per 10,000.

The greatest increase occurred in visits categorized in diagnostic codes as cannabis abuse and unspecified use. Cannabis dependence and cannabis poisoning accounted for only a small fraction of cases, the investigators found.

The researchers did not have data on specific reasons for a visit, or whether patients had smoked or ingested marijuana products. They also could not discern whether patients had used delta-9-tetrahydrocannabinol, which has psychoactive properties, or cannabidiol, which typically does not have the same mind-altering effects.

Dr. Han said the data may not present a full picture of marijuana-related ED visits. “It is important to recognize that older adults have lived through the very putative language around drug use – including cannabis – as part of the racist war on drugs,” which could lead them to omit having used drugs during the intake process.

A 2017 study linked cannabis use among older adults with more injuries, which in turn led to greater emergency department use. Brian Kaskie, PhD, associate professor in health management and policy at the University of Iowa, Iowa City, said in an interview that the new findings show a state-specific, but alarming trend, and that more research is needed.

“Were these first-time users who were not familiar with anxiety-inducing aspects of cannabis use and took high potency products? Did they complete any education about how to use cannabis?” said Dr. Kaskie, who was not involved in the new study. “Were the ER visits for relatively benign, nonemergent reasons or were these ... visits an outcome of a tragic, harmful event like a car accident or overdose?”

Dr. Han and Dr. Kaskie disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

As older adults turn to cannabis to relieve chronic symptoms, or for fun, an increasing number are winding up in emergency departments with side effects from the drug.

Researchers in California found an 18-fold increase in the rate of cannabis-related trips to the ED visits among adults over age 65 in the state from 2005 to 2019.

Addressing potential harms of cannabis use among older adults, who face heightened risk for adverse reactions to the substance, “is urgently required,” the researchers reported at the annual meeting of the American Geriatrics Society.

The researchers advised doctors to discuss cannabis use with older patients and screen older adults for cannabis use. Those living with multiple chronic conditions and taking multiple medications are especially likely to be at risk for harm, coinvestigator Benjamin Han, MD, MPH, a geriatrician at the University of California, San Diego, said in an interview.

Dr. Han added that “very little” is understood about the risks and benefits of cannabis use in the elderly, and more studies are needed “so that clinicians can have data-informed discussions with their patients.”

California legalized medical marijuana in 1996 and recreational marijuana in 2016.

The researchers used diagnostic code data from California’s nonmilitary acute care hospitals, collected by the state’s Department of Healthcare Access and Information, to calculate annual rates of cannabis-related visits per 10,000 ED visits.
 

ED trips up sharply among older adults

Rates of cannabis-related visits increased significantly for all older adult age ranges (P < .001), according to the researchers. Among those aged 65-74 years, the rate increased about 15-fold, from 44.9 per 10,000 visits in 2005 to 714.5 per 100,000 in 2019; for ages 75-84, the rate increased about 22-fold, from 8.4 to 193.9 per 10,000; and for those 85 and older the rate jumped nearly 18-fold, from 2.1 to 39.2 per 10,000.

The greatest increase occurred in visits categorized in diagnostic codes as cannabis abuse and unspecified use. Cannabis dependence and cannabis poisoning accounted for only a small fraction of cases, the investigators found.

The researchers did not have data on specific reasons for a visit, or whether patients had smoked or ingested marijuana products. They also could not discern whether patients had used delta-9-tetrahydrocannabinol, which has psychoactive properties, or cannabidiol, which typically does not have the same mind-altering effects.

Dr. Han said the data may not present a full picture of marijuana-related ED visits. “It is important to recognize that older adults have lived through the very putative language around drug use – including cannabis – as part of the racist war on drugs,” which could lead them to omit having used drugs during the intake process.

A 2017 study linked cannabis use among older adults with more injuries, which in turn led to greater emergency department use. Brian Kaskie, PhD, associate professor in health management and policy at the University of Iowa, Iowa City, said in an interview that the new findings show a state-specific, but alarming trend, and that more research is needed.

“Were these first-time users who were not familiar with anxiety-inducing aspects of cannabis use and took high potency products? Did they complete any education about how to use cannabis?” said Dr. Kaskie, who was not involved in the new study. “Were the ER visits for relatively benign, nonemergent reasons or were these ... visits an outcome of a tragic, harmful event like a car accident or overdose?”

Dr. Han and Dr. Kaskie disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Black patients and those with public insurance are more likely than their White, wealthier counterparts to be screened for marijuana use during pregnancy, researchers have found.

The data build on a growing body of evidence that disparities in age, insurance type, and race affect which women undergo drug testing during pregnancy and come under scrutiny from state social service agencies.

Many states require health care facilities to notify child protective services or law enforcement of a positive drug screening, but the consequences for women vary greatly from state to state. Twenty-four states and the District of Columbia consider prenatal drug use to be child abuse. But recent evidence suggests that urine drug screenings may not be reliable but can lead to separation of parents and babies.

“In many ways, the health system is better equipped to address these concerns than the criminal justice system,” Rebecca Stone, PhD, associate professor of sociology and criminal justice at Suffolk University, Boston, told this news organization. “They shouldn’t be criminal justice problems in many cases,” added Dr. Stone, who was not involved with the study.

The researchers analyzed data from the 2,045 patients who gave birth between January and July 2020. Of those, roughly one-fourth (24%) underwent a urine drug screening. The most common reason for a screen was that clinicians either suspected or patients self-reported use of marijuana during or shortly before pregnancy, according to the researchers, who presented their findings at the American College of Obstetricians and Gynecologists (ACOG) 2022 Annual Meeting.

Nearly 80% of the 209 patients who underwent drug testing because of suspected marijuana use were Black, and nearly 61% had public insurance. The median age of persons who underwent drug testing was 25 years; the overall median age of pregnant patients was 29 years.

Of the 1,561 patients who didn’t undergo drug screening, 43% were Black, and 37% had public insurance coverage.

Clinicians reported that nearly all patients (117/125; 94%) who tested positive for marijuana were reported to the Missouri child abuse/neglect hotline. Only four women who tested positive for marijuana use also tested positive for at least one other illegal drug.

“Marijuana did not predict other drug exposure; thus, we suggest that a history of marijuana use should not be used as a criteria for sending a urine drug screen on patients [who are admitted to the labor unit],” said Jeannie Kelly, MD, medical director of maternal-fetal transport and labor and delivery at the Washington University School of Medicine, St. Louis, who is the senior author of the study. “In our experience, this is a policy that increases inequitable screening without improving our ability to identify families who need extra support or monitoring.”

All patients in the study verbally agreed to a urine drug screening. Hospitals around the country have faced lawsuits for failing to gain consent from women undergoing such tests. A 2001 ruling from the U.S. Supreme Court made informed consent mandatory in the absence of a warrant.
 

Legal consequences of a positive test

Children exposed to marijuana in the womb are at heightened risk for impaired cognition and learning disabilities, according to a 2015 report from ACOG’s Committee on Obstetric Practice. However, a lack of care before birth can be harmful to infants and result in low birth weight and severe neurologic and other problems.

In a 2015 study, Dr. Stone found that women were less likely to seek prenatal care if they worried about the legal consequences of a positive test.

Dr. Kelly said the threat of interference from child protective services is often the top worry of pregnant women with substance use disorders. She argued that clinicians should treat marijuana the same way they do tobacco: discourage its use without reporting patients to law enforcement.

“Our suggestion is that this history you elicit of someone using marijuana probably shouldn’t be used [as a trigger for drug screening],” Dr. Kelly said.

She added that doctors can use discretion in choosing to screen for drugs, and she urged clinicians and health care institutions to reevaluate their drug screening practices to reduce harm and increase equitable care.

“We can only work the system in the places that we have control over,” she said. “I can’t control the downward cascade, but I can definitely control who I send a urine drug screen on.”

Dr. Kelly and Dr. Stone reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Black patients and those with public insurance are more likely than their White, wealthier counterparts to be screened for marijuana use during pregnancy, researchers have found.

The data build on a growing body of evidence that disparities in age, insurance type, and race affect which women undergo drug testing during pregnancy and come under scrutiny from state social service agencies.

Many states require health care facilities to notify child protective services or law enforcement of a positive drug screening, but the consequences for women vary greatly from state to state. Twenty-four states and the District of Columbia consider prenatal drug use to be child abuse. But recent evidence suggests that urine drug screenings may not be reliable but can lead to separation of parents and babies.

“In many ways, the health system is better equipped to address these concerns than the criminal justice system,” Rebecca Stone, PhD, associate professor of sociology and criminal justice at Suffolk University, Boston, told this news organization. “They shouldn’t be criminal justice problems in many cases,” added Dr. Stone, who was not involved with the study.

The researchers analyzed data from the 2,045 patients who gave birth between January and July 2020. Of those, roughly one-fourth (24%) underwent a urine drug screening. The most common reason for a screen was that clinicians either suspected or patients self-reported use of marijuana during or shortly before pregnancy, according to the researchers, who presented their findings at the American College of Obstetricians and Gynecologists (ACOG) 2022 Annual Meeting.

Nearly 80% of the 209 patients who underwent drug testing because of suspected marijuana use were Black, and nearly 61% had public insurance. The median age of persons who underwent drug testing was 25 years; the overall median age of pregnant patients was 29 years.

Of the 1,561 patients who didn’t undergo drug screening, 43% were Black, and 37% had public insurance coverage.

Clinicians reported that nearly all patients (117/125; 94%) who tested positive for marijuana were reported to the Missouri child abuse/neglect hotline. Only four women who tested positive for marijuana use also tested positive for at least one other illegal drug.

“Marijuana did not predict other drug exposure; thus, we suggest that a history of marijuana use should not be used as a criteria for sending a urine drug screen on patients [who are admitted to the labor unit],” said Jeannie Kelly, MD, medical director of maternal-fetal transport and labor and delivery at the Washington University School of Medicine, St. Louis, who is the senior author of the study. “In our experience, this is a policy that increases inequitable screening without improving our ability to identify families who need extra support or monitoring.”

All patients in the study verbally agreed to a urine drug screening. Hospitals around the country have faced lawsuits for failing to gain consent from women undergoing such tests. A 2001 ruling from the U.S. Supreme Court made informed consent mandatory in the absence of a warrant.
 

Legal consequences of a positive test

Children exposed to marijuana in the womb are at heightened risk for impaired cognition and learning disabilities, according to a 2015 report from ACOG’s Committee on Obstetric Practice. However, a lack of care before birth can be harmful to infants and result in low birth weight and severe neurologic and other problems.

In a 2015 study, Dr. Stone found that women were less likely to seek prenatal care if they worried about the legal consequences of a positive test.

Dr. Kelly said the threat of interference from child protective services is often the top worry of pregnant women with substance use disorders. She argued that clinicians should treat marijuana the same way they do tobacco: discourage its use without reporting patients to law enforcement.

“Our suggestion is that this history you elicit of someone using marijuana probably shouldn’t be used [as a trigger for drug screening],” Dr. Kelly said.

She added that doctors can use discretion in choosing to screen for drugs, and she urged clinicians and health care institutions to reevaluate their drug screening practices to reduce harm and increase equitable care.

“We can only work the system in the places that we have control over,” she said. “I can’t control the downward cascade, but I can definitely control who I send a urine drug screen on.”

Dr. Kelly and Dr. Stone reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Black patients and those with public insurance are more likely than their White, wealthier counterparts to be screened for marijuana use during pregnancy, researchers have found.

The data build on a growing body of evidence that disparities in age, insurance type, and race affect which women undergo drug testing during pregnancy and come under scrutiny from state social service agencies.

Many states require health care facilities to notify child protective services or law enforcement of a positive drug screening, but the consequences for women vary greatly from state to state. Twenty-four states and the District of Columbia consider prenatal drug use to be child abuse. But recent evidence suggests that urine drug screenings may not be reliable but can lead to separation of parents and babies.

“In many ways, the health system is better equipped to address these concerns than the criminal justice system,” Rebecca Stone, PhD, associate professor of sociology and criminal justice at Suffolk University, Boston, told this news organization. “They shouldn’t be criminal justice problems in many cases,” added Dr. Stone, who was not involved with the study.

The researchers analyzed data from the 2,045 patients who gave birth between January and July 2020. Of those, roughly one-fourth (24%) underwent a urine drug screening. The most common reason for a screen was that clinicians either suspected or patients self-reported use of marijuana during or shortly before pregnancy, according to the researchers, who presented their findings at the American College of Obstetricians and Gynecologists (ACOG) 2022 Annual Meeting.

Nearly 80% of the 209 patients who underwent drug testing because of suspected marijuana use were Black, and nearly 61% had public insurance. The median age of persons who underwent drug testing was 25 years; the overall median age of pregnant patients was 29 years.

Of the 1,561 patients who didn’t undergo drug screening, 43% were Black, and 37% had public insurance coverage.

Clinicians reported that nearly all patients (117/125; 94%) who tested positive for marijuana were reported to the Missouri child abuse/neglect hotline. Only four women who tested positive for marijuana use also tested positive for at least one other illegal drug.

“Marijuana did not predict other drug exposure; thus, we suggest that a history of marijuana use should not be used as a criteria for sending a urine drug screen on patients [who are admitted to the labor unit],” said Jeannie Kelly, MD, medical director of maternal-fetal transport and labor and delivery at the Washington University School of Medicine, St. Louis, who is the senior author of the study. “In our experience, this is a policy that increases inequitable screening without improving our ability to identify families who need extra support or monitoring.”

All patients in the study verbally agreed to a urine drug screening. Hospitals around the country have faced lawsuits for failing to gain consent from women undergoing such tests. A 2001 ruling from the U.S. Supreme Court made informed consent mandatory in the absence of a warrant.
 

Legal consequences of a positive test

Children exposed to marijuana in the womb are at heightened risk for impaired cognition and learning disabilities, according to a 2015 report from ACOG’s Committee on Obstetric Practice. However, a lack of care before birth can be harmful to infants and result in low birth weight and severe neurologic and other problems.

In a 2015 study, Dr. Stone found that women were less likely to seek prenatal care if they worried about the legal consequences of a positive test.

Dr. Kelly said the threat of interference from child protective services is often the top worry of pregnant women with substance use disorders. She argued that clinicians should treat marijuana the same way they do tobacco: discourage its use without reporting patients to law enforcement.

“Our suggestion is that this history you elicit of someone using marijuana probably shouldn’t be used [as a trigger for drug screening],” Dr. Kelly said.

She added that doctors can use discretion in choosing to screen for drugs, and she urged clinicians and health care institutions to reevaluate their drug screening practices to reduce harm and increase equitable care.

“We can only work the system in the places that we have control over,” she said. “I can’t control the downward cascade, but I can definitely control who I send a urine drug screen on.”

Dr. Kelly and Dr. Stone reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Seven physicians were among 12 medical professionals charged today by the U.S. Department of Justice with opioid distribution offenses.

In coordination with federal and state law enforcement, the DOJ charged the defendants for their involvement in the illegal distribution of opioids. At the time that they were charged with the alleged offenses, 12 of the defendants were medical professionals.

The 12 persons in eight federal districts across the country distributed more than 115 million controlled substances, including buprenorphine, clonazepam, dextroamphetamine-amphetamine, hydrocodone, morphine sulfate, oxycodone, oxymorphone, and Suboxone, per the DOJ.

“Doctors and health care professionals are entrusted with prescribing medicine responsibly and in the best interests of their patients. Today’s takedown targets medical providers across the country whose greed drove them to abandon this responsibility in favor of criminal profits,” said Anne Milgram, administrator of the Drug Enforcement Administration.
 

Medical professionals, others across six states charged

One former nurse, one business manager, and one individual who practiced medicine without a medical credential are among those listed in the indictment. These include the following:

• Eskender Getachew, MD, a Columbus, Ohio, sleep medicine specialist, was charged with unlawful distribution of controlled substances outside the use of professional practice and not for a legitimate medical practice.
• Charles Kistler, DO, an Upper Arlington, Ohio, family practice physician, was charged with unlawful distribution of controlled substances for unlawful prescribing at Midtown Family Practice Clinic in Columbus.
• Yogeshwar Gil, MBBS, a Manchester, Tenn., family medicine doctor and owner of a medical practice, was charged with conspiracy to unlawfully distribute controlled substances and maintaining a drug-involved premises. Dr. Gil was charged in connection with an alleged scheme to distribute opioids and Suboxone outside the usual course of professional practice and without a legitimate medical purpose.
• Contessa Holley, RN, a Pulaski, Tenn., former nurse and clinical director, was charged with wire fraud, aggravated identity theft, and possession of a controlled substance with intent to distribute. She’s alleged to be connected with a scheme to unlawfully obtain opioids by filling fraudulent prescriptions in the names of current and former patients who were in hospice. The indictment alleged that Ms. Holley used the patients’ hospice benefits to cover the opioids’ costs while keeping the drugs for her own use and for further distribution.
• Francene Aretha Gayle, MD, an Orlando, Fla., physician, was charged with conspiracy to unlawfully distribute controlled substances, conspiracy to commit health care fraud, health care fraud, and several substantive counts of illegally issuing opioid prescriptions. Dr. Gayle was charged along with Schara Monique Davis, a Huntsville, Ala.–based business manager. Per the indictment, Dr. Gayle and Ms. Davis operated three medical clinics in Alabama, where Dr. Gayle was the sole physician. The medical clinics billed health insurers for millions of dollars in patient visits that Dr. Gayle had supposedly conducted but during which she was allegedly absent from the clinics; other staff members conducted the visits instead. It’s alleged that Dr. Gayle presigned prescriptions for opioids that were given to patients.
• Robert Taffet, MD, a Haddonfield, N.J., orthopedic surgeon and owner of a medical practice in Sicklerville, N.J., was charged with conspiracy to unlawfully distribute controlled substances. The indictment alleges that he falsified patient files to state that he interacted with patients when he didn’t and that he issued prescriptions for opioids and other controlled substances without assessing the patients in person or by telemedicine. It’s alleged that Dr. Taffett issued prescriptions for more than 179,000 pills that were dispensed by New Jersey pharmacies between April 2020 and December 2021.
• Hau La, MD, a Brentwood, Tenn., family medicine physician and the operator of Absolute Medical Care in Smyrna, Tenn., was charged with sixteen counts of unlawful distribution of a controlled substance. The physician is alleged to have unlawfully prescribed opioids to eight patients outside the usual course of practice and without a legitimate medical purpose.
• Frederick De Mesa, of War, W.Va., practiced as a physician and used a DEA registration number that allowed him to prescribe controlled substances. Mr. De Mesa prescribed these substances without a medical license and didn’t have an active DEA registration number, according to the indictment.
• Loey Kousa, a former internist from Paintsville, Ky., was charged with unlawful distribution of controlled substances, healthcare fraud, and making false statements in connection with the delivery of health care services. The indictment alleges that the former physician issued prescriptions for opioids outside the usual course of professional practice and without a legitimate medical purpose in his capacity as owner and operator of East KY Clinic in Paintsville. He is alleged to have issued the unlawful prescriptions for patients whose treatments were covered by taxpayer-funded programs such as Medicare and Medicaid; he also billed these programs for medically unnecessary procedures for these patients.

Also included in the indictment were Jay Sadrinia, DMD, a Villa Hills, Ky., dentist, who was charged with four counts of illegal distribution of oxycodone and morphine sulfate and one count of illegal distribution of morphine sulfate that resulted in death or serious bodily injury; and Casey Kelleher, an owner-operator of Neighborhood Pharmacy in Boynton Beach, Fla., who allegedly sold large amounts of oxycodone and hydromorphone on the black market.

The Centers for Medicare & Medicaid Services’ Center for Program Integrity has taken six administrative actions against health care providers for their alleged involvement in these offenses, per the DOJ’s announcement.

“Patient care and safety are top priorities for us, and CMS has taken administrative action against six providers to protect critical resources entrusted to Medicare while also safeguarding people with Medicare,” said CMS Administrator Chiquita Brooks-LaSure.

“These actions to combat fraud, waste, and abuse in our federal programs would not be possible without the close and successful partnership of the Centers for Medicare & Medicaid Services, the Department of Justice, and the U.S. Department of Health and Human Services Office of Inspector General,” she added.

A version of this article first appeared on Medscape.com.

Seven physicians were among 12 medical professionals charged today by the U.S. Department of Justice with opioid distribution offenses.

In coordination with federal and state law enforcement, the DOJ charged the defendants for their involvement in the illegal distribution of opioids. At the time that they were charged with the alleged offenses, 12 of the defendants were medical professionals.

The 12 persons in eight federal districts across the country distributed more than 115 million controlled substances, including buprenorphine, clonazepam, dextroamphetamine-amphetamine, hydrocodone, morphine sulfate, oxycodone, oxymorphone, and Suboxone, per the DOJ.

“Doctors and health care professionals are entrusted with prescribing medicine responsibly and in the best interests of their patients. Today’s takedown targets medical providers across the country whose greed drove them to abandon this responsibility in favor of criminal profits,” said Anne Milgram, administrator of the Drug Enforcement Administration.
 

Medical professionals, others across six states charged

One former nurse, one business manager, and one individual who practiced medicine without a medical credential are among those listed in the indictment. These include the following:

• Eskender Getachew, MD, a Columbus, Ohio, sleep medicine specialist, was charged with unlawful distribution of controlled substances outside the use of professional practice and not for a legitimate medical practice.
• Charles Kistler, DO, an Upper Arlington, Ohio, family practice physician, was charged with unlawful distribution of controlled substances for unlawful prescribing at Midtown Family Practice Clinic in Columbus.
• Yogeshwar Gil, MBBS, a Manchester, Tenn., family medicine doctor and owner of a medical practice, was charged with conspiracy to unlawfully distribute controlled substances and maintaining a drug-involved premises. Dr. Gil was charged in connection with an alleged scheme to distribute opioids and Suboxone outside the usual course of professional practice and without a legitimate medical purpose.
• Contessa Holley, RN, a Pulaski, Tenn., former nurse and clinical director, was charged with wire fraud, aggravated identity theft, and possession of a controlled substance with intent to distribute. She’s alleged to be connected with a scheme to unlawfully obtain opioids by filling fraudulent prescriptions in the names of current and former patients who were in hospice. The indictment alleged that Ms. Holley used the patients’ hospice benefits to cover the opioids’ costs while keeping the drugs for her own use and for further distribution.
• Francene Aretha Gayle, MD, an Orlando, Fla., physician, was charged with conspiracy to unlawfully distribute controlled substances, conspiracy to commit health care fraud, health care fraud, and several substantive counts of illegally issuing opioid prescriptions. Dr. Gayle was charged along with Schara Monique Davis, a Huntsville, Ala.–based business manager. Per the indictment, Dr. Gayle and Ms. Davis operated three medical clinics in Alabama, where Dr. Gayle was the sole physician. The medical clinics billed health insurers for millions of dollars in patient visits that Dr. Gayle had supposedly conducted but during which she was allegedly absent from the clinics; other staff members conducted the visits instead. It’s alleged that Dr. Gayle presigned prescriptions for opioids that were given to patients.
• Robert Taffet, MD, a Haddonfield, N.J., orthopedic surgeon and owner of a medical practice in Sicklerville, N.J., was charged with conspiracy to unlawfully distribute controlled substances. The indictment alleges that he falsified patient files to state that he interacted with patients when he didn’t and that he issued prescriptions for opioids and other controlled substances without assessing the patients in person or by telemedicine. It’s alleged that Dr. Taffett issued prescriptions for more than 179,000 pills that were dispensed by New Jersey pharmacies between April 2020 and December 2021.
• Hau La, MD, a Brentwood, Tenn., family medicine physician and the operator of Absolute Medical Care in Smyrna, Tenn., was charged with sixteen counts of unlawful distribution of a controlled substance. The physician is alleged to have unlawfully prescribed opioids to eight patients outside the usual course of practice and without a legitimate medical purpose.
• Frederick De Mesa, of War, W.Va., practiced as a physician and used a DEA registration number that allowed him to prescribe controlled substances. Mr. De Mesa prescribed these substances without a medical license and didn’t have an active DEA registration number, according to the indictment.
• Loey Kousa, a former internist from Paintsville, Ky., was charged with unlawful distribution of controlled substances, healthcare fraud, and making false statements in connection with the delivery of health care services. The indictment alleges that the former physician issued prescriptions for opioids outside the usual course of professional practice and without a legitimate medical purpose in his capacity as owner and operator of East KY Clinic in Paintsville. He is alleged to have issued the unlawful prescriptions for patients whose treatments were covered by taxpayer-funded programs such as Medicare and Medicaid; he also billed these programs for medically unnecessary procedures for these patients.

Also included in the indictment were Jay Sadrinia, DMD, a Villa Hills, Ky., dentist, who was charged with four counts of illegal distribution of oxycodone and morphine sulfate and one count of illegal distribution of morphine sulfate that resulted in death or serious bodily injury; and Casey Kelleher, an owner-operator of Neighborhood Pharmacy in Boynton Beach, Fla., who allegedly sold large amounts of oxycodone and hydromorphone on the black market.

The Centers for Medicare & Medicaid Services’ Center for Program Integrity has taken six administrative actions against health care providers for their alleged involvement in these offenses, per the DOJ’s announcement.

“Patient care and safety are top priorities for us, and CMS has taken administrative action against six providers to protect critical resources entrusted to Medicare while also safeguarding people with Medicare,” said CMS Administrator Chiquita Brooks-LaSure.

“These actions to combat fraud, waste, and abuse in our federal programs would not be possible without the close and successful partnership of the Centers for Medicare & Medicaid Services, the Department of Justice, and the U.S. Department of Health and Human Services Office of Inspector General,” she added.

A version of this article first appeared on Medscape.com.

Seven physicians were among 12 medical professionals charged today by the U.S. Department of Justice with opioid distribution offenses.

In coordination with federal and state law enforcement, the DOJ charged the defendants for their involvement in the illegal distribution of opioids. At the time that they were charged with the alleged offenses, 12 of the defendants were medical professionals.

The 12 persons in eight federal districts across the country distributed more than 115 million controlled substances, including buprenorphine, clonazepam, dextroamphetamine-amphetamine, hydrocodone, morphine sulfate, oxycodone, oxymorphone, and Suboxone, per the DOJ.

“Doctors and health care professionals are entrusted with prescribing medicine responsibly and in the best interests of their patients. Today’s takedown targets medical providers across the country whose greed drove them to abandon this responsibility in favor of criminal profits,” said Anne Milgram, administrator of the Drug Enforcement Administration.
 

Medical professionals, others across six states charged

One former nurse, one business manager, and one individual who practiced medicine without a medical credential are among those listed in the indictment. These include the following:

• Eskender Getachew, MD, a Columbus, Ohio, sleep medicine specialist, was charged with unlawful distribution of controlled substances outside the use of professional practice and not for a legitimate medical practice.
• Charles Kistler, DO, an Upper Arlington, Ohio, family practice physician, was charged with unlawful distribution of controlled substances for unlawful prescribing at Midtown Family Practice Clinic in Columbus.
• Yogeshwar Gil, MBBS, a Manchester, Tenn., family medicine doctor and owner of a medical practice, was charged with conspiracy to unlawfully distribute controlled substances and maintaining a drug-involved premises. Dr. Gil was charged in connection with an alleged scheme to distribute opioids and Suboxone outside the usual course of professional practice and without a legitimate medical purpose.
• Contessa Holley, RN, a Pulaski, Tenn., former nurse and clinical director, was charged with wire fraud, aggravated identity theft, and possession of a controlled substance with intent to distribute. She’s alleged to be connected with a scheme to unlawfully obtain opioids by filling fraudulent prescriptions in the names of current and former patients who were in hospice. The indictment alleged that Ms. Holley used the patients’ hospice benefits to cover the opioids’ costs while keeping the drugs for her own use and for further distribution.
• Francene Aretha Gayle, MD, an Orlando, Fla., physician, was charged with conspiracy to unlawfully distribute controlled substances, conspiracy to commit health care fraud, health care fraud, and several substantive counts of illegally issuing opioid prescriptions. Dr. Gayle was charged along with Schara Monique Davis, a Huntsville, Ala.–based business manager. Per the indictment, Dr. Gayle and Ms. Davis operated three medical clinics in Alabama, where Dr. Gayle was the sole physician. The medical clinics billed health insurers for millions of dollars in patient visits that Dr. Gayle had supposedly conducted but during which she was allegedly absent from the clinics; other staff members conducted the visits instead. It’s alleged that Dr. Gayle presigned prescriptions for opioids that were given to patients.
• Robert Taffet, MD, a Haddonfield, N.J., orthopedic surgeon and owner of a medical practice in Sicklerville, N.J., was charged with conspiracy to unlawfully distribute controlled substances. The indictment alleges that he falsified patient files to state that he interacted with patients when he didn’t and that he issued prescriptions for opioids and other controlled substances without assessing the patients in person or by telemedicine. It’s alleged that Dr. Taffett issued prescriptions for more than 179,000 pills that were dispensed by New Jersey pharmacies between April 2020 and December 2021.
• Hau La, MD, a Brentwood, Tenn., family medicine physician and the operator of Absolute Medical Care in Smyrna, Tenn., was charged with sixteen counts of unlawful distribution of a controlled substance. The physician is alleged to have unlawfully prescribed opioids to eight patients outside the usual course of practice and without a legitimate medical purpose.
• Frederick De Mesa, of War, W.Va., practiced as a physician and used a DEA registration number that allowed him to prescribe controlled substances. Mr. De Mesa prescribed these substances without a medical license and didn’t have an active DEA registration number, according to the indictment.
• Loey Kousa, a former internist from Paintsville, Ky., was charged with unlawful distribution of controlled substances, healthcare fraud, and making false statements in connection with the delivery of health care services. The indictment alleges that the former physician issued prescriptions for opioids outside the usual course of professional practice and without a legitimate medical purpose in his capacity as owner and operator of East KY Clinic in Paintsville. He is alleged to have issued the unlawful prescriptions for patients whose treatments were covered by taxpayer-funded programs such as Medicare and Medicaid; he also billed these programs for medically unnecessary procedures for these patients.

Also included in the indictment were Jay Sadrinia, DMD, a Villa Hills, Ky., dentist, who was charged with four counts of illegal distribution of oxycodone and morphine sulfate and one count of illegal distribution of morphine sulfate that resulted in death or serious bodily injury; and Casey Kelleher, an owner-operator of Neighborhood Pharmacy in Boynton Beach, Fla., who allegedly sold large amounts of oxycodone and hydromorphone on the black market.

The Centers for Medicare & Medicaid Services’ Center for Program Integrity has taken six administrative actions against health care providers for their alleged involvement in these offenses, per the DOJ’s announcement.

“Patient care and safety are top priorities for us, and CMS has taken administrative action against six providers to protect critical resources entrusted to Medicare while also safeguarding people with Medicare,” said CMS Administrator Chiquita Brooks-LaSure.

“These actions to combat fraud, waste, and abuse in our federal programs would not be possible without the close and successful partnership of the Centers for Medicare & Medicaid Services, the Department of Justice, and the U.S. Department of Health and Human Services Office of Inspector General,” she added.

A version of this article first appeared on Medscape.com.

Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.

Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.

In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.

Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.

Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.

The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.

The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.

The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.

The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
 

Potential for postpandemic surge in drug use

Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.

“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.

“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”

The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.

Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.

In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.

Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.

Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.

The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.

The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.

The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.

The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
 

Potential for postpandemic surge in drug use

Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.

“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.

“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”

The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.

Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.

In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.

Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.

Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.

The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.

The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.

The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.

The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
 

Potential for postpandemic surge in drug use

Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.

“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.

“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.

“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”

The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

MADRID, Spain – Individuals with substance use disorders are at higher risk of being infected by and dying from COVID-19 – even if they are fully vaccinated – compared with the general population. Such are the findings of a line of research led by Mexican psychiatrist Nora Volkow, MD, director of the U.S. National Institute on Drug Abuse (NIDA).

A pioneer in the use of brain imaging to investigate how substance use affects brain functions and one of Time magazine’s “Top 100 People Who Shape Our World,” she led the Inaugural Conference at the XXXI Congress of the Spanish Society of Clinical Pharmacology “Drugs and Actions During the Pandemic.” Dr. Volkow spoke about the effects that the current health crisis has had on drug use and the social challenges that arose from lockdowns. She also presented and discussed the results of studies being conducted at NIDA that “are aimed at reviewing what we’ve learned and what the consequences of COVID-19 have been with respect to substance abuse disorder.”

As Dr. Volkow pointed out, drugs affect much more than just the brain. “In particular, the heart, the lungs, the immune system – all of these are significantly harmed by substances like tobacco, alcohol, cocaine, and methamphetamine. This is why, since the beginning of the pandemic, we’ve been worried about seeing what consequences SARS-CoV-2 was going to have on users of these substances, especially in light of the great toll this disease takes on the respiratory system and the vascular system.”
 

Pulmonary ‘predisposition’ and race

Dr. Volkow and her team launched several studies to get a more thorough understanding of the link between substance abuse disorders and poor COVID-19 prognoses. One of them was based on analyses from electronic health records in the United States. The purpose was to determine COVID-19 risk and outcomes in patients based on the type of use disorder (for example, alcohol, opioid, cannabis, cocaine).

“The results showed that regardless of the drug type, all users of these substances had both a higher risk of being infected by COVID-19 and a higher death rate in comparison with the rest of the population,” said Dr. Volkow. “This surprised us, because there’s no evidence that drugs themselves make the virus more infectious. However, what the results did clearly indicate to us was that using these substances was associated with behavior that put these individuals at a greater risk for infection,” Dr. Volkow explained.

“In addition,” she continued, “using, for example, tobacco or cannabis causes inflammation in the lungs. It seems that, as a result, they end up being more vulnerable to infection by COVID. And this has consequences, above all, in terms of mortality.”

Another finding was that, among patients with substance use disorders, race had the largest effect on COVID risk. “From the very start, we saw that, compared with White individuals, Black individuals showed a much higher risk of not only getting COVID, but also dying from it,” said Dr. Volkow. “Therefore, on the one hand, our data show that drug users are more vulnerable to COVID-19 and, on the other hand, they reflect that within this group, Black individuals are even more vulnerable.”

In her presentation, Dr. Volkow drew particular attention to the impact that social surroundings have on these patients and the decisive role they played in terms of vulnerability. “It’s a very complex issue, what with the various factors at play: family, social environment. ... A person living in an at-risk situation can more easily get drugs or even prescription medication, which can also be abused.”

The psychiatrist stressed that when it comes to addictive disorders (and related questions such as prevention, treatment, and social reintegration), one of the most crucial factors has to do with the individual’s social support structures. “The studies also brought to light the role that social interaction has as an inhibitory factor with regard to drug use,” said Dr. Volkow. “And indeed, adequate adherence to treatment requires that the necessary support systems be maintained.”

In the context of the pandemic, this social aspect was also key, especially concerning the high death rate among substance use disorder patients with COVID-19. “There are very significant social determinants, such as the stigma associated with these groups – a stigma that makes these individuals more likely to hesitate to seek out treatment for diseases that may be starting to take hold, in this case COVID-19.”

On that note, Dr. Volkow emphasized the importance of treating drug addicts as though they had a chronic disease in need of treatment. “In fact, the prevalence of pathologies such as hypertension, diabetes, cancer, and dementia is much higher in these individuals than in the general population,” she said. “However, this isn’t widely known. The data reflect that not only the prevalence of these diseases, but also the severity of the symptoms, is higher, and this has a lot to do with these individuals’ reticence when it comes to reaching out for medical care. Added to that are the effects of their economic situation and other factors, such as stress (which can trigger a relapse), lack of ready access to medications, and limited access to community support or other sources of social connection.”
 

Opioids and COVID-19

As for drug use during the pandemic, Dr. Volkow provided context by mentioning that in the United States, the experts and authorities have spent two decades fighting the epidemic of opioid-related drug overdoses, which has caused many deaths. “And on top of this epidemic – one that we still haven’t been able to get control of – there’s the situation brought about by COVID-19. So, we had to see the consequences of a pandemic crossing paths with an epidemic.”

The United States’s epidemic of overdose deaths started with the use of opioid painkillers, medications which are overprescribed. Another issue that the United States faces is that many drugs are contaminated with fentanyl. This contamination has caused an increase in deaths.

“In the United States, fentanyl is everywhere,” said Dr. Volkow. “And what’s more concerning: almost a third of this fentanyl comes in pills that are sold as benzodiazepines. With this comes a high risk for overdose. In line with this, we saw overdose deaths among adolescents nearly double in 1 year, an increase which is likely related to these contaminated pills. It’s a risk that’s just below the surface. We’ve got to be vigilant, because this phenomenon is expected to eventually spread to Europe. After all, these pills are very cheap, hence the rapid increase in their use.”

To provide figures on drug use and overdose deaths since the beginning of the pandemic, Dr. Volkow referred to COVID-19 data provided by the National Center for Health Statistics (NCHS) at the U.S. Centers for Disease Control and Prevention. The data indicate that of the 70,630 drug overdose deaths that occurred in 2019, 49,860 involved opioids (whether prescribed or illicit). “And these numbers have continued to rise, so much so that the current situation can be classified as catastrophic – because this increase has been even greater during the pandemic due to the rise in the use of all drugs,” said Dr. Volkow.

Dr. Volkow referred to an NCHS study that looked at the period between September 2020 and September 2021, finding a 15.9% increase in the number of drug overdose deaths. A breakdown of these data shows that the highest percentage corresponds to deaths from “other psychostimulants,” primarily methamphetamines (35.7%). This category is followed by deaths involving synthetic opioids, mostly illicit fentanyl (25.8%), and deaths from cocaine (13.4%).

“These figures indicate that, for the first time in history, the United States had over 100,000 overdose deaths in 1 year,” said Dr. Volkow. “This is something that has never happened. We can only infer that the pandemic had a hand in making the overdose crisis even worse than it already was.”

As Dr. Volkow explained, policies related to handling overdoses and prescribing medications have been changed in the context of COVID-19. Addiction treatment consequently has been provided through a larger number of telehealth services, and measures such as greater access to treatment for comorbid conditions, expanded access to behavioral treatments, and the establishment of mental health hotlines have been undertaken.
 

Children’s cognitive development

Dr. Volkow also spoke about another of NIDA’s current subjects of research: The role that damage or compromise from drugs has on the neural circuits involved in reinforcement systems. “It’s important that we make people aware of the significance of what’s at play there, because the greatest damage that can be inflicted on the brain comes from using any type of drug during adolescence. In these cases, the likelihood of having an addictive disorder as an adult significantly increases.”

Within this framework, her team has also investigated the impact of the pandemic on the cognitive development of infants under 1 year of age. One of these studies was a pilot program in which pregnant women participated. “We found that children born during the pandemic had lower cognitive development: n = 112 versus n = 554 of those born before January 2019.”

“None of the mothers or children in the study had been infected with SARS-CoV-2,” Dr. Volkow explained. “But the results clearly reflect the negative effect of the circumstances brought about by the pandemic, especially the high level of stress, the isolation, and the lack of stimuli. Another study, currently in preprint, is based on imaging. It analyzed the impact on myelination in children not exposed to COVID-19 but born during the pandemic, compared with pre-pandemic infants. The data showed significantly reduced areas of myelin development (P < .05) in those born after 2019. And the researchers didn’t find significant differences in gestation duration or birth weight.”

The longitudinal characteristics of these studies will let us see whether a change in these individuals’ social circumstances over time also brings to light cognitive changes, even the recovery of lost or underdeveloped cognitive processes, Dr. Volkow concluded.

Dr. Volkow has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID, Spain – Individuals with substance use disorders are at higher risk of being infected by and dying from COVID-19 – even if they are fully vaccinated – compared with the general population. Such are the findings of a line of research led by Mexican psychiatrist Nora Volkow, MD, director of the U.S. National Institute on Drug Abuse (NIDA).

A pioneer in the use of brain imaging to investigate how substance use affects brain functions and one of Time magazine’s “Top 100 People Who Shape Our World,” she led the Inaugural Conference at the XXXI Congress of the Spanish Society of Clinical Pharmacology “Drugs and Actions During the Pandemic.” Dr. Volkow spoke about the effects that the current health crisis has had on drug use and the social challenges that arose from lockdowns. She also presented and discussed the results of studies being conducted at NIDA that “are aimed at reviewing what we’ve learned and what the consequences of COVID-19 have been with respect to substance abuse disorder.”

As Dr. Volkow pointed out, drugs affect much more than just the brain. “In particular, the heart, the lungs, the immune system – all of these are significantly harmed by substances like tobacco, alcohol, cocaine, and methamphetamine. This is why, since the beginning of the pandemic, we’ve been worried about seeing what consequences SARS-CoV-2 was going to have on users of these substances, especially in light of the great toll this disease takes on the respiratory system and the vascular system.”
 

Pulmonary ‘predisposition’ and race

Dr. Volkow and her team launched several studies to get a more thorough understanding of the link between substance abuse disorders and poor COVID-19 prognoses. One of them was based on analyses from electronic health records in the United States. The purpose was to determine COVID-19 risk and outcomes in patients based on the type of use disorder (for example, alcohol, opioid, cannabis, cocaine).

“The results showed that regardless of the drug type, all users of these substances had both a higher risk of being infected by COVID-19 and a higher death rate in comparison with the rest of the population,” said Dr. Volkow. “This surprised us, because there’s no evidence that drugs themselves make the virus more infectious. However, what the results did clearly indicate to us was that using these substances was associated with behavior that put these individuals at a greater risk for infection,” Dr. Volkow explained.

“In addition,” she continued, “using, for example, tobacco or cannabis causes inflammation in the lungs. It seems that, as a result, they end up being more vulnerable to infection by COVID. And this has consequences, above all, in terms of mortality.”

Another finding was that, among patients with substance use disorders, race had the largest effect on COVID risk. “From the very start, we saw that, compared with White individuals, Black individuals showed a much higher risk of not only getting COVID, but also dying from it,” said Dr. Volkow. “Therefore, on the one hand, our data show that drug users are more vulnerable to COVID-19 and, on the other hand, they reflect that within this group, Black individuals are even more vulnerable.”

In her presentation, Dr. Volkow drew particular attention to the impact that social surroundings have on these patients and the decisive role they played in terms of vulnerability. “It’s a very complex issue, what with the various factors at play: family, social environment. ... A person living in an at-risk situation can more easily get drugs or even prescription medication, which can also be abused.”

The psychiatrist stressed that when it comes to addictive disorders (and related questions such as prevention, treatment, and social reintegration), one of the most crucial factors has to do with the individual’s social support structures. “The studies also brought to light the role that social interaction has as an inhibitory factor with regard to drug use,” said Dr. Volkow. “And indeed, adequate adherence to treatment requires that the necessary support systems be maintained.”

In the context of the pandemic, this social aspect was also key, especially concerning the high death rate among substance use disorder patients with COVID-19. “There are very significant social determinants, such as the stigma associated with these groups – a stigma that makes these individuals more likely to hesitate to seek out treatment for diseases that may be starting to take hold, in this case COVID-19.”

On that note, Dr. Volkow emphasized the importance of treating drug addicts as though they had a chronic disease in need of treatment. “In fact, the prevalence of pathologies such as hypertension, diabetes, cancer, and dementia is much higher in these individuals than in the general population,” she said. “However, this isn’t widely known. The data reflect that not only the prevalence of these diseases, but also the severity of the symptoms, is higher, and this has a lot to do with these individuals’ reticence when it comes to reaching out for medical care. Added to that are the effects of their economic situation and other factors, such as stress (which can trigger a relapse), lack of ready access to medications, and limited access to community support or other sources of social connection.”
 

Opioids and COVID-19

As for drug use during the pandemic, Dr. Volkow provided context by mentioning that in the United States, the experts and authorities have spent two decades fighting the epidemic of opioid-related drug overdoses, which has caused many deaths. “And on top of this epidemic – one that we still haven’t been able to get control of – there’s the situation brought about by COVID-19. So, we had to see the consequences of a pandemic crossing paths with an epidemic.”

The United States’s epidemic of overdose deaths started with the use of opioid painkillers, medications which are overprescribed. Another issue that the United States faces is that many drugs are contaminated with fentanyl. This contamination has caused an increase in deaths.

“In the United States, fentanyl is everywhere,” said Dr. Volkow. “And what’s more concerning: almost a third of this fentanyl comes in pills that are sold as benzodiazepines. With this comes a high risk for overdose. In line with this, we saw overdose deaths among adolescents nearly double in 1 year, an increase which is likely related to these contaminated pills. It’s a risk that’s just below the surface. We’ve got to be vigilant, because this phenomenon is expected to eventually spread to Europe. After all, these pills are very cheap, hence the rapid increase in their use.”

To provide figures on drug use and overdose deaths since the beginning of the pandemic, Dr. Volkow referred to COVID-19 data provided by the National Center for Health Statistics (NCHS) at the U.S. Centers for Disease Control and Prevention. The data indicate that of the 70,630 drug overdose deaths that occurred in 2019, 49,860 involved opioids (whether prescribed or illicit). “And these numbers have continued to rise, so much so that the current situation can be classified as catastrophic – because this increase has been even greater during the pandemic due to the rise in the use of all drugs,” said Dr. Volkow.

Dr. Volkow referred to an NCHS study that looked at the period between September 2020 and September 2021, finding a 15.9% increase in the number of drug overdose deaths. A breakdown of these data shows that the highest percentage corresponds to deaths from “other psychostimulants,” primarily methamphetamines (35.7%). This category is followed by deaths involving synthetic opioids, mostly illicit fentanyl (25.8%), and deaths from cocaine (13.4%).

“These figures indicate that, for the first time in history, the United States had over 100,000 overdose deaths in 1 year,” said Dr. Volkow. “This is something that has never happened. We can only infer that the pandemic had a hand in making the overdose crisis even worse than it already was.”

As Dr. Volkow explained, policies related to handling overdoses and prescribing medications have been changed in the context of COVID-19. Addiction treatment consequently has been provided through a larger number of telehealth services, and measures such as greater access to treatment for comorbid conditions, expanded access to behavioral treatments, and the establishment of mental health hotlines have been undertaken.
 

Children’s cognitive development

Dr. Volkow also spoke about another of NIDA’s current subjects of research: The role that damage or compromise from drugs has on the neural circuits involved in reinforcement systems. “It’s important that we make people aware of the significance of what’s at play there, because the greatest damage that can be inflicted on the brain comes from using any type of drug during adolescence. In these cases, the likelihood of having an addictive disorder as an adult significantly increases.”

Within this framework, her team has also investigated the impact of the pandemic on the cognitive development of infants under 1 year of age. One of these studies was a pilot program in which pregnant women participated. “We found that children born during the pandemic had lower cognitive development: n = 112 versus n = 554 of those born before January 2019.”

“None of the mothers or children in the study had been infected with SARS-CoV-2,” Dr. Volkow explained. “But the results clearly reflect the negative effect of the circumstances brought about by the pandemic, especially the high level of stress, the isolation, and the lack of stimuli. Another study, currently in preprint, is based on imaging. It analyzed the impact on myelination in children not exposed to COVID-19 but born during the pandemic, compared with pre-pandemic infants. The data showed significantly reduced areas of myelin development (P < .05) in those born after 2019. And the researchers didn’t find significant differences in gestation duration or birth weight.”

The longitudinal characteristics of these studies will let us see whether a change in these individuals’ social circumstances over time also brings to light cognitive changes, even the recovery of lost or underdeveloped cognitive processes, Dr. Volkow concluded.

Dr. Volkow has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MADRID, Spain – Individuals with substance use disorders are at higher risk of being infected by and dying from COVID-19 – even if they are fully vaccinated – compared with the general population. Such are the findings of a line of research led by Mexican psychiatrist Nora Volkow, MD, director of the U.S. National Institute on Drug Abuse (NIDA).

A pioneer in the use of brain imaging to investigate how substance use affects brain functions and one of Time magazine’s “Top 100 People Who Shape Our World,” she led the Inaugural Conference at the XXXI Congress of the Spanish Society of Clinical Pharmacology “Drugs and Actions During the Pandemic.” Dr. Volkow spoke about the effects that the current health crisis has had on drug use and the social challenges that arose from lockdowns. She also presented and discussed the results of studies being conducted at NIDA that “are aimed at reviewing what we’ve learned and what the consequences of COVID-19 have been with respect to substance abuse disorder.”

As Dr. Volkow pointed out, drugs affect much more than just the brain. “In particular, the heart, the lungs, the immune system – all of these are significantly harmed by substances like tobacco, alcohol, cocaine, and methamphetamine. This is why, since the beginning of the pandemic, we’ve been worried about seeing what consequences SARS-CoV-2 was going to have on users of these substances, especially in light of the great toll this disease takes on the respiratory system and the vascular system.”
 

Pulmonary ‘predisposition’ and race

Dr. Volkow and her team launched several studies to get a more thorough understanding of the link between substance abuse disorders and poor COVID-19 prognoses. One of them was based on analyses from electronic health records in the United States. The purpose was to determine COVID-19 risk and outcomes in patients based on the type of use disorder (for example, alcohol, opioid, cannabis, cocaine).

“The results showed that regardless of the drug type, all users of these substances had both a higher risk of being infected by COVID-19 and a higher death rate in comparison with the rest of the population,” said Dr. Volkow. “This surprised us, because there’s no evidence that drugs themselves make the virus more infectious. However, what the results did clearly indicate to us was that using these substances was associated with behavior that put these individuals at a greater risk for infection,” Dr. Volkow explained.

“In addition,” she continued, “using, for example, tobacco or cannabis causes inflammation in the lungs. It seems that, as a result, they end up being more vulnerable to infection by COVID. And this has consequences, above all, in terms of mortality.”

Another finding was that, among patients with substance use disorders, race had the largest effect on COVID risk. “From the very start, we saw that, compared with White individuals, Black individuals showed a much higher risk of not only getting COVID, but also dying from it,” said Dr. Volkow. “Therefore, on the one hand, our data show that drug users are more vulnerable to COVID-19 and, on the other hand, they reflect that within this group, Black individuals are even more vulnerable.”

In her presentation, Dr. Volkow drew particular attention to the impact that social surroundings have on these patients and the decisive role they played in terms of vulnerability. “It’s a very complex issue, what with the various factors at play: family, social environment. ... A person living in an at-risk situation can more easily get drugs or even prescription medication, which can also be abused.”

The psychiatrist stressed that when it comes to addictive disorders (and related questions such as prevention, treatment, and social reintegration), one of the most crucial factors has to do with the individual’s social support structures. “The studies also brought to light the role that social interaction has as an inhibitory factor with regard to drug use,” said Dr. Volkow. “And indeed, adequate adherence to treatment requires that the necessary support systems be maintained.”

In the context of the pandemic, this social aspect was also key, especially concerning the high death rate among substance use disorder patients with COVID-19. “There are very significant social determinants, such as the stigma associated with these groups – a stigma that makes these individuals more likely to hesitate to seek out treatment for diseases that may be starting to take hold, in this case COVID-19.”

On that note, Dr. Volkow emphasized the importance of treating drug addicts as though they had a chronic disease in need of treatment. “In fact, the prevalence of pathologies such as hypertension, diabetes, cancer, and dementia is much higher in these individuals than in the general population,” she said. “However, this isn’t widely known. The data reflect that not only the prevalence of these diseases, but also the severity of the symptoms, is higher, and this has a lot to do with these individuals’ reticence when it comes to reaching out for medical care. Added to that are the effects of their economic situation and other factors, such as stress (which can trigger a relapse), lack of ready access to medications, and limited access to community support or other sources of social connection.”
 

Opioids and COVID-19

As for drug use during the pandemic, Dr. Volkow provided context by mentioning that in the United States, the experts and authorities have spent two decades fighting the epidemic of opioid-related drug overdoses, which has caused many deaths. “And on top of this epidemic – one that we still haven’t been able to get control of – there’s the situation brought about by COVID-19. So, we had to see the consequences of a pandemic crossing paths with an epidemic.”

The United States’s epidemic of overdose deaths started with the use of opioid painkillers, medications which are overprescribed. Another issue that the United States faces is that many drugs are contaminated with fentanyl. This contamination has caused an increase in deaths.

“In the United States, fentanyl is everywhere,” said Dr. Volkow. “And what’s more concerning: almost a third of this fentanyl comes in pills that are sold as benzodiazepines. With this comes a high risk for overdose. In line with this, we saw overdose deaths among adolescents nearly double in 1 year, an increase which is likely related to these contaminated pills. It’s a risk that’s just below the surface. We’ve got to be vigilant, because this phenomenon is expected to eventually spread to Europe. After all, these pills are very cheap, hence the rapid increase in their use.”

To provide figures on drug use and overdose deaths since the beginning of the pandemic, Dr. Volkow referred to COVID-19 data provided by the National Center for Health Statistics (NCHS) at the U.S. Centers for Disease Control and Prevention. The data indicate that of the 70,630 drug overdose deaths that occurred in 2019, 49,860 involved opioids (whether prescribed or illicit). “And these numbers have continued to rise, so much so that the current situation can be classified as catastrophic – because this increase has been even greater during the pandemic due to the rise in the use of all drugs,” said Dr. Volkow.

Dr. Volkow referred to an NCHS study that looked at the period between September 2020 and September 2021, finding a 15.9% increase in the number of drug overdose deaths. A breakdown of these data shows that the highest percentage corresponds to deaths from “other psychostimulants,” primarily methamphetamines (35.7%). This category is followed by deaths involving synthetic opioids, mostly illicit fentanyl (25.8%), and deaths from cocaine (13.4%).

“These figures indicate that, for the first time in history, the United States had over 100,000 overdose deaths in 1 year,” said Dr. Volkow. “This is something that has never happened. We can only infer that the pandemic had a hand in making the overdose crisis even worse than it already was.”

As Dr. Volkow explained, policies related to handling overdoses and prescribing medications have been changed in the context of COVID-19. Addiction treatment consequently has been provided through a larger number of telehealth services, and measures such as greater access to treatment for comorbid conditions, expanded access to behavioral treatments, and the establishment of mental health hotlines have been undertaken.
 

Children’s cognitive development

Dr. Volkow also spoke about another of NIDA’s current subjects of research: The role that damage or compromise from drugs has on the neural circuits involved in reinforcement systems. “It’s important that we make people aware of the significance of what’s at play there, because the greatest damage that can be inflicted on the brain comes from using any type of drug during adolescence. In these cases, the likelihood of having an addictive disorder as an adult significantly increases.”

Within this framework, her team has also investigated the impact of the pandemic on the cognitive development of infants under 1 year of age. One of these studies was a pilot program in which pregnant women participated. “We found that children born during the pandemic had lower cognitive development: n = 112 versus n = 554 of those born before January 2019.”

“None of the mothers or children in the study had been infected with SARS-CoV-2,” Dr. Volkow explained. “But the results clearly reflect the negative effect of the circumstances brought about by the pandemic, especially the high level of stress, the isolation, and the lack of stimuli. Another study, currently in preprint, is based on imaging. It analyzed the impact on myelination in children not exposed to COVID-19 but born during the pandemic, compared with pre-pandemic infants. The data showed significantly reduced areas of myelin development (P < .05) in those born after 2019. And the researchers didn’t find significant differences in gestation duration or birth weight.”

The longitudinal characteristics of these studies will let us see whether a change in these individuals’ social circumstances over time also brings to light cognitive changes, even the recovery of lost or underdeveloped cognitive processes, Dr. Volkow concluded.

Dr. Volkow has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

A version of this article first appeared on Medscape.com.

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

A version of this article first appeared on Medscape.com.

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; [email protected]