Poppy Seed Brew Triggers Morphine Overdose, Drawing Attention of Lawmakers

Article Type
Changed
Mon, 10/14/2024 - 15:42

It sounds like a joke: poppy seeds infused with opioids.

Indeed, it was a plotline on the sitcom Seinfeld. But for some it has been a tragedy.

People have died after drinking tea brewed from unwashed poppy seeds.

And after eating lemon poppy seed bread or an everything bagel, mothers reportedly have been separated from newborns because the women failed drug tests.

Poppy seeds come from the plant that produces opium and from which narcotics such as morphine and codeine are derived. During harvesting and processing, the seeds can become coated with the opium fluid.

Members of the House and Senate have proposed legislation “to prohibit the distribution and sale of contaminated poppy seeds in order to prevent harm, addiction, and further deaths from morphine-contaminated poppy seeds.” The bill was one of several on the agenda for a September 10 House hearing.

The day before the hearing, The Marshall Project and Reveal reported on a woman who ate a salad with poppy seed dressing before giving birth, tested positive at the hospital for opiates, was reported to child welfare, and saw her baby taken into protective custody. Almost 2 weeks passed before she was allowed to bring her baby home.

“It’s not an urban legend: Eating poppy seeds can cause diners to test positive for codeine on a urinalysis,” the Defense Department warned military personnel in 2023.

The US Anti-Doping Agency long ago issued a similar warning to athletes.

The Center for Science in the Public Interest, a watchdog group, petitioned the Food and Drug Administration (FDA) in 2021 to limit the opiate content of poppy seeds. In May, after more than three years with no response, it sued the agency to force action.

“So far the FDA has been negligent in protecting consumers,” said Steve Hacala, whose son died after consuming poppy seed tea and who has joined forces with CSPI.

The lawsuit was put on hold in July, after the FDA said it would respond to the group’s petition by the end of February 2025.

The FDA did not answer questions for this article. The agency generally does not comment on litigation, spokesperson Courtney Rhodes said.

A 2021 study coauthored by CSPI personnel found more than 100 reports to poison control centers between 2000 and 2018 resulting from intentional abuse or misuse of poppy seeds, said CSPI scientist Eva Greenthal, one of the study’s authors.

Only rarely would baked goods or other food items containing washed poppy seeds trigger positive drug tests, doctors who have studied the issue said.

It’s “exquisitely doubtful” that the “relatively trivial” amount of morphine in an everything bagel or the like would cause anyone harm, said Irving Haber, a doctor who has written about poppy seeds, specializes in pain medicine, and signed the CSPI petition to the FDA.

On the other hand, tea made from large quantities of unwashed poppy seeds could lead to addiction and overdose, doctors said. The risks are heightened if the person drinking the brew is also consuming other opioids, such as prescription pain relievers.

Benjamin Lai, a physician who chairs a program on opioids at the Mayo Clinic in Rochester, Minnesota, said he has been treating a patient who developed long-term opioid addiction from consuming poppy seed tea. The patient, a man in his 30s, found it at a health food store and was under the impression it would help him relax and recover from gym workouts. After a few months, he tried to stop and experienced withdrawal symptoms, Lai said.

Another patient, an older woman, developed withdrawal symptoms under similar circumstances but responded well to treatment, Lai said.

Some websites tout poppy seed tea as offering health benefits. And some sellers “may use specific language such as ‘raw,’ ‘unprocessed,’ or ‘unwashed’ to signal that their products contain higher concentrations of opiates than properly processed seeds,” the CSPI lawsuit said.

Steve Hacala’s son, Stephen Hacala, a music teacher, had been experiencing anxiety and insomnia, for which poppy seed tea is promoted as a natural remedy, the lawsuit said. In 2016, at age 24, he ordered a bag of poppy seeds online, rinsed them with water, and consumed the rinse. He died of morphine poisoning.

The only source of morphine found in Stephen’s home, where he died, was commercially available poppy seeds, a medical examiner at the Arkansas State Crime Lab said in a letter to the father. The medical examiner wrote that poppy seeds “very likely” caused Stephen’s death.

Steve Hacala estimated that the quantity of poppy seeds found in a 1-liter plastic water bottle in his son’s home could have delivered more than 10 times a lethal dose.

Steve Hacala and his wife, Betty, have funded CSPI’s efforts to call attention to the issue. (The publisher of KFF Health News, David Rousseau, is on the CSPI board.)

The lawsuit also cited mothers who, like those in the investigation by The Marshall Project and Reveal, ran afoul of rules meant to protect newborns. For example, though Jamie Silakowski had not used opioids while pregnant, she was initially prevented from leaving the hospital with her baby, the suit said.

Silakowski recalled that, before going to the hospital, she had eaten lemon poppy seed bread at Tim Hortons, a fast-food chain, CSPI said in its petition. “No one in the hospital believed Ms. Silakowski or appeared to be aware that the test results could occur from poppy seeds.”

People from child protective services made unannounced visits to her home, interviewed her other children, and questioned teachers at their school, she said in an interview.

While on maternity leave, she had to undergo drug testing, Silakowski said. “Peeing in front of someone like I’m a criminal — it was just mortifying.”

Even family members were questioning her, and there was nothing she could do to dispel doubts, she said. “Relationships were torn apart,” she said.

The parent company of Tim Hortons, Restaurant Brands International, which also owns Burger King and Popeyes, did not respond to questions from KFF Health News.

In July, The Washington Post reported that Trader Joe’s Everything but the Bagel seasoning was banned and being confiscated in South Korea because it contains poppy seeds. Trader Joe’s did not respond to inquiries for this article. The seasoning is listed for sale on the company’s website.

The US Drug Enforcement Agency says unwashed poppy seeds can kill when used alone or in combination with other drugs. While poppy seeds are exempt from drug control under the Controlled Substances Act, opium contaminants on the seeds are not, the agency says. The Justice Department has brought criminal prosecutions over the sale of unwashed poppy seeds.

Meanwhile, the legislation to control poppy seed contamination has not gained much traction.

The Senate bill, introduced by Sen. Tom Cotton (R-Ark.), has two cosponsors.

The House bill, introduced by Rep. Steve Womack (R-Ark.), has none. Though it was on the agenda, it didn’t come up at the recent hearing.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.

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It sounds like a joke: poppy seeds infused with opioids.

Indeed, it was a plotline on the sitcom Seinfeld. But for some it has been a tragedy.

People have died after drinking tea brewed from unwashed poppy seeds.

And after eating lemon poppy seed bread or an everything bagel, mothers reportedly have been separated from newborns because the women failed drug tests.

Poppy seeds come from the plant that produces opium and from which narcotics such as morphine and codeine are derived. During harvesting and processing, the seeds can become coated with the opium fluid.

Members of the House and Senate have proposed legislation “to prohibit the distribution and sale of contaminated poppy seeds in order to prevent harm, addiction, and further deaths from morphine-contaminated poppy seeds.” The bill was one of several on the agenda for a September 10 House hearing.

The day before the hearing, The Marshall Project and Reveal reported on a woman who ate a salad with poppy seed dressing before giving birth, tested positive at the hospital for opiates, was reported to child welfare, and saw her baby taken into protective custody. Almost 2 weeks passed before she was allowed to bring her baby home.

“It’s not an urban legend: Eating poppy seeds can cause diners to test positive for codeine on a urinalysis,” the Defense Department warned military personnel in 2023.

The US Anti-Doping Agency long ago issued a similar warning to athletes.

The Center for Science in the Public Interest, a watchdog group, petitioned the Food and Drug Administration (FDA) in 2021 to limit the opiate content of poppy seeds. In May, after more than three years with no response, it sued the agency to force action.

“So far the FDA has been negligent in protecting consumers,” said Steve Hacala, whose son died after consuming poppy seed tea and who has joined forces with CSPI.

The lawsuit was put on hold in July, after the FDA said it would respond to the group’s petition by the end of February 2025.

The FDA did not answer questions for this article. The agency generally does not comment on litigation, spokesperson Courtney Rhodes said.

A 2021 study coauthored by CSPI personnel found more than 100 reports to poison control centers between 2000 and 2018 resulting from intentional abuse or misuse of poppy seeds, said CSPI scientist Eva Greenthal, one of the study’s authors.

Only rarely would baked goods or other food items containing washed poppy seeds trigger positive drug tests, doctors who have studied the issue said.

It’s “exquisitely doubtful” that the “relatively trivial” amount of morphine in an everything bagel or the like would cause anyone harm, said Irving Haber, a doctor who has written about poppy seeds, specializes in pain medicine, and signed the CSPI petition to the FDA.

On the other hand, tea made from large quantities of unwashed poppy seeds could lead to addiction and overdose, doctors said. The risks are heightened if the person drinking the brew is also consuming other opioids, such as prescription pain relievers.

Benjamin Lai, a physician who chairs a program on opioids at the Mayo Clinic in Rochester, Minnesota, said he has been treating a patient who developed long-term opioid addiction from consuming poppy seed tea. The patient, a man in his 30s, found it at a health food store and was under the impression it would help him relax and recover from gym workouts. After a few months, he tried to stop and experienced withdrawal symptoms, Lai said.

Another patient, an older woman, developed withdrawal symptoms under similar circumstances but responded well to treatment, Lai said.

Some websites tout poppy seed tea as offering health benefits. And some sellers “may use specific language such as ‘raw,’ ‘unprocessed,’ or ‘unwashed’ to signal that their products contain higher concentrations of opiates than properly processed seeds,” the CSPI lawsuit said.

Steve Hacala’s son, Stephen Hacala, a music teacher, had been experiencing anxiety and insomnia, for which poppy seed tea is promoted as a natural remedy, the lawsuit said. In 2016, at age 24, he ordered a bag of poppy seeds online, rinsed them with water, and consumed the rinse. He died of morphine poisoning.

The only source of morphine found in Stephen’s home, where he died, was commercially available poppy seeds, a medical examiner at the Arkansas State Crime Lab said in a letter to the father. The medical examiner wrote that poppy seeds “very likely” caused Stephen’s death.

Steve Hacala estimated that the quantity of poppy seeds found in a 1-liter plastic water bottle in his son’s home could have delivered more than 10 times a lethal dose.

Steve Hacala and his wife, Betty, have funded CSPI’s efforts to call attention to the issue. (The publisher of KFF Health News, David Rousseau, is on the CSPI board.)

The lawsuit also cited mothers who, like those in the investigation by The Marshall Project and Reveal, ran afoul of rules meant to protect newborns. For example, though Jamie Silakowski had not used opioids while pregnant, she was initially prevented from leaving the hospital with her baby, the suit said.

Silakowski recalled that, before going to the hospital, she had eaten lemon poppy seed bread at Tim Hortons, a fast-food chain, CSPI said in its petition. “No one in the hospital believed Ms. Silakowski or appeared to be aware that the test results could occur from poppy seeds.”

People from child protective services made unannounced visits to her home, interviewed her other children, and questioned teachers at their school, she said in an interview.

While on maternity leave, she had to undergo drug testing, Silakowski said. “Peeing in front of someone like I’m a criminal — it was just mortifying.”

Even family members were questioning her, and there was nothing she could do to dispel doubts, she said. “Relationships were torn apart,” she said.

The parent company of Tim Hortons, Restaurant Brands International, which also owns Burger King and Popeyes, did not respond to questions from KFF Health News.

In July, The Washington Post reported that Trader Joe’s Everything but the Bagel seasoning was banned and being confiscated in South Korea because it contains poppy seeds. Trader Joe’s did not respond to inquiries for this article. The seasoning is listed for sale on the company’s website.

The US Drug Enforcement Agency says unwashed poppy seeds can kill when used alone or in combination with other drugs. While poppy seeds are exempt from drug control under the Controlled Substances Act, opium contaminants on the seeds are not, the agency says. The Justice Department has brought criminal prosecutions over the sale of unwashed poppy seeds.

Meanwhile, the legislation to control poppy seed contamination has not gained much traction.

The Senate bill, introduced by Sen. Tom Cotton (R-Ark.), has two cosponsors.

The House bill, introduced by Rep. Steve Womack (R-Ark.), has none. Though it was on the agenda, it didn’t come up at the recent hearing.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.

It sounds like a joke: poppy seeds infused with opioids.

Indeed, it was a plotline on the sitcom Seinfeld. But for some it has been a tragedy.

People have died after drinking tea brewed from unwashed poppy seeds.

And after eating lemon poppy seed bread or an everything bagel, mothers reportedly have been separated from newborns because the women failed drug tests.

Poppy seeds come from the plant that produces opium and from which narcotics such as morphine and codeine are derived. During harvesting and processing, the seeds can become coated with the opium fluid.

Members of the House and Senate have proposed legislation “to prohibit the distribution and sale of contaminated poppy seeds in order to prevent harm, addiction, and further deaths from morphine-contaminated poppy seeds.” The bill was one of several on the agenda for a September 10 House hearing.

The day before the hearing, The Marshall Project and Reveal reported on a woman who ate a salad with poppy seed dressing before giving birth, tested positive at the hospital for opiates, was reported to child welfare, and saw her baby taken into protective custody. Almost 2 weeks passed before she was allowed to bring her baby home.

“It’s not an urban legend: Eating poppy seeds can cause diners to test positive for codeine on a urinalysis,” the Defense Department warned military personnel in 2023.

The US Anti-Doping Agency long ago issued a similar warning to athletes.

The Center for Science in the Public Interest, a watchdog group, petitioned the Food and Drug Administration (FDA) in 2021 to limit the opiate content of poppy seeds. In May, after more than three years with no response, it sued the agency to force action.

“So far the FDA has been negligent in protecting consumers,” said Steve Hacala, whose son died after consuming poppy seed tea and who has joined forces with CSPI.

The lawsuit was put on hold in July, after the FDA said it would respond to the group’s petition by the end of February 2025.

The FDA did not answer questions for this article. The agency generally does not comment on litigation, spokesperson Courtney Rhodes said.

A 2021 study coauthored by CSPI personnel found more than 100 reports to poison control centers between 2000 and 2018 resulting from intentional abuse or misuse of poppy seeds, said CSPI scientist Eva Greenthal, one of the study’s authors.

Only rarely would baked goods or other food items containing washed poppy seeds trigger positive drug tests, doctors who have studied the issue said.

It’s “exquisitely doubtful” that the “relatively trivial” amount of morphine in an everything bagel or the like would cause anyone harm, said Irving Haber, a doctor who has written about poppy seeds, specializes in pain medicine, and signed the CSPI petition to the FDA.

On the other hand, tea made from large quantities of unwashed poppy seeds could lead to addiction and overdose, doctors said. The risks are heightened if the person drinking the brew is also consuming other opioids, such as prescription pain relievers.

Benjamin Lai, a physician who chairs a program on opioids at the Mayo Clinic in Rochester, Minnesota, said he has been treating a patient who developed long-term opioid addiction from consuming poppy seed tea. The patient, a man in his 30s, found it at a health food store and was under the impression it would help him relax and recover from gym workouts. After a few months, he tried to stop and experienced withdrawal symptoms, Lai said.

Another patient, an older woman, developed withdrawal symptoms under similar circumstances but responded well to treatment, Lai said.

Some websites tout poppy seed tea as offering health benefits. And some sellers “may use specific language such as ‘raw,’ ‘unprocessed,’ or ‘unwashed’ to signal that their products contain higher concentrations of opiates than properly processed seeds,” the CSPI lawsuit said.

Steve Hacala’s son, Stephen Hacala, a music teacher, had been experiencing anxiety and insomnia, for which poppy seed tea is promoted as a natural remedy, the lawsuit said. In 2016, at age 24, he ordered a bag of poppy seeds online, rinsed them with water, and consumed the rinse. He died of morphine poisoning.

The only source of morphine found in Stephen’s home, where he died, was commercially available poppy seeds, a medical examiner at the Arkansas State Crime Lab said in a letter to the father. The medical examiner wrote that poppy seeds “very likely” caused Stephen’s death.

Steve Hacala estimated that the quantity of poppy seeds found in a 1-liter plastic water bottle in his son’s home could have delivered more than 10 times a lethal dose.

Steve Hacala and his wife, Betty, have funded CSPI’s efforts to call attention to the issue. (The publisher of KFF Health News, David Rousseau, is on the CSPI board.)

The lawsuit also cited mothers who, like those in the investigation by The Marshall Project and Reveal, ran afoul of rules meant to protect newborns. For example, though Jamie Silakowski had not used opioids while pregnant, she was initially prevented from leaving the hospital with her baby, the suit said.

Silakowski recalled that, before going to the hospital, she had eaten lemon poppy seed bread at Tim Hortons, a fast-food chain, CSPI said in its petition. “No one in the hospital believed Ms. Silakowski or appeared to be aware that the test results could occur from poppy seeds.”

People from child protective services made unannounced visits to her home, interviewed her other children, and questioned teachers at their school, she said in an interview.

While on maternity leave, she had to undergo drug testing, Silakowski said. “Peeing in front of someone like I’m a criminal — it was just mortifying.”

Even family members were questioning her, and there was nothing she could do to dispel doubts, she said. “Relationships were torn apart,” she said.

The parent company of Tim Hortons, Restaurant Brands International, which also owns Burger King and Popeyes, did not respond to questions from KFF Health News.

In July, The Washington Post reported that Trader Joe’s Everything but the Bagel seasoning was banned and being confiscated in South Korea because it contains poppy seeds. Trader Joe’s did not respond to inquiries for this article. The seasoning is listed for sale on the company’s website.

The US Drug Enforcement Agency says unwashed poppy seeds can kill when used alone or in combination with other drugs. While poppy seeds are exempt from drug control under the Controlled Substances Act, opium contaminants on the seeds are not, the agency says. The Justice Department has brought criminal prosecutions over the sale of unwashed poppy seeds.

Meanwhile, the legislation to control poppy seed contamination has not gained much traction.

The Senate bill, introduced by Sen. Tom Cotton (R-Ark.), has two cosponsors.

The House bill, introduced by Rep. Steve Womack (R-Ark.), has none. Though it was on the agenda, it didn’t come up at the recent hearing.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.

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Semaglutide a Potential Treatment Option for Opioid Use Disorder?

Article Type
Changed
Thu, 10/10/2024 - 13:05

Semaglutide (Ozempic, Novo Nordisk) is associated with a significantly lower risk for overdose in individuals with opioid use disorder (OUD), new research shows.

The findings suggest that the drug may be a promising treatment option for OUD, adding to the growing evidence of the potential psychiatric benefits of glucagon-like peptide 1 (GLP-1) inhibitors.

“Our study provided real-world evidence suggesting that semaglutide could have benefits in preventing opioid overdose and treating opioid use disorder,” co–lead author Rong Xu, PhD, director of the Center for Artificial Intelligence in Drug Discovery at Case Western Reserve University School of Medicine, Cleveland, Ohio, said in an interview.

However, Xu cautioned that this evidence is preliminary and randomized clinical trials are required to confirm these findings.

The study published online in a research letter on September 25 in JAMA Network Open.
 

New Addiction Meds an Urgent Priority

Investigators analyzed electronic medical records from 33,006 patients with type 2 diabetes and OUD who were prescribed one of eight antidiabetic medications between 2017 and 2023. 

Drugs included in the study were semaglutide, insulin, metformin, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, dipeptidyl peptidase–4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, and thiazolidinediones. 

Participants in the semaglutide and each comparison group were matched for certain covariates at baseline, such as socioeconomic status and OUD medications. 

After 1 year, semaglutide was associated with a 42%-68% lower risk for opioid overdose than other antidiabetic medications, including other GLP-1s (range of hazard ratio [HR]: HR, 0.32; 95% CI, 0.12-0.89; to HR, 0.58; 95%CI, 0.38-0.87). 

Xu noted a number of study limitations including the effect of possible confounders and sole reliance on prescription data.

However, the findings are in line with those of prior studies showing that semaglutide may be associated with lower rates of alcohol and nicotine use, she said. 

Earlier this year, Xu, along with National Institute on Drug Abuse Director Nora Volkow, MD, and colleagues, published a retrospective cohort study of nearly 84,000 patients with obesity. That analysis showed that semaglutide was associated with a significantly lower risk of new alcohol use disorder diagnoses. 

In a previous editorial by Xu and Volkow that summarized the research to-date on GLP-1s for nicotine, alcohol, and substance use disorders, they note that “closing the addiction treatment gap and discovering new, more effective addiction medications are urgent priorities. In this regard, investigating the potential of GLP-1 analogue medications to treat substance use disorder deserves fast and rigorous testing.”
 

Caution Warranted

Commenting on the study, Riccardo De Giorgi, MD, PhD, department of psychiatry, University of Oxford in England, said at this point, “we have to be very careful about how we interpret these data.” 

In August, De Giorgi published a study showing that semaglutide was associated with reduced risk for several neurologic and psychiatric outcomes including dementia and nicotine misuse. 

While there is enough observational evidence linking GLP-1 medications with reduced SUD risk, he noted that “now is the time to move on and conduct some randomized clinical trials, specifically testing our hypothesis in people who have psychiatric disorders.”

De Giorgi also called for mechanistic studies of semaglutide and other so that researchers could learn more about how it works to reduce cravings. “Instead of going from bench to bed, we need to go back to the bench,” he said.

As previously reported, De Giorgi recently called on experts in the field to actively explore the potential of GLP-1 inhibitors for mental illness. 

The study was funded by National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, the National Center for Advancing Translational Sciences, and the Intramural Research Program of the National Institutes of Health. Xu reported no relevant financial relationships. De Giorgi reported receiving funding from the National Institute for Health Research Oxford Health Biomedical Research Centre.

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

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Semaglutide (Ozempic, Novo Nordisk) is associated with a significantly lower risk for overdose in individuals with opioid use disorder (OUD), new research shows.

The findings suggest that the drug may be a promising treatment option for OUD, adding to the growing evidence of the potential psychiatric benefits of glucagon-like peptide 1 (GLP-1) inhibitors.

“Our study provided real-world evidence suggesting that semaglutide could have benefits in preventing opioid overdose and treating opioid use disorder,” co–lead author Rong Xu, PhD, director of the Center for Artificial Intelligence in Drug Discovery at Case Western Reserve University School of Medicine, Cleveland, Ohio, said in an interview.

However, Xu cautioned that this evidence is preliminary and randomized clinical trials are required to confirm these findings.

The study published online in a research letter on September 25 in JAMA Network Open.
 

New Addiction Meds an Urgent Priority

Investigators analyzed electronic medical records from 33,006 patients with type 2 diabetes and OUD who were prescribed one of eight antidiabetic medications between 2017 and 2023. 

Drugs included in the study were semaglutide, insulin, metformin, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, dipeptidyl peptidase–4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, and thiazolidinediones. 

Participants in the semaglutide and each comparison group were matched for certain covariates at baseline, such as socioeconomic status and OUD medications. 

After 1 year, semaglutide was associated with a 42%-68% lower risk for opioid overdose than other antidiabetic medications, including other GLP-1s (range of hazard ratio [HR]: HR, 0.32; 95% CI, 0.12-0.89; to HR, 0.58; 95%CI, 0.38-0.87). 

Xu noted a number of study limitations including the effect of possible confounders and sole reliance on prescription data.

However, the findings are in line with those of prior studies showing that semaglutide may be associated with lower rates of alcohol and nicotine use, she said. 

Earlier this year, Xu, along with National Institute on Drug Abuse Director Nora Volkow, MD, and colleagues, published a retrospective cohort study of nearly 84,000 patients with obesity. That analysis showed that semaglutide was associated with a significantly lower risk of new alcohol use disorder diagnoses. 

In a previous editorial by Xu and Volkow that summarized the research to-date on GLP-1s for nicotine, alcohol, and substance use disorders, they note that “closing the addiction treatment gap and discovering new, more effective addiction medications are urgent priorities. In this regard, investigating the potential of GLP-1 analogue medications to treat substance use disorder deserves fast and rigorous testing.”
 

Caution Warranted

Commenting on the study, Riccardo De Giorgi, MD, PhD, department of psychiatry, University of Oxford in England, said at this point, “we have to be very careful about how we interpret these data.” 

In August, De Giorgi published a study showing that semaglutide was associated with reduced risk for several neurologic and psychiatric outcomes including dementia and nicotine misuse. 

While there is enough observational evidence linking GLP-1 medications with reduced SUD risk, he noted that “now is the time to move on and conduct some randomized clinical trials, specifically testing our hypothesis in people who have psychiatric disorders.”

De Giorgi also called for mechanistic studies of semaglutide and other so that researchers could learn more about how it works to reduce cravings. “Instead of going from bench to bed, we need to go back to the bench,” he said.

As previously reported, De Giorgi recently called on experts in the field to actively explore the potential of GLP-1 inhibitors for mental illness. 

The study was funded by National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, the National Center for Advancing Translational Sciences, and the Intramural Research Program of the National Institutes of Health. Xu reported no relevant financial relationships. De Giorgi reported receiving funding from the National Institute for Health Research Oxford Health Biomedical Research Centre.

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

Semaglutide (Ozempic, Novo Nordisk) is associated with a significantly lower risk for overdose in individuals with opioid use disorder (OUD), new research shows.

The findings suggest that the drug may be a promising treatment option for OUD, adding to the growing evidence of the potential psychiatric benefits of glucagon-like peptide 1 (GLP-1) inhibitors.

“Our study provided real-world evidence suggesting that semaglutide could have benefits in preventing opioid overdose and treating opioid use disorder,” co–lead author Rong Xu, PhD, director of the Center for Artificial Intelligence in Drug Discovery at Case Western Reserve University School of Medicine, Cleveland, Ohio, said in an interview.

However, Xu cautioned that this evidence is preliminary and randomized clinical trials are required to confirm these findings.

The study published online in a research letter on September 25 in JAMA Network Open.
 

New Addiction Meds an Urgent Priority

Investigators analyzed electronic medical records from 33,006 patients with type 2 diabetes and OUD who were prescribed one of eight antidiabetic medications between 2017 and 2023. 

Drugs included in the study were semaglutide, insulin, metformin, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, dipeptidyl peptidase–4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, and thiazolidinediones. 

Participants in the semaglutide and each comparison group were matched for certain covariates at baseline, such as socioeconomic status and OUD medications. 

After 1 year, semaglutide was associated with a 42%-68% lower risk for opioid overdose than other antidiabetic medications, including other GLP-1s (range of hazard ratio [HR]: HR, 0.32; 95% CI, 0.12-0.89; to HR, 0.58; 95%CI, 0.38-0.87). 

Xu noted a number of study limitations including the effect of possible confounders and sole reliance on prescription data.

However, the findings are in line with those of prior studies showing that semaglutide may be associated with lower rates of alcohol and nicotine use, she said. 

Earlier this year, Xu, along with National Institute on Drug Abuse Director Nora Volkow, MD, and colleagues, published a retrospective cohort study of nearly 84,000 patients with obesity. That analysis showed that semaglutide was associated with a significantly lower risk of new alcohol use disorder diagnoses. 

In a previous editorial by Xu and Volkow that summarized the research to-date on GLP-1s for nicotine, alcohol, and substance use disorders, they note that “closing the addiction treatment gap and discovering new, more effective addiction medications are urgent priorities. In this regard, investigating the potential of GLP-1 analogue medications to treat substance use disorder deserves fast and rigorous testing.”
 

Caution Warranted

Commenting on the study, Riccardo De Giorgi, MD, PhD, department of psychiatry, University of Oxford in England, said at this point, “we have to be very careful about how we interpret these data.” 

In August, De Giorgi published a study showing that semaglutide was associated with reduced risk for several neurologic and psychiatric outcomes including dementia and nicotine misuse. 

While there is enough observational evidence linking GLP-1 medications with reduced SUD risk, he noted that “now is the time to move on and conduct some randomized clinical trials, specifically testing our hypothesis in people who have psychiatric disorders.”

De Giorgi also called for mechanistic studies of semaglutide and other so that researchers could learn more about how it works to reduce cravings. “Instead of going from bench to bed, we need to go back to the bench,” he said.

As previously reported, De Giorgi recently called on experts in the field to actively explore the potential of GLP-1 inhibitors for mental illness. 

The study was funded by National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, the National Center for Advancing Translational Sciences, and the Intramural Research Program of the National Institutes of Health. Xu reported no relevant financial relationships. De Giorgi reported receiving funding from the National Institute for Health Research Oxford Health Biomedical Research Centre.

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

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Wide Availability of Naloxone and Education on Its Use Can Save Pediatric Lives

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— More than half of youth improved after receiving a dose of naloxone by emergency medical services (EMS) after an emergency dispatch call, according to research presented at the American Academy of Pediatrics 2024 National Conference.

“Emergency responders or EMS are often the first to arrive to an opioid poisoning, and they’re often the first to give naloxone, a potentially lifesaving medication,” said Christopher E. Gaw, MD, MPH, MBE, assistant professor of pediatrics at The Ohio State University College of Medicine and an emergency medicine physician at Nationwide Children’s Hospital in Columbus, Ohio.

Ohio State University
Dr. Christopher E. Gaw

“Our study highlights and underscores its safety of use in the prehospital setting, and this is also supported by other data,” Gaw said. “Efforts to support public distribution and education on naloxone can really help each and every one of us as individual citizens prevent pediatric harm from the opioid crisis.”

Additional research at the meeting showed that teens’ knowledge, attitudes, and confidence about recognizing overdoses and assisting with naloxone administration improved following a peer-to-peer training program, suggesting that teens can play an important role in reducing youth mortality from overdoses.

An average of 22 American teens died from overdose every week in 2022, and as counterfeit pill use has increased among youth, research has found that fentanyl was detected in 93% of overdose deaths with counterfeit pills, according to Talia Puzantian, PharmD, BCPP, of the Keck Graduate Institute School of Pharmacy, Claremont, California, who led the study on peer education. Yet a recent survey had found that less than a third of teens (30%) knew what naloxone was, and only 14% knew how to administer it.

“Ensuring that adolescents have easy and confidential access to naloxone is important and can save lives,” said Taylor Nichols, MD, assistant clinical professor at the University of California San Francisco and an emergency medicine and addiction medicine–certified physician. “I have had teen patients who have told me that they have had to use naloxone obtained from our clinic on friends when they have accidentally overdosed.”

University of California
Dr. Taylor Nichols


Nichols, who was not involved in either study, added that all 50 states have some version of Good Samaritan laws that offer protection to individuals who attempt to aid in emergency assistance in good faith, and all except Kansas and Wyoming have laws specifically protecting people trying to help with overdose prevention.

“I tell people that everyone should carry naloxone and have naloxone available to be able to reverse an overdose, whether they personally use opioids or know people who use opioids because if they happen to come into a situation in which someone is passed out and unresponsive, that timely administration of naloxone may save their life,” Nichols said.

He added that primary care physicians, “particularly in family medicine and pediatrics, should be asking about any opioids in the home prescribed to anyone else and ensure that those patients also are prescribed or have access to naloxone to keep at home. Just as with asking about any other potential safety hazards, making sure they have naloxone available is crucial.”
 

 

 

EMS Naloxone Administration to Youth

EMS clinicians are often the first healthcare providers to respond to an opioid overdose or poisoning event, and evidence-based guidelines for EMS naloxone administration were developed in 2019 to support this intervention. Gaw’s team investigated the frequency and demographics of pediatric administration of naloxone.

They analyzed data from the National Emergency Medical Services Information System on EMS activations for administration of at least one dose of naloxone during 2022 to those aged 0-17. There were 6215 EMS pediatric administrations of naloxone that year, and in the vast majority of cases (82%), the patient had not received a naloxone injection prior to EMS’s arrival.

Most patients (79%) were aged 13-17 years, but 10% were in the 6-12 age group. The remaining patients included 6% infants younger than 1 year and 4% aged 6-12 years. Just over half were for males (55%), and most were dispatched to a home or residential setting (61%). One in five incidents (22%) occurred at a non-healthcare business, 9% on a street or highway, and the rest at a healthcare facility or another location.

Most of the incidents occurred in urban areas (86%), followed by rural (7%), suburban (6%), and wilderness (1.4%). More occurred in the US South (42%) than in the West (29%), Midwest (22%), or Northeast (7.5%).

A key takeaway of those demographic findings is that ingestions and accidental poisonings with opioids can occur in children of any age, Nichols said. “Every single home that has any opioids in the home should absolutely have naloxone immediately available as well,” he said. “Every single person who is prescribed opioids should also have naloxone available and accessible and to be sure that the naloxone is not expired or otherwise tampered with and update that every few years.” He noted that Narcan expiration was recently extended from 3 years to 4 years by the US Food and Drug Administration (FDA).

“I always advise that people who have opioid medications keep them stored safely and securely,” Nichols said. “However, I also acknowledge that even perfect systems fail and that people make mistakes and may accidentally leave medication out, within reach, or otherwise unsecured. If that happens, and someone were to intentionally or unintentionally get into that medication and potentially overdose as a result, we want to have that reversal medication immediately available to reverse the overdose.”

In nearly all cases (91%), EMS provided advanced life support, with only 7.5% patients receiving basic life support and 1.5% receiving specialty critical care. Just under a third (29%) of the dispatch calls were for “overdose/poisoning/ingestion.” Other dispatch calls included “unconscious/fainting/near-fainting” (21%) or “cardiac arrest/death” (17%), but the frequency of each dispatch label varied by age groups.

For example, 38% of calls for infants were for cardiac arrest, compared with 15% of calls for older teens and 18% of calls for 6-12 year olds. An overdose/poisoning dispatch was meanwhile more common for teens (32%) than for infants (13%), younger children (23%), and older children/tweens (18%). Other dispatch complaints included “sick person/person down/unknown problem” (12%) and “breathing problem” (5%).

A possible reason for these variations is that “an overdose might be mistaken for another medical emergency, or vice versa, because opioid poisonings can be challenging to recognize, especially in young children and in the pediatric population,” Gaw said. “Both the public and emergency responders should maintain a high level of suspicion” of possible overdose for children with the signs or symptoms of it, such as low breathing, unresponsiveness, or small pupils.

In most cases (87%), the patient was not in cardiac arrest, though the patient had entered cardiac arrest before EMS’s arrival in 11.5% of cases. Two thirds of cases only involved one dose of naloxone, while the other 33% involved two doses.

Ryan Marino, MD, an addiction medicine specialist and an associate professor of emergency medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio, who was not involved in the study, took note of the high proportion of cases in which two doses were administered.

“While there is, in my professional opinion, almost no downside to giving naloxone in situations like this, and everybody should have it available and know how to use it, I would caution people on the risk of anchor bias, especially when more than two doses of naloxone are given, since we know that one should be an effective amount for any known opioid overdose,” Marino said. Anchoring bias refers to the tendency for individuals to rely more heavily on the first piece of information they receive about a topic or situation.

“For first responders and healthcare professionals, the importance of additional resuscitation measures like oxygenation and ventilation are just as crucial,” Marino said. “People should not be discouraged if someone doesn’t immediately respond to naloxone as overdose physiology can cause mental status to stay impaired for other reasons beyond direct drug effect, such as hypercarbia, but continue to seek and/or provide additional emergency care in these situations.”

Patients improved after one dose in just over half the cases (54%), and their conditions were unchanged in 46% of cases. There were only 11 cases in which the patient’s condition worsened after a naloxone dose (0.2%). Most of the cases (88%) were transported by EMS, and there were 13 total deaths at the scene (0.2%).

Nichols found the low incidence of worsening clinical status particularly striking. “This is further evidence of a critically important point — naloxone is purely an opioid antagonist, and only binds to opioid receptors, such that if a person has not overdosed on opioids or does not otherwise have opioids in their system, naloxone will not have a significant effect and will not cause them harm,” Nichols said.

“The most common causes of harm are due to rapid reversal of overdose and the potential risks involved in the rapid reversal of opioid effects and potentially precipitating withdrawal, and as this paper demonstrates, these are exceedingly rare,” he said. “Given that, we should have an incredibly low barrier to administer naloxone appropriately.”

The study was limited by inability to know how many true pediatric opioid poisonings are managed by EMS, so future research could look at linking EMS and emergency room hospital databases.
 

 

 

Improved Self-Efficacy in Teens

Another study showed that a peer-to-peer training program increased teens’ knowledge about overdoses from 34% before training to 79% after (P < .0001), and it substantially improved their confidence in recognizing an overdose and administering naloxone.

Nichols said the study shows the importance of ensuring “that adolescents know how to keep themselves and their friends safe in the case that they or anyone they know does end up using illicit substances which either intentionally or unintentionally contain opioids.”

This study assessed a training program with 206 students in a Los Angeles County high school who were trained by their peers between November 2023 and March 2024. The training included trends in teen overdose deaths, defining what opioids and fentanyl are, recognizing an overdose, and responding to one with naloxone.

The teens were an average 16 years old, about evenly split between boys and girls, and mostly in 11th (40%) or 12th (28%) grade, though nearly a third (29%) were 9th graders.

The students’ knowledge about fentanyl’s presence in counterfeit pills increased from 21% before the training to 68% afterward, and their correct identification of an overdose increased from 47% of participants to 90%.

The students’ confidence and attitudes toward helping with an overdose also improved substantially after the training. About two thirds agreed that non-medical people should be able to carry naloxone before the training, and that rose to 88% agreeing after the training. The proportion who agreed they would be willing to assist in an overdose rose from 77% before to 89% after training.

More dramatically, the teens’ confidence after training more than doubled in recognizing an overdose (from 31% to 81%) and more than tripled in their ability to give naloxone during an overdose (from 26% to 83%).

“The critical piece to keep in mind is that the concern about opioid overdose is respiratory depression leading to a lack of oxygen getting to the brain,” Nichols explained. “In the event of an overdose, time is brain — the longer the brain is deprived of oxygen, the lower the chance of survival. There is no specific time at which naloxone would become less effective at reversing an overdose.”

Therefore, people do not need to know the exact time that someone may have overdosed or how long they have been passed out in order to administer naloxone, he said. “The sooner naloxone is administered to someone who is unresponsive and who may have overdosed on opioids, the higher the likelihood of a successful reversal of an overdose and of saving a life.”

The peer-to-peer program was sponsored by the CARLOW Center for Medical Innovation, and the EMS study used no external funding. The authors of both studies and Marino had no disclosures. Nichols has consulted or clinically advised TV shows and health tech startup companies and has no disclosures related to naloxone or the pharmaceutical industry.
 

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

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— More than half of youth improved after receiving a dose of naloxone by emergency medical services (EMS) after an emergency dispatch call, according to research presented at the American Academy of Pediatrics 2024 National Conference.

“Emergency responders or EMS are often the first to arrive to an opioid poisoning, and they’re often the first to give naloxone, a potentially lifesaving medication,” said Christopher E. Gaw, MD, MPH, MBE, assistant professor of pediatrics at The Ohio State University College of Medicine and an emergency medicine physician at Nationwide Children’s Hospital in Columbus, Ohio.

Ohio State University
Dr. Christopher E. Gaw

“Our study highlights and underscores its safety of use in the prehospital setting, and this is also supported by other data,” Gaw said. “Efforts to support public distribution and education on naloxone can really help each and every one of us as individual citizens prevent pediatric harm from the opioid crisis.”

Additional research at the meeting showed that teens’ knowledge, attitudes, and confidence about recognizing overdoses and assisting with naloxone administration improved following a peer-to-peer training program, suggesting that teens can play an important role in reducing youth mortality from overdoses.

An average of 22 American teens died from overdose every week in 2022, and as counterfeit pill use has increased among youth, research has found that fentanyl was detected in 93% of overdose deaths with counterfeit pills, according to Talia Puzantian, PharmD, BCPP, of the Keck Graduate Institute School of Pharmacy, Claremont, California, who led the study on peer education. Yet a recent survey had found that less than a third of teens (30%) knew what naloxone was, and only 14% knew how to administer it.

“Ensuring that adolescents have easy and confidential access to naloxone is important and can save lives,” said Taylor Nichols, MD, assistant clinical professor at the University of California San Francisco and an emergency medicine and addiction medicine–certified physician. “I have had teen patients who have told me that they have had to use naloxone obtained from our clinic on friends when they have accidentally overdosed.”

University of California
Dr. Taylor Nichols


Nichols, who was not involved in either study, added that all 50 states have some version of Good Samaritan laws that offer protection to individuals who attempt to aid in emergency assistance in good faith, and all except Kansas and Wyoming have laws specifically protecting people trying to help with overdose prevention.

“I tell people that everyone should carry naloxone and have naloxone available to be able to reverse an overdose, whether they personally use opioids or know people who use opioids because if they happen to come into a situation in which someone is passed out and unresponsive, that timely administration of naloxone may save their life,” Nichols said.

He added that primary care physicians, “particularly in family medicine and pediatrics, should be asking about any opioids in the home prescribed to anyone else and ensure that those patients also are prescribed or have access to naloxone to keep at home. Just as with asking about any other potential safety hazards, making sure they have naloxone available is crucial.”
 

 

 

EMS Naloxone Administration to Youth

EMS clinicians are often the first healthcare providers to respond to an opioid overdose or poisoning event, and evidence-based guidelines for EMS naloxone administration were developed in 2019 to support this intervention. Gaw’s team investigated the frequency and demographics of pediatric administration of naloxone.

They analyzed data from the National Emergency Medical Services Information System on EMS activations for administration of at least one dose of naloxone during 2022 to those aged 0-17. There were 6215 EMS pediatric administrations of naloxone that year, and in the vast majority of cases (82%), the patient had not received a naloxone injection prior to EMS’s arrival.

Most patients (79%) were aged 13-17 years, but 10% were in the 6-12 age group. The remaining patients included 6% infants younger than 1 year and 4% aged 6-12 years. Just over half were for males (55%), and most were dispatched to a home or residential setting (61%). One in five incidents (22%) occurred at a non-healthcare business, 9% on a street or highway, and the rest at a healthcare facility or another location.

Most of the incidents occurred in urban areas (86%), followed by rural (7%), suburban (6%), and wilderness (1.4%). More occurred in the US South (42%) than in the West (29%), Midwest (22%), or Northeast (7.5%).

A key takeaway of those demographic findings is that ingestions and accidental poisonings with opioids can occur in children of any age, Nichols said. “Every single home that has any opioids in the home should absolutely have naloxone immediately available as well,” he said. “Every single person who is prescribed opioids should also have naloxone available and accessible and to be sure that the naloxone is not expired or otherwise tampered with and update that every few years.” He noted that Narcan expiration was recently extended from 3 years to 4 years by the US Food and Drug Administration (FDA).

“I always advise that people who have opioid medications keep them stored safely and securely,” Nichols said. “However, I also acknowledge that even perfect systems fail and that people make mistakes and may accidentally leave medication out, within reach, or otherwise unsecured. If that happens, and someone were to intentionally or unintentionally get into that medication and potentially overdose as a result, we want to have that reversal medication immediately available to reverse the overdose.”

In nearly all cases (91%), EMS provided advanced life support, with only 7.5% patients receiving basic life support and 1.5% receiving specialty critical care. Just under a third (29%) of the dispatch calls were for “overdose/poisoning/ingestion.” Other dispatch calls included “unconscious/fainting/near-fainting” (21%) or “cardiac arrest/death” (17%), but the frequency of each dispatch label varied by age groups.

For example, 38% of calls for infants were for cardiac arrest, compared with 15% of calls for older teens and 18% of calls for 6-12 year olds. An overdose/poisoning dispatch was meanwhile more common for teens (32%) than for infants (13%), younger children (23%), and older children/tweens (18%). Other dispatch complaints included “sick person/person down/unknown problem” (12%) and “breathing problem” (5%).

A possible reason for these variations is that “an overdose might be mistaken for another medical emergency, or vice versa, because opioid poisonings can be challenging to recognize, especially in young children and in the pediatric population,” Gaw said. “Both the public and emergency responders should maintain a high level of suspicion” of possible overdose for children with the signs or symptoms of it, such as low breathing, unresponsiveness, or small pupils.

In most cases (87%), the patient was not in cardiac arrest, though the patient had entered cardiac arrest before EMS’s arrival in 11.5% of cases. Two thirds of cases only involved one dose of naloxone, while the other 33% involved two doses.

Ryan Marino, MD, an addiction medicine specialist and an associate professor of emergency medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio, who was not involved in the study, took note of the high proportion of cases in which two doses were administered.

“While there is, in my professional opinion, almost no downside to giving naloxone in situations like this, and everybody should have it available and know how to use it, I would caution people on the risk of anchor bias, especially when more than two doses of naloxone are given, since we know that one should be an effective amount for any known opioid overdose,” Marino said. Anchoring bias refers to the tendency for individuals to rely more heavily on the first piece of information they receive about a topic or situation.

“For first responders and healthcare professionals, the importance of additional resuscitation measures like oxygenation and ventilation are just as crucial,” Marino said. “People should not be discouraged if someone doesn’t immediately respond to naloxone as overdose physiology can cause mental status to stay impaired for other reasons beyond direct drug effect, such as hypercarbia, but continue to seek and/or provide additional emergency care in these situations.”

Patients improved after one dose in just over half the cases (54%), and their conditions were unchanged in 46% of cases. There were only 11 cases in which the patient’s condition worsened after a naloxone dose (0.2%). Most of the cases (88%) were transported by EMS, and there were 13 total deaths at the scene (0.2%).

Nichols found the low incidence of worsening clinical status particularly striking. “This is further evidence of a critically important point — naloxone is purely an opioid antagonist, and only binds to opioid receptors, such that if a person has not overdosed on opioids or does not otherwise have opioids in their system, naloxone will not have a significant effect and will not cause them harm,” Nichols said.

“The most common causes of harm are due to rapid reversal of overdose and the potential risks involved in the rapid reversal of opioid effects and potentially precipitating withdrawal, and as this paper demonstrates, these are exceedingly rare,” he said. “Given that, we should have an incredibly low barrier to administer naloxone appropriately.”

The study was limited by inability to know how many true pediatric opioid poisonings are managed by EMS, so future research could look at linking EMS and emergency room hospital databases.
 

 

 

Improved Self-Efficacy in Teens

Another study showed that a peer-to-peer training program increased teens’ knowledge about overdoses from 34% before training to 79% after (P < .0001), and it substantially improved their confidence in recognizing an overdose and administering naloxone.

Nichols said the study shows the importance of ensuring “that adolescents know how to keep themselves and their friends safe in the case that they or anyone they know does end up using illicit substances which either intentionally or unintentionally contain opioids.”

This study assessed a training program with 206 students in a Los Angeles County high school who were trained by their peers between November 2023 and March 2024. The training included trends in teen overdose deaths, defining what opioids and fentanyl are, recognizing an overdose, and responding to one with naloxone.

The teens were an average 16 years old, about evenly split between boys and girls, and mostly in 11th (40%) or 12th (28%) grade, though nearly a third (29%) were 9th graders.

The students’ knowledge about fentanyl’s presence in counterfeit pills increased from 21% before the training to 68% afterward, and their correct identification of an overdose increased from 47% of participants to 90%.

The students’ confidence and attitudes toward helping with an overdose also improved substantially after the training. About two thirds agreed that non-medical people should be able to carry naloxone before the training, and that rose to 88% agreeing after the training. The proportion who agreed they would be willing to assist in an overdose rose from 77% before to 89% after training.

More dramatically, the teens’ confidence after training more than doubled in recognizing an overdose (from 31% to 81%) and more than tripled in their ability to give naloxone during an overdose (from 26% to 83%).

“The critical piece to keep in mind is that the concern about opioid overdose is respiratory depression leading to a lack of oxygen getting to the brain,” Nichols explained. “In the event of an overdose, time is brain — the longer the brain is deprived of oxygen, the lower the chance of survival. There is no specific time at which naloxone would become less effective at reversing an overdose.”

Therefore, people do not need to know the exact time that someone may have overdosed or how long they have been passed out in order to administer naloxone, he said. “The sooner naloxone is administered to someone who is unresponsive and who may have overdosed on opioids, the higher the likelihood of a successful reversal of an overdose and of saving a life.”

The peer-to-peer program was sponsored by the CARLOW Center for Medical Innovation, and the EMS study used no external funding. The authors of both studies and Marino had no disclosures. Nichols has consulted or clinically advised TV shows and health tech startup companies and has no disclosures related to naloxone or the pharmaceutical industry.
 

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

— More than half of youth improved after receiving a dose of naloxone by emergency medical services (EMS) after an emergency dispatch call, according to research presented at the American Academy of Pediatrics 2024 National Conference.

“Emergency responders or EMS are often the first to arrive to an opioid poisoning, and they’re often the first to give naloxone, a potentially lifesaving medication,” said Christopher E. Gaw, MD, MPH, MBE, assistant professor of pediatrics at The Ohio State University College of Medicine and an emergency medicine physician at Nationwide Children’s Hospital in Columbus, Ohio.

Ohio State University
Dr. Christopher E. Gaw

“Our study highlights and underscores its safety of use in the prehospital setting, and this is also supported by other data,” Gaw said. “Efforts to support public distribution and education on naloxone can really help each and every one of us as individual citizens prevent pediatric harm from the opioid crisis.”

Additional research at the meeting showed that teens’ knowledge, attitudes, and confidence about recognizing overdoses and assisting with naloxone administration improved following a peer-to-peer training program, suggesting that teens can play an important role in reducing youth mortality from overdoses.

An average of 22 American teens died from overdose every week in 2022, and as counterfeit pill use has increased among youth, research has found that fentanyl was detected in 93% of overdose deaths with counterfeit pills, according to Talia Puzantian, PharmD, BCPP, of the Keck Graduate Institute School of Pharmacy, Claremont, California, who led the study on peer education. Yet a recent survey had found that less than a third of teens (30%) knew what naloxone was, and only 14% knew how to administer it.

“Ensuring that adolescents have easy and confidential access to naloxone is important and can save lives,” said Taylor Nichols, MD, assistant clinical professor at the University of California San Francisco and an emergency medicine and addiction medicine–certified physician. “I have had teen patients who have told me that they have had to use naloxone obtained from our clinic on friends when they have accidentally overdosed.”

University of California
Dr. Taylor Nichols


Nichols, who was not involved in either study, added that all 50 states have some version of Good Samaritan laws that offer protection to individuals who attempt to aid in emergency assistance in good faith, and all except Kansas and Wyoming have laws specifically protecting people trying to help with overdose prevention.

“I tell people that everyone should carry naloxone and have naloxone available to be able to reverse an overdose, whether they personally use opioids or know people who use opioids because if they happen to come into a situation in which someone is passed out and unresponsive, that timely administration of naloxone may save their life,” Nichols said.

He added that primary care physicians, “particularly in family medicine and pediatrics, should be asking about any opioids in the home prescribed to anyone else and ensure that those patients also are prescribed or have access to naloxone to keep at home. Just as with asking about any other potential safety hazards, making sure they have naloxone available is crucial.”
 

 

 

EMS Naloxone Administration to Youth

EMS clinicians are often the first healthcare providers to respond to an opioid overdose or poisoning event, and evidence-based guidelines for EMS naloxone administration were developed in 2019 to support this intervention. Gaw’s team investigated the frequency and demographics of pediatric administration of naloxone.

They analyzed data from the National Emergency Medical Services Information System on EMS activations for administration of at least one dose of naloxone during 2022 to those aged 0-17. There were 6215 EMS pediatric administrations of naloxone that year, and in the vast majority of cases (82%), the patient had not received a naloxone injection prior to EMS’s arrival.

Most patients (79%) were aged 13-17 years, but 10% were in the 6-12 age group. The remaining patients included 6% infants younger than 1 year and 4% aged 6-12 years. Just over half were for males (55%), and most were dispatched to a home or residential setting (61%). One in five incidents (22%) occurred at a non-healthcare business, 9% on a street or highway, and the rest at a healthcare facility or another location.

Most of the incidents occurred in urban areas (86%), followed by rural (7%), suburban (6%), and wilderness (1.4%). More occurred in the US South (42%) than in the West (29%), Midwest (22%), or Northeast (7.5%).

A key takeaway of those demographic findings is that ingestions and accidental poisonings with opioids can occur in children of any age, Nichols said. “Every single home that has any opioids in the home should absolutely have naloxone immediately available as well,” he said. “Every single person who is prescribed opioids should also have naloxone available and accessible and to be sure that the naloxone is not expired or otherwise tampered with and update that every few years.” He noted that Narcan expiration was recently extended from 3 years to 4 years by the US Food and Drug Administration (FDA).

“I always advise that people who have opioid medications keep them stored safely and securely,” Nichols said. “However, I also acknowledge that even perfect systems fail and that people make mistakes and may accidentally leave medication out, within reach, or otherwise unsecured. If that happens, and someone were to intentionally or unintentionally get into that medication and potentially overdose as a result, we want to have that reversal medication immediately available to reverse the overdose.”

In nearly all cases (91%), EMS provided advanced life support, with only 7.5% patients receiving basic life support and 1.5% receiving specialty critical care. Just under a third (29%) of the dispatch calls were for “overdose/poisoning/ingestion.” Other dispatch calls included “unconscious/fainting/near-fainting” (21%) or “cardiac arrest/death” (17%), but the frequency of each dispatch label varied by age groups.

For example, 38% of calls for infants were for cardiac arrest, compared with 15% of calls for older teens and 18% of calls for 6-12 year olds. An overdose/poisoning dispatch was meanwhile more common for teens (32%) than for infants (13%), younger children (23%), and older children/tweens (18%). Other dispatch complaints included “sick person/person down/unknown problem” (12%) and “breathing problem” (5%).

A possible reason for these variations is that “an overdose might be mistaken for another medical emergency, or vice versa, because opioid poisonings can be challenging to recognize, especially in young children and in the pediatric population,” Gaw said. “Both the public and emergency responders should maintain a high level of suspicion” of possible overdose for children with the signs or symptoms of it, such as low breathing, unresponsiveness, or small pupils.

In most cases (87%), the patient was not in cardiac arrest, though the patient had entered cardiac arrest before EMS’s arrival in 11.5% of cases. Two thirds of cases only involved one dose of naloxone, while the other 33% involved two doses.

Ryan Marino, MD, an addiction medicine specialist and an associate professor of emergency medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio, who was not involved in the study, took note of the high proportion of cases in which two doses were administered.

“While there is, in my professional opinion, almost no downside to giving naloxone in situations like this, and everybody should have it available and know how to use it, I would caution people on the risk of anchor bias, especially when more than two doses of naloxone are given, since we know that one should be an effective amount for any known opioid overdose,” Marino said. Anchoring bias refers to the tendency for individuals to rely more heavily on the first piece of information they receive about a topic or situation.

“For first responders and healthcare professionals, the importance of additional resuscitation measures like oxygenation and ventilation are just as crucial,” Marino said. “People should not be discouraged if someone doesn’t immediately respond to naloxone as overdose physiology can cause mental status to stay impaired for other reasons beyond direct drug effect, such as hypercarbia, but continue to seek and/or provide additional emergency care in these situations.”

Patients improved after one dose in just over half the cases (54%), and their conditions were unchanged in 46% of cases. There were only 11 cases in which the patient’s condition worsened after a naloxone dose (0.2%). Most of the cases (88%) were transported by EMS, and there were 13 total deaths at the scene (0.2%).

Nichols found the low incidence of worsening clinical status particularly striking. “This is further evidence of a critically important point — naloxone is purely an opioid antagonist, and only binds to opioid receptors, such that if a person has not overdosed on opioids or does not otherwise have opioids in their system, naloxone will not have a significant effect and will not cause them harm,” Nichols said.

“The most common causes of harm are due to rapid reversal of overdose and the potential risks involved in the rapid reversal of opioid effects and potentially precipitating withdrawal, and as this paper demonstrates, these are exceedingly rare,” he said. “Given that, we should have an incredibly low barrier to administer naloxone appropriately.”

The study was limited by inability to know how many true pediatric opioid poisonings are managed by EMS, so future research could look at linking EMS and emergency room hospital databases.
 

 

 

Improved Self-Efficacy in Teens

Another study showed that a peer-to-peer training program increased teens’ knowledge about overdoses from 34% before training to 79% after (P < .0001), and it substantially improved their confidence in recognizing an overdose and administering naloxone.

Nichols said the study shows the importance of ensuring “that adolescents know how to keep themselves and their friends safe in the case that they or anyone they know does end up using illicit substances which either intentionally or unintentionally contain opioids.”

This study assessed a training program with 206 students in a Los Angeles County high school who were trained by their peers between November 2023 and March 2024. The training included trends in teen overdose deaths, defining what opioids and fentanyl are, recognizing an overdose, and responding to one with naloxone.

The teens were an average 16 years old, about evenly split between boys and girls, and mostly in 11th (40%) or 12th (28%) grade, though nearly a third (29%) were 9th graders.

The students’ knowledge about fentanyl’s presence in counterfeit pills increased from 21% before the training to 68% afterward, and their correct identification of an overdose increased from 47% of participants to 90%.

The students’ confidence and attitudes toward helping with an overdose also improved substantially after the training. About two thirds agreed that non-medical people should be able to carry naloxone before the training, and that rose to 88% agreeing after the training. The proportion who agreed they would be willing to assist in an overdose rose from 77% before to 89% after training.

More dramatically, the teens’ confidence after training more than doubled in recognizing an overdose (from 31% to 81%) and more than tripled in their ability to give naloxone during an overdose (from 26% to 83%).

“The critical piece to keep in mind is that the concern about opioid overdose is respiratory depression leading to a lack of oxygen getting to the brain,” Nichols explained. “In the event of an overdose, time is brain — the longer the brain is deprived of oxygen, the lower the chance of survival. There is no specific time at which naloxone would become less effective at reversing an overdose.”

Therefore, people do not need to know the exact time that someone may have overdosed or how long they have been passed out in order to administer naloxone, he said. “The sooner naloxone is administered to someone who is unresponsive and who may have overdosed on opioids, the higher the likelihood of a successful reversal of an overdose and of saving a life.”

The peer-to-peer program was sponsored by the CARLOW Center for Medical Innovation, and the EMS study used no external funding. The authors of both studies and Marino had no disclosures. Nichols has consulted or clinically advised TV shows and health tech startup companies and has no disclosures related to naloxone or the pharmaceutical industry.
 

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

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Cannabis Use Rising in Diabetes: What Do Endos Need to Know?

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Cannabis use is becoming increasingly common among people with diabetes. A recent US prevalence study estimated that 9% adults with diabetes used cannabis in the last month, a 33.7% increase between 2021 and 2022. Nearly half (48.9%) of users were younger than 50 years.

Cannabis use is also increasing sharply among those aged 65 years or older, many of whom have diabetes and other chronic conditions. In this demographic, the perceived risk surrounding regular cannabis use has dropped significantly, even as the data tell another story — that they are particularly at risk from emergency department visits for cannabis poisoning.

As legalization continues and cannabis products proliferate, endocrinologists will likely face more patients of all ages seeking advice about its use. Yet with few evidence-based resources to turn to, endocrinologists advising patients in this area are mostly left fending for themselves.
 

Evidence ‘Limited’

“The evidence on cannabis is limited mainly because of its scheduling in the United States,” Jay Shubrook, DO, a professor and diabetologist at College of Osteopathic Medicine, Touro University California, in Vallejo, California, told this news organization. 

“It was declared to be a schedule I drug in the 1970s, which meant it was ‘dangerous’ and ‘had no medical benefit.’ This made it hard to access and study in human trials.” 

That will likely change soon. On May 16, 2024, the US Department of Justice submitted a proposal to move marijuana from a schedule I to a schedule III drug under the Controlled Substances Act, emphasizing its accepted medical use. If approved, the door will open to more investigators seeking to study the effects of cannabis. 

Yet, even in Canada, where recreational use has been legal since 2018 and cannabis is sold widely with government support, there are little hard data to guide practice. In 2019, Diabetes Canada issued a position statement on recreational cannabis use in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). It sought to evaluate the effects of cannabis on metabolic factors and diabetes complications, as well as self-management behaviors in those aged 13 years or older.

The authors noted that five of the six studies upon which the statement was based did not consider or report the routes of cannabis administration, which have differing risks. In addition, their recommendations were based on grade D evidence and consensus.
 

What Patients Are Taking

Cannabis — also known as marijuana, weed, pot, or bud — refers to the dried flowers, leaves, stems, and seeds of the cannabis plant. The plant contains more than 100 compounds, including tetrahydrocannabinol (THC), which is responsible for the euphoric “high,” and other active compounds, including cannabidiol (CBD), which by itself is not mind-altering.

Cannabis can be ingested in several ways. It can be smoked (ie, joints, blunts, pipes, and water pipes), ingested in edible form (mixed or infused into foods), and inhaled using electronic vaporizing devices (ie, e-cigarettes or vape pens).

Compounds in cannabis can also be extracted to make oils and concentrates that can be vaped or inhaled. Smoking oils, concentrates, and extracts from the cannabis plant, known as “dabbing,” are on the rise in the United States.

There are no validated or standard dosage recommendations for cannabis strains and formulations, THC/CBD ratios, or modes of administration. Therefore, the Canadian Pharmacists Association prepared a guide for finding a safe and effective dose for medical purposes. GoodRx, a website with information on prescription drug prices, says that larger doses of THC pose greater risks, noting that the potency of cannabis has increased from 4% in 1995 to about 14% in 2019.
 

 

 

Potential Risks and Benefits: Canadian and US Perspectives

Health and safety risks vary with each of the different ways of using cannabis for individuals with and without diabetes, depending on a host of patient- and product-specific factors.

In a recent article proposing a “THC unit” for Canada’s legal cannabis market, researchers reported that consumers lack familiarity with THC levels, don’t know what constitutes a “low” or “high” THC amount, have trouble dosing, overconsume, and commonly experience adverse health events from cannabis use.

recent study suggested that most clinicians are similarly uninformed, with “a lack of knowledge of beneficial effects, adverse effects, and of how to advise patients,” even for medical cannabis.

Diabetes Canada takes a stab at summarizing what’s known with respect to cannabis and diabetes, stating that:

“Research on recreational cannabis use suggests it may negatively impact diabetes metabolic factors and self-management behaviors. The safety of recreational cannabis use has not been demonstrated, whereas regular cannabis use is associated with worsening glycemic control, more diabetes-related complications, and poorer self-care behaviors, such as adequate glucose monitoring, adherence to medications, and compliance with dietary and physical activity recommendations for people living with both type 1 and type 2 diabetes.”

The American Diabetes Association’s information on cannabis consists of a patient-oriented article on CBD oil. The article stated:

“There’s a lot of hype surrounding CBD oil and diabetes. There is no noticeable effect on blood glucose (blood sugar) or insulin levels in people with type 2 diabetes. Researchers continue to study the effects of CBD on diabetes in animal studies.”

It concludes that:

“Although many claims continue to be made about CBD oil, there is little evidence of any benefit. It’s certainly not an alternative to traditional diabetes management. The safety of CBD is also unknown — it may have dangerous side effects that we won’t know about unless further research is done.”
 

A Roundup of Recent Studies

A smattering of recent studies have touched on various aspects of cannabis consumption and diabetes.

Angela Bryan, PhD, professor and co-director of CUChange at the University of Colorado Boulder, has been evaluating cannabis use in young adults (ages 21-40 years) in the SONIC study. Dr. Bryan reported at the American Diabetes Association (ADA) 84th Scientific Sessions that cannabis users were more likely to have a lower body mass index and less likely to develop T2D. Furthermore, chronic cannabis users were less likely to have measures of inflammation and no loss of insulin sensitivity.

Another study by Dr. Bryan’s group found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.

Similarly positive results were found in a 15-week, double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD spray for neuropathic pain among treatment-resistant patients. The investigators reported that “clinically important improvements” were seen in pain, sleep quality, and subjective impressions of pain. Another small study of inhaled cannabis in treatment-refractory patients found a dose-dependent reduction in diabetic peripheral neuropathy pain.

Findings from a 9-year longitudinal study of approximately 18,000 Swedish men and women suggested no association between cannabis and subsequent T2D development after controlling for age, although these authors also called for longer follow-up and more detailed information about cannabis use to make “more robust” conclusions.

On the other side of the spectrum, a “rapid” review of recreational cannabis use in people with T1D and T2D found that recreational cannabis use may negatively impact diabetes metabolic factors and self-management behaviors and may increase risks for peripheral arterial occlusion, myocardial infarction, and renal disease. However, the authors cautioned that more robust research is needed to confirm the potential impact of cannabis on diabetes.
 

 

 

How to Advise Patients

When Dr. Shubrook was working with patients with diabetes in his family medicine practice in Ohio, cannabis wasn’t legal. 

“’Don’t ask, don’t tell’ was the way we handled it then,” he said. 

By contrast, in California, where he’s currently located, “it’s pretty well accepted and legal, and patients volunteer information about use, even if it’s recreational,” he said. “Realizing this was something we could talk about was really eye-opening to me.” 

Talking to patients about cannabis use is a “20-minute conversation that details what they’re doing,” he said. He proceeds by asking questions: Are you using for recreational or medicinal purposes? What do you take? What do you take it for? Does it work? 

“People will tell you,” Dr. Shubrook said. “They know exactly what it works or doesn’t work for and how it affects their glucose control, which in most cases is only minimally.”

He tells patients he would prefer they don’t inhale cannabis, given the risks posed to the lungs. 

“Edibles may have a slower onset of effect, but depending on what they’re adding it to, glucose might be affected,” he noted. “And I have seen that chronic use can lead to hyperemesis syndrome.”

Overall, he said, “Take the time to talk to your patients about cannabis — it will allow them to be honest with you, and you can improve the specificity and safety of its use. If cannabis is legal in your state, encourage people to go to legal dispensaries, which will reduce the risk of it being laced with another drug that could increase the danger of use.”

A recent US prevalence study found that people with diabetes who use cannabis likely engage in other substance and psychoactive substance use, including tobacco use, binge drinking, and misuse of opioids and stimulants. 

“Use of these additional substances could further exacerbate the health risks associated with diabetes and also emphasizes the importance of addressing polysubstance use among adults with diabetes,” the study’s author Benjamin H. Han, MD, Division of Geriatrics, Gerontology and Palliative Care, Department of Medicine, US San Diego School of Medicine in La Jolla, California, told this news organization.

“We were surprised at how strong the associations were, especially with use of substances that can increase cardiovascular risk,” Dr. Han added. “And given the strong association we found between cannabis use and use of other psychoactive substances in diabetes, clinicians must screen all their patients for psychoactive substance use.” 

Diabetes Canada’s position paper states that despite the limited evidence, “there were sufficient data to begin developing recommendations for type 1 and type 2 diabetes about education, counseling, and management related to recreational cannabis use.” 

Their recommendations include the following:

  • Healthcare professionals should engage their patients in discussions about substance use on a regular basis, with a nonjudgmental approach.
  • The use of recreational cannabis is not recommended for adolescents and adults with diabetes.
  • People with T1D should avoid recreational cannabis use because of the increased risk for diabetic ketoacidosis.
  • For adults with T1D or T2D who intend to use cannabis recreationally, individualized assessment and counseling should be offered to inform them of the general risks of cannabis, with a focus on harm reduction and reduction of the risk for potential adverse effects on diabetes management and complications.
  • People with T1D or T2D should be offered education on and encouraged to read public information available through resources from various Canadian health authorities about the general risks of cannabis use to reduce the risk for nondiabetes-related adverse effects of cannabis consumption.

Of note, in 2018, the Canadian government produced an exhaustive compendium of information on cannabis for healthcare professionals that includes information relevant to managing patients with diabetes. 

Dr. Shubrook and Dr. Han reported no competing interests.
 

A version of this article appeared on Medscape.com.

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Cannabis use is becoming increasingly common among people with diabetes. A recent US prevalence study estimated that 9% adults with diabetes used cannabis in the last month, a 33.7% increase between 2021 and 2022. Nearly half (48.9%) of users were younger than 50 years.

Cannabis use is also increasing sharply among those aged 65 years or older, many of whom have diabetes and other chronic conditions. In this demographic, the perceived risk surrounding regular cannabis use has dropped significantly, even as the data tell another story — that they are particularly at risk from emergency department visits for cannabis poisoning.

As legalization continues and cannabis products proliferate, endocrinologists will likely face more patients of all ages seeking advice about its use. Yet with few evidence-based resources to turn to, endocrinologists advising patients in this area are mostly left fending for themselves.
 

Evidence ‘Limited’

“The evidence on cannabis is limited mainly because of its scheduling in the United States,” Jay Shubrook, DO, a professor and diabetologist at College of Osteopathic Medicine, Touro University California, in Vallejo, California, told this news organization. 

“It was declared to be a schedule I drug in the 1970s, which meant it was ‘dangerous’ and ‘had no medical benefit.’ This made it hard to access and study in human trials.” 

That will likely change soon. On May 16, 2024, the US Department of Justice submitted a proposal to move marijuana from a schedule I to a schedule III drug under the Controlled Substances Act, emphasizing its accepted medical use. If approved, the door will open to more investigators seeking to study the effects of cannabis. 

Yet, even in Canada, where recreational use has been legal since 2018 and cannabis is sold widely with government support, there are little hard data to guide practice. In 2019, Diabetes Canada issued a position statement on recreational cannabis use in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). It sought to evaluate the effects of cannabis on metabolic factors and diabetes complications, as well as self-management behaviors in those aged 13 years or older.

The authors noted that five of the six studies upon which the statement was based did not consider or report the routes of cannabis administration, which have differing risks. In addition, their recommendations were based on grade D evidence and consensus.
 

What Patients Are Taking

Cannabis — also known as marijuana, weed, pot, or bud — refers to the dried flowers, leaves, stems, and seeds of the cannabis plant. The plant contains more than 100 compounds, including tetrahydrocannabinol (THC), which is responsible for the euphoric “high,” and other active compounds, including cannabidiol (CBD), which by itself is not mind-altering.

Cannabis can be ingested in several ways. It can be smoked (ie, joints, blunts, pipes, and water pipes), ingested in edible form (mixed or infused into foods), and inhaled using electronic vaporizing devices (ie, e-cigarettes or vape pens).

Compounds in cannabis can also be extracted to make oils and concentrates that can be vaped or inhaled. Smoking oils, concentrates, and extracts from the cannabis plant, known as “dabbing,” are on the rise in the United States.

There are no validated or standard dosage recommendations for cannabis strains and formulations, THC/CBD ratios, or modes of administration. Therefore, the Canadian Pharmacists Association prepared a guide for finding a safe and effective dose for medical purposes. GoodRx, a website with information on prescription drug prices, says that larger doses of THC pose greater risks, noting that the potency of cannabis has increased from 4% in 1995 to about 14% in 2019.
 

 

 

Potential Risks and Benefits: Canadian and US Perspectives

Health and safety risks vary with each of the different ways of using cannabis for individuals with and without diabetes, depending on a host of patient- and product-specific factors.

In a recent article proposing a “THC unit” for Canada’s legal cannabis market, researchers reported that consumers lack familiarity with THC levels, don’t know what constitutes a “low” or “high” THC amount, have trouble dosing, overconsume, and commonly experience adverse health events from cannabis use.

recent study suggested that most clinicians are similarly uninformed, with “a lack of knowledge of beneficial effects, adverse effects, and of how to advise patients,” even for medical cannabis.

Diabetes Canada takes a stab at summarizing what’s known with respect to cannabis and diabetes, stating that:

“Research on recreational cannabis use suggests it may negatively impact diabetes metabolic factors and self-management behaviors. The safety of recreational cannabis use has not been demonstrated, whereas regular cannabis use is associated with worsening glycemic control, more diabetes-related complications, and poorer self-care behaviors, such as adequate glucose monitoring, adherence to medications, and compliance with dietary and physical activity recommendations for people living with both type 1 and type 2 diabetes.”

The American Diabetes Association’s information on cannabis consists of a patient-oriented article on CBD oil. The article stated:

“There’s a lot of hype surrounding CBD oil and diabetes. There is no noticeable effect on blood glucose (blood sugar) or insulin levels in people with type 2 diabetes. Researchers continue to study the effects of CBD on diabetes in animal studies.”

It concludes that:

“Although many claims continue to be made about CBD oil, there is little evidence of any benefit. It’s certainly not an alternative to traditional diabetes management. The safety of CBD is also unknown — it may have dangerous side effects that we won’t know about unless further research is done.”
 

A Roundup of Recent Studies

A smattering of recent studies have touched on various aspects of cannabis consumption and diabetes.

Angela Bryan, PhD, professor and co-director of CUChange at the University of Colorado Boulder, has been evaluating cannabis use in young adults (ages 21-40 years) in the SONIC study. Dr. Bryan reported at the American Diabetes Association (ADA) 84th Scientific Sessions that cannabis users were more likely to have a lower body mass index and less likely to develop T2D. Furthermore, chronic cannabis users were less likely to have measures of inflammation and no loss of insulin sensitivity.

Another study by Dr. Bryan’s group found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.

Similarly positive results were found in a 15-week, double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD spray for neuropathic pain among treatment-resistant patients. The investigators reported that “clinically important improvements” were seen in pain, sleep quality, and subjective impressions of pain. Another small study of inhaled cannabis in treatment-refractory patients found a dose-dependent reduction in diabetic peripheral neuropathy pain.

Findings from a 9-year longitudinal study of approximately 18,000 Swedish men and women suggested no association between cannabis and subsequent T2D development after controlling for age, although these authors also called for longer follow-up and more detailed information about cannabis use to make “more robust” conclusions.

On the other side of the spectrum, a “rapid” review of recreational cannabis use in people with T1D and T2D found that recreational cannabis use may negatively impact diabetes metabolic factors and self-management behaviors and may increase risks for peripheral arterial occlusion, myocardial infarction, and renal disease. However, the authors cautioned that more robust research is needed to confirm the potential impact of cannabis on diabetes.
 

 

 

How to Advise Patients

When Dr. Shubrook was working with patients with diabetes in his family medicine practice in Ohio, cannabis wasn’t legal. 

“’Don’t ask, don’t tell’ was the way we handled it then,” he said. 

By contrast, in California, where he’s currently located, “it’s pretty well accepted and legal, and patients volunteer information about use, even if it’s recreational,” he said. “Realizing this was something we could talk about was really eye-opening to me.” 

Talking to patients about cannabis use is a “20-minute conversation that details what they’re doing,” he said. He proceeds by asking questions: Are you using for recreational or medicinal purposes? What do you take? What do you take it for? Does it work? 

“People will tell you,” Dr. Shubrook said. “They know exactly what it works or doesn’t work for and how it affects their glucose control, which in most cases is only minimally.”

He tells patients he would prefer they don’t inhale cannabis, given the risks posed to the lungs. 

“Edibles may have a slower onset of effect, but depending on what they’re adding it to, glucose might be affected,” he noted. “And I have seen that chronic use can lead to hyperemesis syndrome.”

Overall, he said, “Take the time to talk to your patients about cannabis — it will allow them to be honest with you, and you can improve the specificity and safety of its use. If cannabis is legal in your state, encourage people to go to legal dispensaries, which will reduce the risk of it being laced with another drug that could increase the danger of use.”

A recent US prevalence study found that people with diabetes who use cannabis likely engage in other substance and psychoactive substance use, including tobacco use, binge drinking, and misuse of opioids and stimulants. 

“Use of these additional substances could further exacerbate the health risks associated with diabetes and also emphasizes the importance of addressing polysubstance use among adults with diabetes,” the study’s author Benjamin H. Han, MD, Division of Geriatrics, Gerontology and Palliative Care, Department of Medicine, US San Diego School of Medicine in La Jolla, California, told this news organization.

“We were surprised at how strong the associations were, especially with use of substances that can increase cardiovascular risk,” Dr. Han added. “And given the strong association we found between cannabis use and use of other psychoactive substances in diabetes, clinicians must screen all their patients for psychoactive substance use.” 

Diabetes Canada’s position paper states that despite the limited evidence, “there were sufficient data to begin developing recommendations for type 1 and type 2 diabetes about education, counseling, and management related to recreational cannabis use.” 

Their recommendations include the following:

  • Healthcare professionals should engage their patients in discussions about substance use on a regular basis, with a nonjudgmental approach.
  • The use of recreational cannabis is not recommended for adolescents and adults with diabetes.
  • People with T1D should avoid recreational cannabis use because of the increased risk for diabetic ketoacidosis.
  • For adults with T1D or T2D who intend to use cannabis recreationally, individualized assessment and counseling should be offered to inform them of the general risks of cannabis, with a focus on harm reduction and reduction of the risk for potential adverse effects on diabetes management and complications.
  • People with T1D or T2D should be offered education on and encouraged to read public information available through resources from various Canadian health authorities about the general risks of cannabis use to reduce the risk for nondiabetes-related adverse effects of cannabis consumption.

Of note, in 2018, the Canadian government produced an exhaustive compendium of information on cannabis for healthcare professionals that includes information relevant to managing patients with diabetes. 

Dr. Shubrook and Dr. Han reported no competing interests.
 

A version of this article appeared on Medscape.com.

Cannabis use is becoming increasingly common among people with diabetes. A recent US prevalence study estimated that 9% adults with diabetes used cannabis in the last month, a 33.7% increase between 2021 and 2022. Nearly half (48.9%) of users were younger than 50 years.

Cannabis use is also increasing sharply among those aged 65 years or older, many of whom have diabetes and other chronic conditions. In this demographic, the perceived risk surrounding regular cannabis use has dropped significantly, even as the data tell another story — that they are particularly at risk from emergency department visits for cannabis poisoning.

As legalization continues and cannabis products proliferate, endocrinologists will likely face more patients of all ages seeking advice about its use. Yet with few evidence-based resources to turn to, endocrinologists advising patients in this area are mostly left fending for themselves.
 

Evidence ‘Limited’

“The evidence on cannabis is limited mainly because of its scheduling in the United States,” Jay Shubrook, DO, a professor and diabetologist at College of Osteopathic Medicine, Touro University California, in Vallejo, California, told this news organization. 

“It was declared to be a schedule I drug in the 1970s, which meant it was ‘dangerous’ and ‘had no medical benefit.’ This made it hard to access and study in human trials.” 

That will likely change soon. On May 16, 2024, the US Department of Justice submitted a proposal to move marijuana from a schedule I to a schedule III drug under the Controlled Substances Act, emphasizing its accepted medical use. If approved, the door will open to more investigators seeking to study the effects of cannabis. 

Yet, even in Canada, where recreational use has been legal since 2018 and cannabis is sold widely with government support, there are little hard data to guide practice. In 2019, Diabetes Canada issued a position statement on recreational cannabis use in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). It sought to evaluate the effects of cannabis on metabolic factors and diabetes complications, as well as self-management behaviors in those aged 13 years or older.

The authors noted that five of the six studies upon which the statement was based did not consider or report the routes of cannabis administration, which have differing risks. In addition, their recommendations were based on grade D evidence and consensus.
 

What Patients Are Taking

Cannabis — also known as marijuana, weed, pot, or bud — refers to the dried flowers, leaves, stems, and seeds of the cannabis plant. The plant contains more than 100 compounds, including tetrahydrocannabinol (THC), which is responsible for the euphoric “high,” and other active compounds, including cannabidiol (CBD), which by itself is not mind-altering.

Cannabis can be ingested in several ways. It can be smoked (ie, joints, blunts, pipes, and water pipes), ingested in edible form (mixed or infused into foods), and inhaled using electronic vaporizing devices (ie, e-cigarettes or vape pens).

Compounds in cannabis can also be extracted to make oils and concentrates that can be vaped or inhaled. Smoking oils, concentrates, and extracts from the cannabis plant, known as “dabbing,” are on the rise in the United States.

There are no validated or standard dosage recommendations for cannabis strains and formulations, THC/CBD ratios, or modes of administration. Therefore, the Canadian Pharmacists Association prepared a guide for finding a safe and effective dose for medical purposes. GoodRx, a website with information on prescription drug prices, says that larger doses of THC pose greater risks, noting that the potency of cannabis has increased from 4% in 1995 to about 14% in 2019.
 

 

 

Potential Risks and Benefits: Canadian and US Perspectives

Health and safety risks vary with each of the different ways of using cannabis for individuals with and without diabetes, depending on a host of patient- and product-specific factors.

In a recent article proposing a “THC unit” for Canada’s legal cannabis market, researchers reported that consumers lack familiarity with THC levels, don’t know what constitutes a “low” or “high” THC amount, have trouble dosing, overconsume, and commonly experience adverse health events from cannabis use.

recent study suggested that most clinicians are similarly uninformed, with “a lack of knowledge of beneficial effects, adverse effects, and of how to advise patients,” even for medical cannabis.

Diabetes Canada takes a stab at summarizing what’s known with respect to cannabis and diabetes, stating that:

“Research on recreational cannabis use suggests it may negatively impact diabetes metabolic factors and self-management behaviors. The safety of recreational cannabis use has not been demonstrated, whereas regular cannabis use is associated with worsening glycemic control, more diabetes-related complications, and poorer self-care behaviors, such as adequate glucose monitoring, adherence to medications, and compliance with dietary and physical activity recommendations for people living with both type 1 and type 2 diabetes.”

The American Diabetes Association’s information on cannabis consists of a patient-oriented article on CBD oil. The article stated:

“There’s a lot of hype surrounding CBD oil and diabetes. There is no noticeable effect on blood glucose (blood sugar) or insulin levels in people with type 2 diabetes. Researchers continue to study the effects of CBD on diabetes in animal studies.”

It concludes that:

“Although many claims continue to be made about CBD oil, there is little evidence of any benefit. It’s certainly not an alternative to traditional diabetes management. The safety of CBD is also unknown — it may have dangerous side effects that we won’t know about unless further research is done.”
 

A Roundup of Recent Studies

A smattering of recent studies have touched on various aspects of cannabis consumption and diabetes.

Angela Bryan, PhD, professor and co-director of CUChange at the University of Colorado Boulder, has been evaluating cannabis use in young adults (ages 21-40 years) in the SONIC study. Dr. Bryan reported at the American Diabetes Association (ADA) 84th Scientific Sessions that cannabis users were more likely to have a lower body mass index and less likely to develop T2D. Furthermore, chronic cannabis users were less likely to have measures of inflammation and no loss of insulin sensitivity.

Another study by Dr. Bryan’s group found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.

Similarly positive results were found in a 15-week, double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD spray for neuropathic pain among treatment-resistant patients. The investigators reported that “clinically important improvements” were seen in pain, sleep quality, and subjective impressions of pain. Another small study of inhaled cannabis in treatment-refractory patients found a dose-dependent reduction in diabetic peripheral neuropathy pain.

Findings from a 9-year longitudinal study of approximately 18,000 Swedish men and women suggested no association between cannabis and subsequent T2D development after controlling for age, although these authors also called for longer follow-up and more detailed information about cannabis use to make “more robust” conclusions.

On the other side of the spectrum, a “rapid” review of recreational cannabis use in people with T1D and T2D found that recreational cannabis use may negatively impact diabetes metabolic factors and self-management behaviors and may increase risks for peripheral arterial occlusion, myocardial infarction, and renal disease. However, the authors cautioned that more robust research is needed to confirm the potential impact of cannabis on diabetes.
 

 

 

How to Advise Patients

When Dr. Shubrook was working with patients with diabetes in his family medicine practice in Ohio, cannabis wasn’t legal. 

“’Don’t ask, don’t tell’ was the way we handled it then,” he said. 

By contrast, in California, where he’s currently located, “it’s pretty well accepted and legal, and patients volunteer information about use, even if it’s recreational,” he said. “Realizing this was something we could talk about was really eye-opening to me.” 

Talking to patients about cannabis use is a “20-minute conversation that details what they’re doing,” he said. He proceeds by asking questions: Are you using for recreational or medicinal purposes? What do you take? What do you take it for? Does it work? 

“People will tell you,” Dr. Shubrook said. “They know exactly what it works or doesn’t work for and how it affects their glucose control, which in most cases is only minimally.”

He tells patients he would prefer they don’t inhale cannabis, given the risks posed to the lungs. 

“Edibles may have a slower onset of effect, but depending on what they’re adding it to, glucose might be affected,” he noted. “And I have seen that chronic use can lead to hyperemesis syndrome.”

Overall, he said, “Take the time to talk to your patients about cannabis — it will allow them to be honest with you, and you can improve the specificity and safety of its use. If cannabis is legal in your state, encourage people to go to legal dispensaries, which will reduce the risk of it being laced with another drug that could increase the danger of use.”

A recent US prevalence study found that people with diabetes who use cannabis likely engage in other substance and psychoactive substance use, including tobacco use, binge drinking, and misuse of opioids and stimulants. 

“Use of these additional substances could further exacerbate the health risks associated with diabetes and also emphasizes the importance of addressing polysubstance use among adults with diabetes,” the study’s author Benjamin H. Han, MD, Division of Geriatrics, Gerontology and Palliative Care, Department of Medicine, US San Diego School of Medicine in La Jolla, California, told this news organization.

“We were surprised at how strong the associations were, especially with use of substances that can increase cardiovascular risk,” Dr. Han added. “And given the strong association we found between cannabis use and use of other psychoactive substances in diabetes, clinicians must screen all their patients for psychoactive substance use.” 

Diabetes Canada’s position paper states that despite the limited evidence, “there were sufficient data to begin developing recommendations for type 1 and type 2 diabetes about education, counseling, and management related to recreational cannabis use.” 

Their recommendations include the following:

  • Healthcare professionals should engage their patients in discussions about substance use on a regular basis, with a nonjudgmental approach.
  • The use of recreational cannabis is not recommended for adolescents and adults with diabetes.
  • People with T1D should avoid recreational cannabis use because of the increased risk for diabetic ketoacidosis.
  • For adults with T1D or T2D who intend to use cannabis recreationally, individualized assessment and counseling should be offered to inform them of the general risks of cannabis, with a focus on harm reduction and reduction of the risk for potential adverse effects on diabetes management and complications.
  • People with T1D or T2D should be offered education on and encouraged to read public information available through resources from various Canadian health authorities about the general risks of cannabis use to reduce the risk for nondiabetes-related adverse effects of cannabis consumption.

Of note, in 2018, the Canadian government produced an exhaustive compendium of information on cannabis for healthcare professionals that includes information relevant to managing patients with diabetes. 

Dr. Shubrook and Dr. Han reported no competing interests.
 

A version of this article appeared on Medscape.com.

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Higher Daily Buprenorphine Doses Help Manage OUD: AMA Recommends Policy Change

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Changed
Fri, 10/04/2024 - 13:34

Higher daily buprenorphine doses may help patients better manage opioid use disorder (OUD), data from a National Institutes of Health (NIH) study suggested.

The new data highlight that the dose size currently recommended by the US Food and Drug Administration (FDA) and insurance caps on doses are outdated and harmful in the age of fentanyl overdoses, according to the American Medical Association (AMA) and physicians who have studied the issue.

Findings of the study, led by Sarah Axeen, PhD, with the Schaeffer Center for Health Policy & Economics, University of Southern California, Los Angeles, were published in JAMA Network Open.

The researchers reviewed insurance claims data from more than 35,000 people diagnosed with OUD who started on buprenorphine treatment between 2016 and 2021. They found that 12.5% had an emergency department (ED) or inpatient visit related to behavioral health within the study period.

They analyzed whether a patient’s buprenorphine dose was linked with the length of time between treatment start and an ED or inpatient visit.
 

Higher Doses, Better Outcomes

The FDA’s recommended target dose for buprenorphine is 16 mg/d. Dr. Axeen’s team found that those taking higher daily doses (> 16 to 24 mg) took 20% longer to have an ED or inpatient visit related to behavioral health within the first year after receiving treatment than those who took > 8 to 16 mg/d.

“Those taking daily doses of more than 24 mg of buprenorphine went 50% longer before having a subsequent emergency or inpatient healthcare visit related to behavioral health within the first year after receiving treatment, compared to those receiving > 8 to 16 mg a day,” the researchers said in a press release.
 

AMA Says the Findings Should Change Policies

Bobby Mukkamala, MD, president-elect of the AMA and Chair of the AMA Substance Use and Pain Care Task Force, said the association welcomed the study findings and urged policymakers and insurance providers to act on them with updated policies.

“The findings support AMA policy calling for flexibility in buprenorphine dosing, allowing patients to receive doses exceeding FDA-approved limits when clinically recommended by their prescriber,” he said in a statement. “Policymakers must take note of these findings and the growing body of evidence that further affirm buprenorphine as a safe, effective, and lifesaving tool in the fight against the illicit fentanyl overdose epidemic. It is also critically important for health insurance companies, Medicaid, and Medicare to remove dosage caps for buprenorphine.”
 

‘Tangible Economic Impact’

Lucinda Grande, MD, a family physician and addiction specialist with Pioneer Family Practice in Lacey, Washington, said in an interview that she was happy to see this study because “it is the first buprenorphine dose study that addresses an outcome with a tangible economic impact that would affect the bottom line of payers and healthcare systems” and may capture the attention of policymakers in changing what she says are outdated recommendations.

“This study is also unusual because it looked specifically at the dose range above 24 mg. Even though that top tier included only a tiny proportion (1.8%) of patients, it was the group that had the greatest long-term benefit from buprenorphine,” Dr. Grande said, adding that other studies have not included that high a dose.

Dr. Grande, who published on a related topic in 2023, noted that Medicaid patients were excluded from the current study, and they make up a substantial portion of those using buprenorphine for OUD. Had they been included, she said, she suspects the evidence would have been even stronger in favor of higher doses.

Physicians can prescribe higher doses off-label, but buprenorphine is expensive, and some insurers have caps based on the FDA recommendations. Dr. Grande says she rarely prescribes > 32 mg/d, and the patients who need the higher doses often have chronic pain. “In Washington State,” she said, “we have had the luxury of prescribing up to 32 mg daily to Medicaid patients for years. I have had a lot of opportunity to work in that dose rage for people who really need it, and I can really see a difference.”

As fentanyl has grown into the primary illicit opioid, she says, the FDA recommendations for buprenorphine have become progressively weaker.

“Fentanyl is 50 times more potent than heroin, the opioid prevalent when the FDA guidelines were written,” she said. “It’s like a popgun that you’re using against a cannon.”

This manuscript was prepared with support from the National Institute on Drug Abuse. Dr. Axeen reported no relevant financial disclosures. Coauthor Jessica S. Merlin, MD, reported grants from Cambia Health Foundation outside the submitted work. Adam J. Gordon, MD, reported grants from NIH and the Veterans Affairs (institution) during the conduct of the study; he reported service as editor-in-chief with the Association for Multidisciplinary Education and Research in Substance use and Addiction. Bradley D. Stein, MD, reported grants from the NIH during the conduct of the study. Dr. Mukkamala and Dr. Grande reported no relevant financial relationships.
 

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

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Higher daily buprenorphine doses may help patients better manage opioid use disorder (OUD), data from a National Institutes of Health (NIH) study suggested.

The new data highlight that the dose size currently recommended by the US Food and Drug Administration (FDA) and insurance caps on doses are outdated and harmful in the age of fentanyl overdoses, according to the American Medical Association (AMA) and physicians who have studied the issue.

Findings of the study, led by Sarah Axeen, PhD, with the Schaeffer Center for Health Policy & Economics, University of Southern California, Los Angeles, were published in JAMA Network Open.

The researchers reviewed insurance claims data from more than 35,000 people diagnosed with OUD who started on buprenorphine treatment between 2016 and 2021. They found that 12.5% had an emergency department (ED) or inpatient visit related to behavioral health within the study period.

They analyzed whether a patient’s buprenorphine dose was linked with the length of time between treatment start and an ED or inpatient visit.
 

Higher Doses, Better Outcomes

The FDA’s recommended target dose for buprenorphine is 16 mg/d. Dr. Axeen’s team found that those taking higher daily doses (> 16 to 24 mg) took 20% longer to have an ED or inpatient visit related to behavioral health within the first year after receiving treatment than those who took > 8 to 16 mg/d.

“Those taking daily doses of more than 24 mg of buprenorphine went 50% longer before having a subsequent emergency or inpatient healthcare visit related to behavioral health within the first year after receiving treatment, compared to those receiving > 8 to 16 mg a day,” the researchers said in a press release.
 

AMA Says the Findings Should Change Policies

Bobby Mukkamala, MD, president-elect of the AMA and Chair of the AMA Substance Use and Pain Care Task Force, said the association welcomed the study findings and urged policymakers and insurance providers to act on them with updated policies.

“The findings support AMA policy calling for flexibility in buprenorphine dosing, allowing patients to receive doses exceeding FDA-approved limits when clinically recommended by their prescriber,” he said in a statement. “Policymakers must take note of these findings and the growing body of evidence that further affirm buprenorphine as a safe, effective, and lifesaving tool in the fight against the illicit fentanyl overdose epidemic. It is also critically important for health insurance companies, Medicaid, and Medicare to remove dosage caps for buprenorphine.”
 

‘Tangible Economic Impact’

Lucinda Grande, MD, a family physician and addiction specialist with Pioneer Family Practice in Lacey, Washington, said in an interview that she was happy to see this study because “it is the first buprenorphine dose study that addresses an outcome with a tangible economic impact that would affect the bottom line of payers and healthcare systems” and may capture the attention of policymakers in changing what she says are outdated recommendations.

“This study is also unusual because it looked specifically at the dose range above 24 mg. Even though that top tier included only a tiny proportion (1.8%) of patients, it was the group that had the greatest long-term benefit from buprenorphine,” Dr. Grande said, adding that other studies have not included that high a dose.

Dr. Grande, who published on a related topic in 2023, noted that Medicaid patients were excluded from the current study, and they make up a substantial portion of those using buprenorphine for OUD. Had they been included, she said, she suspects the evidence would have been even stronger in favor of higher doses.

Physicians can prescribe higher doses off-label, but buprenorphine is expensive, and some insurers have caps based on the FDA recommendations. Dr. Grande says she rarely prescribes > 32 mg/d, and the patients who need the higher doses often have chronic pain. “In Washington State,” she said, “we have had the luxury of prescribing up to 32 mg daily to Medicaid patients for years. I have had a lot of opportunity to work in that dose rage for people who really need it, and I can really see a difference.”

As fentanyl has grown into the primary illicit opioid, she says, the FDA recommendations for buprenorphine have become progressively weaker.

“Fentanyl is 50 times more potent than heroin, the opioid prevalent when the FDA guidelines were written,” she said. “It’s like a popgun that you’re using against a cannon.”

This manuscript was prepared with support from the National Institute on Drug Abuse. Dr. Axeen reported no relevant financial disclosures. Coauthor Jessica S. Merlin, MD, reported grants from Cambia Health Foundation outside the submitted work. Adam J. Gordon, MD, reported grants from NIH and the Veterans Affairs (institution) during the conduct of the study; he reported service as editor-in-chief with the Association for Multidisciplinary Education and Research in Substance use and Addiction. Bradley D. Stein, MD, reported grants from the NIH during the conduct of the study. Dr. Mukkamala and Dr. Grande reported no relevant financial relationships.
 

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

Higher daily buprenorphine doses may help patients better manage opioid use disorder (OUD), data from a National Institutes of Health (NIH) study suggested.

The new data highlight that the dose size currently recommended by the US Food and Drug Administration (FDA) and insurance caps on doses are outdated and harmful in the age of fentanyl overdoses, according to the American Medical Association (AMA) and physicians who have studied the issue.

Findings of the study, led by Sarah Axeen, PhD, with the Schaeffer Center for Health Policy & Economics, University of Southern California, Los Angeles, were published in JAMA Network Open.

The researchers reviewed insurance claims data from more than 35,000 people diagnosed with OUD who started on buprenorphine treatment between 2016 and 2021. They found that 12.5% had an emergency department (ED) or inpatient visit related to behavioral health within the study period.

They analyzed whether a patient’s buprenorphine dose was linked with the length of time between treatment start and an ED or inpatient visit.
 

Higher Doses, Better Outcomes

The FDA’s recommended target dose for buprenorphine is 16 mg/d. Dr. Axeen’s team found that those taking higher daily doses (> 16 to 24 mg) took 20% longer to have an ED or inpatient visit related to behavioral health within the first year after receiving treatment than those who took > 8 to 16 mg/d.

“Those taking daily doses of more than 24 mg of buprenorphine went 50% longer before having a subsequent emergency or inpatient healthcare visit related to behavioral health within the first year after receiving treatment, compared to those receiving > 8 to 16 mg a day,” the researchers said in a press release.
 

AMA Says the Findings Should Change Policies

Bobby Mukkamala, MD, president-elect of the AMA and Chair of the AMA Substance Use and Pain Care Task Force, said the association welcomed the study findings and urged policymakers and insurance providers to act on them with updated policies.

“The findings support AMA policy calling for flexibility in buprenorphine dosing, allowing patients to receive doses exceeding FDA-approved limits when clinically recommended by their prescriber,” he said in a statement. “Policymakers must take note of these findings and the growing body of evidence that further affirm buprenorphine as a safe, effective, and lifesaving tool in the fight against the illicit fentanyl overdose epidemic. It is also critically important for health insurance companies, Medicaid, and Medicare to remove dosage caps for buprenorphine.”
 

‘Tangible Economic Impact’

Lucinda Grande, MD, a family physician and addiction specialist with Pioneer Family Practice in Lacey, Washington, said in an interview that she was happy to see this study because “it is the first buprenorphine dose study that addresses an outcome with a tangible economic impact that would affect the bottom line of payers and healthcare systems” and may capture the attention of policymakers in changing what she says are outdated recommendations.

“This study is also unusual because it looked specifically at the dose range above 24 mg. Even though that top tier included only a tiny proportion (1.8%) of patients, it was the group that had the greatest long-term benefit from buprenorphine,” Dr. Grande said, adding that other studies have not included that high a dose.

Dr. Grande, who published on a related topic in 2023, noted that Medicaid patients were excluded from the current study, and they make up a substantial portion of those using buprenorphine for OUD. Had they been included, she said, she suspects the evidence would have been even stronger in favor of higher doses.

Physicians can prescribe higher doses off-label, but buprenorphine is expensive, and some insurers have caps based on the FDA recommendations. Dr. Grande says she rarely prescribes > 32 mg/d, and the patients who need the higher doses often have chronic pain. “In Washington State,” she said, “we have had the luxury of prescribing up to 32 mg daily to Medicaid patients for years. I have had a lot of opportunity to work in that dose rage for people who really need it, and I can really see a difference.”

As fentanyl has grown into the primary illicit opioid, she says, the FDA recommendations for buprenorphine have become progressively weaker.

“Fentanyl is 50 times more potent than heroin, the opioid prevalent when the FDA guidelines were written,” she said. “It’s like a popgun that you’re using against a cannon.”

This manuscript was prepared with support from the National Institute on Drug Abuse. Dr. Axeen reported no relevant financial disclosures. Coauthor Jessica S. Merlin, MD, reported grants from Cambia Health Foundation outside the submitted work. Adam J. Gordon, MD, reported grants from NIH and the Veterans Affairs (institution) during the conduct of the study; he reported service as editor-in-chief with the Association for Multidisciplinary Education and Research in Substance use and Addiction. Bradley D. Stein, MD, reported grants from the NIH during the conduct of the study. Dr. Mukkamala and Dr. Grande reported no relevant financial relationships.
 

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

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Can Hormones Guide Sex-Specific Treatments for Alcohol Use Disorder?

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Mon, 09/30/2024 - 12:26

MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.

“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
 

Sex Hormone Signatures

Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.

However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.

The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.

Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.

Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.

“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
 

What Works for Men May Not Work for Women

Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).

In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).

In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).

In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).

Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.

What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
 

 

 

Toward Gender Equity

The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.

Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.

“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.

In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”

“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”

Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.

This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
 

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

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MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.

“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
 

Sex Hormone Signatures

Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.

However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.

The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.

Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.

Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.

“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
 

What Works for Men May Not Work for Women

Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).

In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).

In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).

In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).

Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.

What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
 

 

 

Toward Gender Equity

The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.

Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.

“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.

In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”

“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”

Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.

This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
 

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

MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.

“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
 

Sex Hormone Signatures

Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.

However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.

The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.

Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.

Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.

“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
 

What Works for Men May Not Work for Women

Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).

In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).

In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).

In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).

Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.

What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
 

 

 

Toward Gender Equity

The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.

Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.

“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.

In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”

“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”

Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.

This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
 

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

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One in Five Overdose Deaths in 2022 had an Unrelated Mental Illness

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Tue, 09/17/2024 - 11:08

 

TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

  • The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
  • A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
  • MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
  • Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

  • In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
  • Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
  • Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
  • About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

  • The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
  • A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
  • MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
  • Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

  • In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
  • Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
  • Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
  • About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

 

TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

  • The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
  • A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
  • MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
  • Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

  • In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
  • Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
  • Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
  • About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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GLP-1 RA Therapy for Alcohol Use Disorder?

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Tue, 09/17/2024 - 19:46

 

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

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This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

 

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

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FROM ADA 2024

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Do Cannabis Users Need More Anesthesia During Surgery?

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TOPLINE: 

Cannabis users aged 65 years or older undergoing general anesthesia for surgery required higher doses of inhalational anesthetics than nonusers. However, the clinical relevance of this difference remains unclear.

METHODOLOGY:

  • To assess if cannabis use leads to higher doses of inhalational anesthesia during surgery, the researchers conducted a retrospective cohort study comparing the average intraoperative minimum alveolar concentrations of volatile anesthetics (isoflurane and sevoflurane) between older adults who used cannabis products and those who did not.
  • The researchers reviewed electronic health records of 22,476 patients aged 65 years or older who underwent surgery at the University of Florida Health System between 2018 and 2020.
  • Overall, 268 patients who reported using cannabis within 60 days of surgery (median age, 69 years; 35% women) were matched to 1072 nonusers.
  • The median duration of anesthesia was 175 minutes.
  • The primary outcome was the intraoperative time-weighted average of isoflurane or sevoflurane minimum alveolar concentration equivalents.

TAKEAWAY:

  • Cannabis users had significantly higher average minimum alveolar concentrations of isoflurane or sevoflurane than nonusers (mean, 0.58 vs 0.54; mean difference, 0.04; P = .021).
  • The findings were confirmed in a sensitivity analysis that revealed higher mean average minimum alveolar concentrations of anesthesia in cannabis users than in nonusers (0.57 vs 0.53; P = .029).
  • Although the 0.04 difference in minimum alveolar concentration between cannabis users and nonusers was statistically significant, its clinical importance is unclear.

IN PRACTICE:

“While recent guidelines underscore the importance of universal screening for cannabinoids before surgery, caution is paramount to prevent clinical bias leading to the administration of unnecessary higher doses of inhalational anesthesia, especially as robust evidence supporting such practices remains lacking,” the authors of the study wrote.
 

SOURCE:

This study was led by Ruba Sajdeya, MD, PhD, of the Department of Epidemiology at the University of Florida, Gainesville, and was published online in August 2024 in Anesthesiology.

LIMITATIONS: 

This study lacked access to prescription or dispensed medications, including opioids, which may have introduced residual confounding. Potential underdocumentation of cannabis use in medical records could have led to exposure misclassification. The causality between cannabis usage and increased anesthetic dosing could not be established due to the observational nature of this study. 

DISCLOSURES:

This study was supported by the National Institute on Aging, the National Institutes of Health, and in part by the University of Florida Clinical and Translational Science Institute. Some authors declared receiving research support, consulting fees, and honoraria and having other ties with pharmaceutical companies and various other sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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TOPLINE: 

Cannabis users aged 65 years or older undergoing general anesthesia for surgery required higher doses of inhalational anesthetics than nonusers. However, the clinical relevance of this difference remains unclear.

METHODOLOGY:

  • To assess if cannabis use leads to higher doses of inhalational anesthesia during surgery, the researchers conducted a retrospective cohort study comparing the average intraoperative minimum alveolar concentrations of volatile anesthetics (isoflurane and sevoflurane) between older adults who used cannabis products and those who did not.
  • The researchers reviewed electronic health records of 22,476 patients aged 65 years or older who underwent surgery at the University of Florida Health System between 2018 and 2020.
  • Overall, 268 patients who reported using cannabis within 60 days of surgery (median age, 69 years; 35% women) were matched to 1072 nonusers.
  • The median duration of anesthesia was 175 minutes.
  • The primary outcome was the intraoperative time-weighted average of isoflurane or sevoflurane minimum alveolar concentration equivalents.

TAKEAWAY:

  • Cannabis users had significantly higher average minimum alveolar concentrations of isoflurane or sevoflurane than nonusers (mean, 0.58 vs 0.54; mean difference, 0.04; P = .021).
  • The findings were confirmed in a sensitivity analysis that revealed higher mean average minimum alveolar concentrations of anesthesia in cannabis users than in nonusers (0.57 vs 0.53; P = .029).
  • Although the 0.04 difference in minimum alveolar concentration between cannabis users and nonusers was statistically significant, its clinical importance is unclear.

IN PRACTICE:

“While recent guidelines underscore the importance of universal screening for cannabinoids before surgery, caution is paramount to prevent clinical bias leading to the administration of unnecessary higher doses of inhalational anesthesia, especially as robust evidence supporting such practices remains lacking,” the authors of the study wrote.
 

SOURCE:

This study was led by Ruba Sajdeya, MD, PhD, of the Department of Epidemiology at the University of Florida, Gainesville, and was published online in August 2024 in Anesthesiology.

LIMITATIONS: 

This study lacked access to prescription or dispensed medications, including opioids, which may have introduced residual confounding. Potential underdocumentation of cannabis use in medical records could have led to exposure misclassification. The causality between cannabis usage and increased anesthetic dosing could not be established due to the observational nature of this study. 

DISCLOSURES:

This study was supported by the National Institute on Aging, the National Institutes of Health, and in part by the University of Florida Clinical and Translational Science Institute. Some authors declared receiving research support, consulting fees, and honoraria and having other ties with pharmaceutical companies and various other sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

 

TOPLINE: 

Cannabis users aged 65 years or older undergoing general anesthesia for surgery required higher doses of inhalational anesthetics than nonusers. However, the clinical relevance of this difference remains unclear.

METHODOLOGY:

  • To assess if cannabis use leads to higher doses of inhalational anesthesia during surgery, the researchers conducted a retrospective cohort study comparing the average intraoperative minimum alveolar concentrations of volatile anesthetics (isoflurane and sevoflurane) between older adults who used cannabis products and those who did not.
  • The researchers reviewed electronic health records of 22,476 patients aged 65 years or older who underwent surgery at the University of Florida Health System between 2018 and 2020.
  • Overall, 268 patients who reported using cannabis within 60 days of surgery (median age, 69 years; 35% women) were matched to 1072 nonusers.
  • The median duration of anesthesia was 175 minutes.
  • The primary outcome was the intraoperative time-weighted average of isoflurane or sevoflurane minimum alveolar concentration equivalents.

TAKEAWAY:

  • Cannabis users had significantly higher average minimum alveolar concentrations of isoflurane or sevoflurane than nonusers (mean, 0.58 vs 0.54; mean difference, 0.04; P = .021).
  • The findings were confirmed in a sensitivity analysis that revealed higher mean average minimum alveolar concentrations of anesthesia in cannabis users than in nonusers (0.57 vs 0.53; P = .029).
  • Although the 0.04 difference in minimum alveolar concentration between cannabis users and nonusers was statistically significant, its clinical importance is unclear.

IN PRACTICE:

“While recent guidelines underscore the importance of universal screening for cannabinoids before surgery, caution is paramount to prevent clinical bias leading to the administration of unnecessary higher doses of inhalational anesthesia, especially as robust evidence supporting such practices remains lacking,” the authors of the study wrote.
 

SOURCE:

This study was led by Ruba Sajdeya, MD, PhD, of the Department of Epidemiology at the University of Florida, Gainesville, and was published online in August 2024 in Anesthesiology.

LIMITATIONS: 

This study lacked access to prescription or dispensed medications, including opioids, which may have introduced residual confounding. Potential underdocumentation of cannabis use in medical records could have led to exposure misclassification. The causality between cannabis usage and increased anesthetic dosing could not be established due to the observational nature of this study. 

DISCLOSURES:

This study was supported by the National Institute on Aging, the National Institutes of Health, and in part by the University of Florida Clinical and Translational Science Institute. Some authors declared receiving research support, consulting fees, and honoraria and having other ties with pharmaceutical companies and various other sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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Alcohol-Associated Liver Disease’s Changing Demographics

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Fri, 08/30/2024 - 10:56

 

Alcohol-associated liver disease (ALD) is a significant global health concernaccounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

 

 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

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Alcohol-associated liver disease (ALD) is a significant global health concernaccounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

 

 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

 

Alcohol-associated liver disease (ALD) is a significant global health concernaccounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

 

 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

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