John Watson

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

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

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

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

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

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

You are what you eat, as the adage goes. But a growing body of evidence indicates that it’s not just what and how much you eat that influence your health. How fast and when you eat also play a role.

Research now indicates that these two factors may affect the risk for gastrointestinal problems, obesity, and type 2 diabetes (T2D). Because meal timing and speed of consumption are modifiable, they present new opportunities to change patient behavior to help prevent and perhaps address these conditions.

Not So Fast

Most people are well acquainted with the short-term gastrointestinal effects of eating too quickly, which include indigestion, gas, bloating, and nausea. But regularly eating too fast can cause long-term consequences.

Obtaining a sense of fullness is key to staving off overeating and excess caloric intake. However, it takes approximately 20 minutes for the stomach to alert the brain to feelings of fullness. Eat too quickly and the fullness signaling might not set in until you’ve consumed more calories than intended. Research links this habit to excess body weight.

The practice also can lead to gastrointestinal diseases over the long term because overeating causes food to remain in the stomach longer, thus prolonging the time that the gastric mucosa is exposed to gastric acids.

A study of 10,893 adults in Korea reported that those with the fastest eating speed (< 5 min/meal) had a 1.7 times greater likelihood of endoscopic erosive gastritis than those with the slowest times (≥ 15 min/meal). Faster eating also was linked to increased risk for functional dyspepsia in a study involving 89 young-adult female military cadets in Korea with relatively controlled eating patterns.

On the extreme end of the spectrum, researchers who performed an assessment of a competitive speed eater speculated that the observed physiological accommodation required for the role (expanding the stomach to form a large flaccid sac) makes speed eaters vulnerable to morbid obesity, gastroparesis, intractable nausea and vomiting, and the need for gastrectomy.

The risk for metabolic changes and eventual development of T2D also appear to be linked to how quickly food is consumed.

Two clinical studies conducted in Japan — a cohort study of 2050 male factory workers and a nationwide study with 197,825 participants — identified a significant association between faster eating and T2D and insulin resistance. A case-control study involving 234 patients with new onset T2D and 468 controls from Lithuania linked faster eating to a greater than twofold risk for T2D. And a Chinese cross-sectional study of 7972 adults indicated that faster eating significantly increased the risk for metabolic syndrome, elevated blood pressure, and central obesity in adults.

Various hypotheses have been proposed to explain why fast eating may upset metabolic processes, including a delayed sense of fullness contributing to spiking postprandial glucose levels, lack of time for mastication causing higher glucose concentrations, and the triggering of specific cytokines (eg, interleukin-1 beta and interleukin-6) that lead to insulin resistance. It is also possible that the association is the result of people who eat quickly having relatively higher body weights, which translates to a higher risk for T2D.

However, there’s an opportunity in the association of rapid meal consumption with gastrointestinal and metabolic diseases, as people can slow the speed at which they eat so they feel full before they overeat.

A 2019 study in which 21 participants were instructed to eat a 600-kcal meal at a “normal” or “slow” pace (6 minutes or 24 minutes) found that the latter group reported feeling fuller while consuming fewer calories.

This approach may not work for all patients, however. There’s evidence to suggest that tactics to slow down eating may not limit the energy intake of those who are already overweight or obese.

Patients with obesity may physiologically differ in their processing of food, according to Michael Camilleri, MD, consultant in the Division of Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota.

“We have demonstrated that about 20%-25% of people with obesity actually have rapid gastric emptying,” he told this news organization. “As a result, they don’t feel full after they eat a meal and that might impact the total volume of food that they eat before they really feel full.”

The Ideal Time to Eat

It’s not only the speed at which individuals eat that may influence outcomes but when they take their meals. Research indicates that eating earlier in the day to align meals with the body’s circadian rhythms in metabolism offers health benefits.

“The focus would be to eat a meal that syncs during those daytime hours,” Collin Popp, PhD, MS, RD, a research scientist at the NYU Grossman School of Medicine in New York, told this news organization. “I typically suggest patients have their largest meal in the morning, whether that’s a large or medium-sized breakfast, or a big lunch.”

A recent cross-sectional study of 2050 participants found that having the largest meal at lunch protected against obesity (odds ratio [OR], 0.71), whereas having it at dinner increased the risk for obesity (OR, 1.67) and led to higher body mass index.

Consuming the majority of calories in meals earlier in the day may have metabolic health benefits, as well.

A 2015 randomized controlled trial involving 18 adults with obesity and T2D found that eating a high-energy breakfast and a low-energy dinner leads to reduced hyperglycemia throughout the day compared with eating a low-energy breakfast and a high-energy dinner.

Time-restricted eating (TRE), a form of intermittent fasting, also can improve metabolic health depending on the time of day.

A 2023 meta-analysis found that TRE was more effective at reducing fasting glucose levels in participants who were overweight and obese if done earlier rather than later in the day. Similarly, a 2022 study involving 82 healthy patients without diabetes or obesity found that early TRE was more effective than mid-day TRE at improving insulin sensitivity and that it improved fasting glucose and reduced total body mass and adiposity, while mid-day TRE did not.

A study that analyzed the effects of TRE in eight adult men with overweight and prediabetes found “better insulin resistance when the window of food consumption was earlier in the day,» noted endocrinologist Beverly Tchang, MD, an assistant professor of clinical medicine at Weill Cornell Medicine with a focus on obesity medication.

Patients May Benefit From Behavioral Interventions

Patients potentially negatively affected by eating too quickly or at late hours may benefit from adopting behavioral interventions to address these tendencies. To determine if a patient is a candidate for such interventions, Dr. Popp recommends starting with a simple conversation.

“When I first meet patients, I always ask them to describe to me a typical day for how they eat — when they’re eating, what they’re eating, the food quality, who are they with — to see if there’s social aspects to it. Then try and make the recommendations based on that,” said Dr. Popp, whose work focuses on biobehavioral interventions for the treatment and prevention of obesity, T2D, and other cardiometabolic outcomes.

Dr. Tchang said she encourages her patients to be mindful of hunger and fullness cues.

“Eat if you’re hungry; don’t force yourself to eat if you’re not hungry,” she said. “If you’re not sure whether you’re hungry or not, speak to a doctor because this points to an abnormality in your appetite-regulation system, which can be helped with GLP-1 [glucagon-like peptide 1] receptor agonists.”

Adjusting what patients eat can help them improve their meal timing.

“For example, we know that a high-fiber diet or a diet that has a large amount of fat in it tends to empty from the stomach slower,” Dr. Camilleri said. “That might give a sensation of fullness that lasts longer and that might prevent, for instance, the ingestion of the next meal.”

Those trying to eat more slowly are advised to seek out foods that are hard in texture and minimally processed.

A study involving 50 patients with healthy weights found that hard foods are consumed more slowly than soft foods and that energy intake is lowest with hard, minimally processed foods. Combining hard-textured foods with explicit instructions to reduce eating speed has also been shown to be an effective strategy. For those inclined to seek out technology-based solution, evidence suggests that a self-monitoring wearable device can slow the eating rate.

Although the evidence is mounting that the timing and duration of meals have an impact on certain chronic diseases, clinicians should remember that these two factors are far from the most important contributors, Dr. Popp said.

“We also have to consider total caloric intake, food quality, sleep, alcohol use, smoking, and physical activity,” he said. “Meal timing should be considered as under the umbrella of health that is important for a lot of folks.”

A version of this article appeared on Medscape.com.

You are what you eat, as the adage goes. But a growing body of evidence indicates that it’s not just what and how much you eat that influence your health. How fast and when you eat also play a role.

Research now indicates that these two factors may affect the risk for gastrointestinal problems, obesity, and type 2 diabetes (T2D). Because meal timing and speed of consumption are modifiable, they present new opportunities to change patient behavior to help prevent and perhaps address these conditions.

Not So Fast

Most people are well acquainted with the short-term gastrointestinal effects of eating too quickly, which include indigestion, gas, bloating, and nausea. But regularly eating too fast can cause long-term consequences.

Obtaining a sense of fullness is key to staving off overeating and excess caloric intake. However, it takes approximately 20 minutes for the stomach to alert the brain to feelings of fullness. Eat too quickly and the fullness signaling might not set in until you’ve consumed more calories than intended. Research links this habit to excess body weight.

The practice also can lead to gastrointestinal diseases over the long term because overeating causes food to remain in the stomach longer, thus prolonging the time that the gastric mucosa is exposed to gastric acids.

A study of 10,893 adults in Korea reported that those with the fastest eating speed (< 5 min/meal) had a 1.7 times greater likelihood of endoscopic erosive gastritis than those with the slowest times (≥ 15 min/meal). Faster eating also was linked to increased risk for functional dyspepsia in a study involving 89 young-adult female military cadets in Korea with relatively controlled eating patterns.

On the extreme end of the spectrum, researchers who performed an assessment of a competitive speed eater speculated that the observed physiological accommodation required for the role (expanding the stomach to form a large flaccid sac) makes speed eaters vulnerable to morbid obesity, gastroparesis, intractable nausea and vomiting, and the need for gastrectomy.

The risk for metabolic changes and eventual development of T2D also appear to be linked to how quickly food is consumed.

Two clinical studies conducted in Japan — a cohort study of 2050 male factory workers and a nationwide study with 197,825 participants — identified a significant association between faster eating and T2D and insulin resistance. A case-control study involving 234 patients with new onset T2D and 468 controls from Lithuania linked faster eating to a greater than twofold risk for T2D. And a Chinese cross-sectional study of 7972 adults indicated that faster eating significantly increased the risk for metabolic syndrome, elevated blood pressure, and central obesity in adults.

Various hypotheses have been proposed to explain why fast eating may upset metabolic processes, including a delayed sense of fullness contributing to spiking postprandial glucose levels, lack of time for mastication causing higher glucose concentrations, and the triggering of specific cytokines (eg, interleukin-1 beta and interleukin-6) that lead to insulin resistance. It is also possible that the association is the result of people who eat quickly having relatively higher body weights, which translates to a higher risk for T2D.

However, there’s an opportunity in the association of rapid meal consumption with gastrointestinal and metabolic diseases, as people can slow the speed at which they eat so they feel full before they overeat.

A 2019 study in which 21 participants were instructed to eat a 600-kcal meal at a “normal” or “slow” pace (6 minutes or 24 minutes) found that the latter group reported feeling fuller while consuming fewer calories.

This approach may not work for all patients, however. There’s evidence to suggest that tactics to slow down eating may not limit the energy intake of those who are already overweight or obese.

Patients with obesity may physiologically differ in their processing of food, according to Michael Camilleri, MD, consultant in the Division of Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota.

“We have demonstrated that about 20%-25% of people with obesity actually have rapid gastric emptying,” he told this news organization. “As a result, they don’t feel full after they eat a meal and that might impact the total volume of food that they eat before they really feel full.”

The Ideal Time to Eat

It’s not only the speed at which individuals eat that may influence outcomes but when they take their meals. Research indicates that eating earlier in the day to align meals with the body’s circadian rhythms in metabolism offers health benefits.

“The focus would be to eat a meal that syncs during those daytime hours,” Collin Popp, PhD, MS, RD, a research scientist at the NYU Grossman School of Medicine in New York, told this news organization. “I typically suggest patients have their largest meal in the morning, whether that’s a large or medium-sized breakfast, or a big lunch.”

A recent cross-sectional study of 2050 participants found that having the largest meal at lunch protected against obesity (odds ratio [OR], 0.71), whereas having it at dinner increased the risk for obesity (OR, 1.67) and led to higher body mass index.

Consuming the majority of calories in meals earlier in the day may have metabolic health benefits, as well.

A 2015 randomized controlled trial involving 18 adults with obesity and T2D found that eating a high-energy breakfast and a low-energy dinner leads to reduced hyperglycemia throughout the day compared with eating a low-energy breakfast and a high-energy dinner.

Time-restricted eating (TRE), a form of intermittent fasting, also can improve metabolic health depending on the time of day.

A 2023 meta-analysis found that TRE was more effective at reducing fasting glucose levels in participants who were overweight and obese if done earlier rather than later in the day. Similarly, a 2022 study involving 82 healthy patients without diabetes or obesity found that early TRE was more effective than mid-day TRE at improving insulin sensitivity and that it improved fasting glucose and reduced total body mass and adiposity, while mid-day TRE did not.

A study that analyzed the effects of TRE in eight adult men with overweight and prediabetes found “better insulin resistance when the window of food consumption was earlier in the day,» noted endocrinologist Beverly Tchang, MD, an assistant professor of clinical medicine at Weill Cornell Medicine with a focus on obesity medication.

Patients May Benefit From Behavioral Interventions

Patients potentially negatively affected by eating too quickly or at late hours may benefit from adopting behavioral interventions to address these tendencies. To determine if a patient is a candidate for such interventions, Dr. Popp recommends starting with a simple conversation.

“When I first meet patients, I always ask them to describe to me a typical day for how they eat — when they’re eating, what they’re eating, the food quality, who are they with — to see if there’s social aspects to it. Then try and make the recommendations based on that,” said Dr. Popp, whose work focuses on biobehavioral interventions for the treatment and prevention of obesity, T2D, and other cardiometabolic outcomes.

Dr. Tchang said she encourages her patients to be mindful of hunger and fullness cues.

“Eat if you’re hungry; don’t force yourself to eat if you’re not hungry,” she said. “If you’re not sure whether you’re hungry or not, speak to a doctor because this points to an abnormality in your appetite-regulation system, which can be helped with GLP-1 [glucagon-like peptide 1] receptor agonists.”

Adjusting what patients eat can help them improve their meal timing.

“For example, we know that a high-fiber diet or a diet that has a large amount of fat in it tends to empty from the stomach slower,” Dr. Camilleri said. “That might give a sensation of fullness that lasts longer and that might prevent, for instance, the ingestion of the next meal.”

Those trying to eat more slowly are advised to seek out foods that are hard in texture and minimally processed.

A study involving 50 patients with healthy weights found that hard foods are consumed more slowly than soft foods and that energy intake is lowest with hard, minimally processed foods. Combining hard-textured foods with explicit instructions to reduce eating speed has also been shown to be an effective strategy. For those inclined to seek out technology-based solution, evidence suggests that a self-monitoring wearable device can slow the eating rate.

Although the evidence is mounting that the timing and duration of meals have an impact on certain chronic diseases, clinicians should remember that these two factors are far from the most important contributors, Dr. Popp said.

“We also have to consider total caloric intake, food quality, sleep, alcohol use, smoking, and physical activity,” he said. “Meal timing should be considered as under the umbrella of health that is important for a lot of folks.”

A version of this article appeared on Medscape.com.

You are what you eat, as the adage goes. But a growing body of evidence indicates that it’s not just what and how much you eat that influence your health. How fast and when you eat also play a role.

Research now indicates that these two factors may affect the risk for gastrointestinal problems, obesity, and type 2 diabetes (T2D). Because meal timing and speed of consumption are modifiable, they present new opportunities to change patient behavior to help prevent and perhaps address these conditions.

Not So Fast

Most people are well acquainted with the short-term gastrointestinal effects of eating too quickly, which include indigestion, gas, bloating, and nausea. But regularly eating too fast can cause long-term consequences.

Obtaining a sense of fullness is key to staving off overeating and excess caloric intake. However, it takes approximately 20 minutes for the stomach to alert the brain to feelings of fullness. Eat too quickly and the fullness signaling might not set in until you’ve consumed more calories than intended. Research links this habit to excess body weight.

The practice also can lead to gastrointestinal diseases over the long term because overeating causes food to remain in the stomach longer, thus prolonging the time that the gastric mucosa is exposed to gastric acids.

A study of 10,893 adults in Korea reported that those with the fastest eating speed (< 5 min/meal) had a 1.7 times greater likelihood of endoscopic erosive gastritis than those with the slowest times (≥ 15 min/meal). Faster eating also was linked to increased risk for functional dyspepsia in a study involving 89 young-adult female military cadets in Korea with relatively controlled eating patterns.

On the extreme end of the spectrum, researchers who performed an assessment of a competitive speed eater speculated that the observed physiological accommodation required for the role (expanding the stomach to form a large flaccid sac) makes speed eaters vulnerable to morbid obesity, gastroparesis, intractable nausea and vomiting, and the need for gastrectomy.

The risk for metabolic changes and eventual development of T2D also appear to be linked to how quickly food is consumed.

Two clinical studies conducted in Japan — a cohort study of 2050 male factory workers and a nationwide study with 197,825 participants — identified a significant association between faster eating and T2D and insulin resistance. A case-control study involving 234 patients with new onset T2D and 468 controls from Lithuania linked faster eating to a greater than twofold risk for T2D. And a Chinese cross-sectional study of 7972 adults indicated that faster eating significantly increased the risk for metabolic syndrome, elevated blood pressure, and central obesity in adults.

Various hypotheses have been proposed to explain why fast eating may upset metabolic processes, including a delayed sense of fullness contributing to spiking postprandial glucose levels, lack of time for mastication causing higher glucose concentrations, and the triggering of specific cytokines (eg, interleukin-1 beta and interleukin-6) that lead to insulin resistance. It is also possible that the association is the result of people who eat quickly having relatively higher body weights, which translates to a higher risk for T2D.

However, there’s an opportunity in the association of rapid meal consumption with gastrointestinal and metabolic diseases, as people can slow the speed at which they eat so they feel full before they overeat.

A 2019 study in which 21 participants were instructed to eat a 600-kcal meal at a “normal” or “slow” pace (6 minutes or 24 minutes) found that the latter group reported feeling fuller while consuming fewer calories.

This approach may not work for all patients, however. There’s evidence to suggest that tactics to slow down eating may not limit the energy intake of those who are already overweight or obese.

Patients with obesity may physiologically differ in their processing of food, according to Michael Camilleri, MD, consultant in the Division of Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota.

“We have demonstrated that about 20%-25% of people with obesity actually have rapid gastric emptying,” he told this news organization. “As a result, they don’t feel full after they eat a meal and that might impact the total volume of food that they eat before they really feel full.”

The Ideal Time to Eat

It’s not only the speed at which individuals eat that may influence outcomes but when they take their meals. Research indicates that eating earlier in the day to align meals with the body’s circadian rhythms in metabolism offers health benefits.

“The focus would be to eat a meal that syncs during those daytime hours,” Collin Popp, PhD, MS, RD, a research scientist at the NYU Grossman School of Medicine in New York, told this news organization. “I typically suggest patients have their largest meal in the morning, whether that’s a large or medium-sized breakfast, or a big lunch.”

A recent cross-sectional study of 2050 participants found that having the largest meal at lunch protected against obesity (odds ratio [OR], 0.71), whereas having it at dinner increased the risk for obesity (OR, 1.67) and led to higher body mass index.

Consuming the majority of calories in meals earlier in the day may have metabolic health benefits, as well.

A 2015 randomized controlled trial involving 18 adults with obesity and T2D found that eating a high-energy breakfast and a low-energy dinner leads to reduced hyperglycemia throughout the day compared with eating a low-energy breakfast and a high-energy dinner.

Time-restricted eating (TRE), a form of intermittent fasting, also can improve metabolic health depending on the time of day.

A 2023 meta-analysis found that TRE was more effective at reducing fasting glucose levels in participants who were overweight and obese if done earlier rather than later in the day. Similarly, a 2022 study involving 82 healthy patients without diabetes or obesity found that early TRE was more effective than mid-day TRE at improving insulin sensitivity and that it improved fasting glucose and reduced total body mass and adiposity, while mid-day TRE did not.

A study that analyzed the effects of TRE in eight adult men with overweight and prediabetes found “better insulin resistance when the window of food consumption was earlier in the day,» noted endocrinologist Beverly Tchang, MD, an assistant professor of clinical medicine at Weill Cornell Medicine with a focus on obesity medication.

Patients May Benefit From Behavioral Interventions

Patients potentially negatively affected by eating too quickly or at late hours may benefit from adopting behavioral interventions to address these tendencies. To determine if a patient is a candidate for such interventions, Dr. Popp recommends starting with a simple conversation.

“When I first meet patients, I always ask them to describe to me a typical day for how they eat — when they’re eating, what they’re eating, the food quality, who are they with — to see if there’s social aspects to it. Then try and make the recommendations based on that,” said Dr. Popp, whose work focuses on biobehavioral interventions for the treatment and prevention of obesity, T2D, and other cardiometabolic outcomes.

Dr. Tchang said she encourages her patients to be mindful of hunger and fullness cues.

“Eat if you’re hungry; don’t force yourself to eat if you’re not hungry,” she said. “If you’re not sure whether you’re hungry or not, speak to a doctor because this points to an abnormality in your appetite-regulation system, which can be helped with GLP-1 [glucagon-like peptide 1] receptor agonists.”

Adjusting what patients eat can help them improve their meal timing.

“For example, we know that a high-fiber diet or a diet that has a large amount of fat in it tends to empty from the stomach slower,” Dr. Camilleri said. “That might give a sensation of fullness that lasts longer and that might prevent, for instance, the ingestion of the next meal.”

Those trying to eat more slowly are advised to seek out foods that are hard in texture and minimally processed.

A study involving 50 patients with healthy weights found that hard foods are consumed more slowly than soft foods and that energy intake is lowest with hard, minimally processed foods. Combining hard-textured foods with explicit instructions to reduce eating speed has also been shown to be an effective strategy. For those inclined to seek out technology-based solution, evidence suggests that a self-monitoring wearable device can slow the eating rate.

Although the evidence is mounting that the timing and duration of meals have an impact on certain chronic diseases, clinicians should remember that these two factors are far from the most important contributors, Dr. Popp said.

“We also have to consider total caloric intake, food quality, sleep, alcohol use, smoking, and physical activity,” he said. “Meal timing should be considered as under the umbrella of health that is important for a lot of folks.”

A version of this article appeared on Medscape.com.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that affects both children and adults. EoE is defined by symptoms of esophageal dysfunction (eg, dysphagia, vomiting, difficulty in feeding), with presentation varying depending on patient age.

The global incidence of EoE has increased in recent decades. In the United States alone, EoE is estimated to affect approximately 150,000 people and result in as much as $1.4 billion in annual healthcare costs.

There currently is no clear treatment hierarchy for EoE, and long delays between symptom onset and diagnoses are common.

Still, the knowledge base surrounding the disease is growing, and existing interventions have shown tremendous success at curbing symptoms and disease progression. The recent approvals of a monoclonal antibody and the first oral agent for EoE treatment have suddenly expanded medication options — at a time when other promising therapies are being investigated too.

To help clinicians stay up to date on the latest information on this debilitating disease, here are five things to know about EoE.

1. EoE prevalence is increasing although not consistently around the globe.

EoE was first recognized as a distinct clinical entity in the early 1990s, when it was considered a relatively rare disease. Now, the incidence and prevalence rates of EoE are escalating at rates that cannot be explained by increased disease awareness and detection. 

Although EoE has been diagnosed in Latin America, the Middle East, and Asia, such instances are relatively uncommon in comparison with the spiking rates noted in the United States; in Western Europe, including Denmark, the Netherlands, and Switzerland; and in Australia. 

Emerging data suggest that climate and location may be a factor in the varying incidence rates of EoE. An analysis of 233,649 patients in a US pathology database reported that EoE was more common in cold and arid climate zones than in tropical zones. Another study suggests that EoE is more common in low-density, rural environments compared with urban settings. 

2. Environmental and food exposures may trigger EoE, and genetics probably play a role.

The unequal geographic distribution of EoE lends credence to the theory that external triggers, which naturally differ in various locales, play an outsized role in its development.

Mice studies have indicated that the inhalation of allergens induces notable eosinophil infiltration and degranulation, and a pilot study conducted in New York City found that EoE symptoms peaked during the July-to-September period when grass pollen counts were at their highest.

Early-life factors that can result in alteration to the microbiome have also been identified as possibly influencing EoE development. They include cesarean delivery, preterm delivery, admission to a neonatal intensive care unit, infant formula use, and maternal or infant use of antibiotics. Conversely, evidence suggests that Helicobacter pylori infection may be protective against EoE due to immunomodulating effects that have not yet been sufficiently identified in the literature.

Yet, the clearest association between EoE and outside triggers is found with food exposures. In one analysis of pediatric patients, the items that were most commonly associated with elevated food-specific serum immunoglobulin E antibodies in patients with EoE were milk (78%), wheat (69%), eggs (64%), peanuts (54%), and soy (51%). Food allergies are also on the uptick in countries with rising EoE rates, suggesting that the two trends may be interrelated.

From a genetic standpoint, EoE is more likely to develop in those with first-degree relatives with the disease than in the general population. Thirty independent genes thought to be associated with EoE have been identified. EoE is also significantly more common in men than in women.

3. Diagnosis requires knowing the symptoms, excluding other disorders, and performing biopsy.

EoE can occur early in life, with approximately one third of children with the disease presenting under age 5 years. The prevalence rises with age, eventually peaking in those aged 35-45 years. 

The presentation of EoE can be quite variable depending on patient age. Pediatric patients are significantly more likely to experience failure to thrive, vomiting, and heartburn, whereas their adult counterparts more often present with food impaction and dysphagia. 

At the 2018 AGREE international consensus conference, researchers defined diagnostic criteria as presence of esophageal dysfunction symptoms; exclusion of non-EoE disorders, such as gastroesophageal reflux disease and achalasia; and esophageal biopsy findings of at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm²). 

Endoscopic findings can also be crucial in diagnosing EoE because patients with this disease often present with inflammatory patterns recognizable in the form of exudates, furrows, and edema and/or fibrotic phenotypes such as the presence of rings and stenosis. Clinicians are advised to refer to the Endoscopic Reference Score proposed by Hirano and colleagues. 

4. Treatment approaches rely on the ‘3 Ds.’

Although there is currently no leading strategy for the primary treatment of EoE, clinicians can avail themselves of suggested pathways. 

The lack of a treatment hierarchy means that patients typically are very involved in selecting the therapy that works best for them. Physicians should be aware that patients researching EoE on their own might not find the information they need. A recent study found that the artificial intelligence tool ChatGPT was highly inaccurate when it came to providing answers about EoE.

The treatment strategies that clinicians and their patients can choose from revolve around the “3 Ds”: diet, drugs, and dilation. 

Diet:

Three dietary interventions are available for EoE treatment: 

• Elemental diet, in which patients consume only an amino-acid based formula that does not include any intact proteins
• Empiric elimination diet, which removes foods more commonly associated with food allergy regardless of whether there has been a positive allergy testing result
• Allergy testing-directed food elimination, which involves avoidance of all foods for which specific antibodies were detected or that tested positive on skin-prick tests

Each of these dietary interventions has clear advantages and drawbacks that should be discussed with patients. Elemental diets achieve robust histologic responses, yet their highly restrictive nature makes compliance difficult and can greatly impair patients’ quality of life. 

Empiric elimination diets are the most popular choice and have shown high response rates. A common approach is to begin by removing six common foods (milk, wheat, egg, soy, nuts, and fish/seafood), which are then gradually reintroduced to identify the culprits. However, patients must be motivated to follow this process, and the likelihood it will be successful is greatly enhanced with assistance from a dietitian, which may not always be possible.

Last, allergy testing-guided food elimination diets have been reported to produce remissions rates of just under 50%, and the skin allergy tests they primarily rely on have been criticized for being unreliable. 

Drugs:

The treatment of EoE experienced a significant advance in 2022 when dupilumab, a monoclonal antibody that binds to the interleukin (IL)–4 receptor alpha, became the first drug approved by the US Food and Drug Administration (FDA) for treating EoE in adults and pediatric patients aged 12 years or older. The drug was approved by the European Commission in 2023. In late January 2024, the FDA expanded dupilumab’s approval to children aged 1-11 years and weighing ≥ 15 kg after positive histologic remission and safety results were reported in the two-part phase 3 EoE KIDS trial. 

In addition, the FDA approved budesonide, the first oral treatment for EoE, in February 2024. 

These approvals have expanded treatment options beyond proton pump inhibitors (PPIs) and topical glucocorticosteroids, both of which received only nuanced recommendations for use under US and UK clinical guidelines. 

A recent meta-analysis found that PPIs, off-label and EoE-specific topical steroids, and biologics had greater efficacy than did placebo in achieving histological remission. However, significant heterogeneity in the included studies’ eligibility criteria and outcome measures prevented development of a “solid therapeutic hierarchy,” the authors noted. 

In addition, researchers are investigating therapies targeting IL-5 (eg, mepolizumab, reslizumab, and benralizumab) and other key inflammatory mediators in EoE, such as Siglec-8 (lirentelimab), IL-13 (cendakimab), and the sphingosine 1–phosphate receptor (etrasimod). 

Dilation:

Finally, patients with significant strictures can benefit from dilation performed via through-the-scope balloons or Savary-Gilliard bougies, which can significantly and immediately improve symptoms even if they cannot address the underlying inflammation. Concerns that dilation would lead to increased complications, such as perforation and mucosal tears, do not appear to be borne out by recent data. 

5. Reducing diagnosis delays is crucial for limiting EoE-associated morbidity.

Despite efforts to bring attention to EoE, evidence suggests that delays between symptom onset and diagnosis are common, and result in treatment delays. One study found a median lag time of 6 years. 

The longer the delay in treatment, the more likely patients are to develop esophageal rings, a long narrowing in the esophageal caliber, or focal strictures. For example, diagnostic delays of more than 20 years result in prevalence rates of 70.8% for esophageal strictures, compared with 17.2% with delays of 0-2 years. 

Simply put, the sooner one can identify EoE and begin treatment, the more likely patients are to be spared its worst effects. 
 

A version of this article appeared on Medscape.com.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that affects both children and adults. EoE is defined by symptoms of esophageal dysfunction (eg, dysphagia, vomiting, difficulty in feeding), with presentation varying depending on patient age.

The global incidence of EoE has increased in recent decades. In the United States alone, EoE is estimated to affect approximately 150,000 people and result in as much as $1.4 billion in annual healthcare costs.

There currently is no clear treatment hierarchy for EoE, and long delays between symptom onset and diagnoses are common.

Still, the knowledge base surrounding the disease is growing, and existing interventions have shown tremendous success at curbing symptoms and disease progression. The recent approvals of a monoclonal antibody and the first oral agent for EoE treatment have suddenly expanded medication options — at a time when other promising therapies are being investigated too.

To help clinicians stay up to date on the latest information on this debilitating disease, here are five things to know about EoE.

1. EoE prevalence is increasing although not consistently around the globe.

EoE was first recognized as a distinct clinical entity in the early 1990s, when it was considered a relatively rare disease. Now, the incidence and prevalence rates of EoE are escalating at rates that cannot be explained by increased disease awareness and detection. 

Although EoE has been diagnosed in Latin America, the Middle East, and Asia, such instances are relatively uncommon in comparison with the spiking rates noted in the United States; in Western Europe, including Denmark, the Netherlands, and Switzerland; and in Australia. 

Emerging data suggest that climate and location may be a factor in the varying incidence rates of EoE. An analysis of 233,649 patients in a US pathology database reported that EoE was more common in cold and arid climate zones than in tropical zones. Another study suggests that EoE is more common in low-density, rural environments compared with urban settings. 

2. Environmental and food exposures may trigger EoE, and genetics probably play a role.

The unequal geographic distribution of EoE lends credence to the theory that external triggers, which naturally differ in various locales, play an outsized role in its development.

Mice studies have indicated that the inhalation of allergens induces notable eosinophil infiltration and degranulation, and a pilot study conducted in New York City found that EoE symptoms peaked during the July-to-September period when grass pollen counts were at their highest.

Early-life factors that can result in alteration to the microbiome have also been identified as possibly influencing EoE development. They include cesarean delivery, preterm delivery, admission to a neonatal intensive care unit, infant formula use, and maternal or infant use of antibiotics. Conversely, evidence suggests that Helicobacter pylori infection may be protective against EoE due to immunomodulating effects that have not yet been sufficiently identified in the literature.

Yet, the clearest association between EoE and outside triggers is found with food exposures. In one analysis of pediatric patients, the items that were most commonly associated with elevated food-specific serum immunoglobulin E antibodies in patients with EoE were milk (78%), wheat (69%), eggs (64%), peanuts (54%), and soy (51%). Food allergies are also on the uptick in countries with rising EoE rates, suggesting that the two trends may be interrelated.

From a genetic standpoint, EoE is more likely to develop in those with first-degree relatives with the disease than in the general population. Thirty independent genes thought to be associated with EoE have been identified. EoE is also significantly more common in men than in women.

3. Diagnosis requires knowing the symptoms, excluding other disorders, and performing biopsy.

EoE can occur early in life, with approximately one third of children with the disease presenting under age 5 years. The prevalence rises with age, eventually peaking in those aged 35-45 years. 

The presentation of EoE can be quite variable depending on patient age. Pediatric patients are significantly more likely to experience failure to thrive, vomiting, and heartburn, whereas their adult counterparts more often present with food impaction and dysphagia. 

At the 2018 AGREE international consensus conference, researchers defined diagnostic criteria as presence of esophageal dysfunction symptoms; exclusion of non-EoE disorders, such as gastroesophageal reflux disease and achalasia; and esophageal biopsy findings of at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm²). 

Endoscopic findings can also be crucial in diagnosing EoE because patients with this disease often present with inflammatory patterns recognizable in the form of exudates, furrows, and edema and/or fibrotic phenotypes such as the presence of rings and stenosis. Clinicians are advised to refer to the Endoscopic Reference Score proposed by Hirano and colleagues. 

4. Treatment approaches rely on the ‘3 Ds.’

Although there is currently no leading strategy for the primary treatment of EoE, clinicians can avail themselves of suggested pathways. 

The lack of a treatment hierarchy means that patients typically are very involved in selecting the therapy that works best for them. Physicians should be aware that patients researching EoE on their own might not find the information they need. A recent study found that the artificial intelligence tool ChatGPT was highly inaccurate when it came to providing answers about EoE.

The treatment strategies that clinicians and their patients can choose from revolve around the “3 Ds”: diet, drugs, and dilation. 

Diet:

Three dietary interventions are available for EoE treatment: 

• Elemental diet, in which patients consume only an amino-acid based formula that does not include any intact proteins
• Empiric elimination diet, which removes foods more commonly associated with food allergy regardless of whether there has been a positive allergy testing result
• Allergy testing-directed food elimination, which involves avoidance of all foods for which specific antibodies were detected or that tested positive on skin-prick tests

Each of these dietary interventions has clear advantages and drawbacks that should be discussed with patients. Elemental diets achieve robust histologic responses, yet their highly restrictive nature makes compliance difficult and can greatly impair patients’ quality of life. 

Empiric elimination diets are the most popular choice and have shown high response rates. A common approach is to begin by removing six common foods (milk, wheat, egg, soy, nuts, and fish/seafood), which are then gradually reintroduced to identify the culprits. However, patients must be motivated to follow this process, and the likelihood it will be successful is greatly enhanced with assistance from a dietitian, which may not always be possible.

Last, allergy testing-guided food elimination diets have been reported to produce remissions rates of just under 50%, and the skin allergy tests they primarily rely on have been criticized for being unreliable. 

Drugs:

The treatment of EoE experienced a significant advance in 2022 when dupilumab, a monoclonal antibody that binds to the interleukin (IL)–4 receptor alpha, became the first drug approved by the US Food and Drug Administration (FDA) for treating EoE in adults and pediatric patients aged 12 years or older. The drug was approved by the European Commission in 2023. In late January 2024, the FDA expanded dupilumab’s approval to children aged 1-11 years and weighing ≥ 15 kg after positive histologic remission and safety results were reported in the two-part phase 3 EoE KIDS trial. 

In addition, the FDA approved budesonide, the first oral treatment for EoE, in February 2024. 

These approvals have expanded treatment options beyond proton pump inhibitors (PPIs) and topical glucocorticosteroids, both of which received only nuanced recommendations for use under US and UK clinical guidelines. 

A recent meta-analysis found that PPIs, off-label and EoE-specific topical steroids, and biologics had greater efficacy than did placebo in achieving histological remission. However, significant heterogeneity in the included studies’ eligibility criteria and outcome measures prevented development of a “solid therapeutic hierarchy,” the authors noted. 

In addition, researchers are investigating therapies targeting IL-5 (eg, mepolizumab, reslizumab, and benralizumab) and other key inflammatory mediators in EoE, such as Siglec-8 (lirentelimab), IL-13 (cendakimab), and the sphingosine 1–phosphate receptor (etrasimod). 

Dilation:

Finally, patients with significant strictures can benefit from dilation performed via through-the-scope balloons or Savary-Gilliard bougies, which can significantly and immediately improve symptoms even if they cannot address the underlying inflammation. Concerns that dilation would lead to increased complications, such as perforation and mucosal tears, do not appear to be borne out by recent data. 

5. Reducing diagnosis delays is crucial for limiting EoE-associated morbidity.

Despite efforts to bring attention to EoE, evidence suggests that delays between symptom onset and diagnosis are common, and result in treatment delays. One study found a median lag time of 6 years. 

The longer the delay in treatment, the more likely patients are to develop esophageal rings, a long narrowing in the esophageal caliber, or focal strictures. For example, diagnostic delays of more than 20 years result in prevalence rates of 70.8% for esophageal strictures, compared with 17.2% with delays of 0-2 years. 

Simply put, the sooner one can identify EoE and begin treatment, the more likely patients are to be spared its worst effects. 
 

A version of this article appeared on Medscape.com.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that affects both children and adults. EoE is defined by symptoms of esophageal dysfunction (eg, dysphagia, vomiting, difficulty in feeding), with presentation varying depending on patient age.

The global incidence of EoE has increased in recent decades. In the United States alone, EoE is estimated to affect approximately 150,000 people and result in as much as $1.4 billion in annual healthcare costs.

There currently is no clear treatment hierarchy for EoE, and long delays between symptom onset and diagnoses are common.

Still, the knowledge base surrounding the disease is growing, and existing interventions have shown tremendous success at curbing symptoms and disease progression. The recent approvals of a monoclonal antibody and the first oral agent for EoE treatment have suddenly expanded medication options — at a time when other promising therapies are being investigated too.

To help clinicians stay up to date on the latest information on this debilitating disease, here are five things to know about EoE.

1. EoE prevalence is increasing although not consistently around the globe.

EoE was first recognized as a distinct clinical entity in the early 1990s, when it was considered a relatively rare disease. Now, the incidence and prevalence rates of EoE are escalating at rates that cannot be explained by increased disease awareness and detection. 

Although EoE has been diagnosed in Latin America, the Middle East, and Asia, such instances are relatively uncommon in comparison with the spiking rates noted in the United States; in Western Europe, including Denmark, the Netherlands, and Switzerland; and in Australia. 

Emerging data suggest that climate and location may be a factor in the varying incidence rates of EoE. An analysis of 233,649 patients in a US pathology database reported that EoE was more common in cold and arid climate zones than in tropical zones. Another study suggests that EoE is more common in low-density, rural environments compared with urban settings. 

2. Environmental and food exposures may trigger EoE, and genetics probably play a role.

The unequal geographic distribution of EoE lends credence to the theory that external triggers, which naturally differ in various locales, play an outsized role in its development.

Mice studies have indicated that the inhalation of allergens induces notable eosinophil infiltration and degranulation, and a pilot study conducted in New York City found that EoE symptoms peaked during the July-to-September period when grass pollen counts were at their highest.

Early-life factors that can result in alteration to the microbiome have also been identified as possibly influencing EoE development. They include cesarean delivery, preterm delivery, admission to a neonatal intensive care unit, infant formula use, and maternal or infant use of antibiotics. Conversely, evidence suggests that Helicobacter pylori infection may be protective against EoE due to immunomodulating effects that have not yet been sufficiently identified in the literature.

Yet, the clearest association between EoE and outside triggers is found with food exposures. In one analysis of pediatric patients, the items that were most commonly associated with elevated food-specific serum immunoglobulin E antibodies in patients with EoE were milk (78%), wheat (69%), eggs (64%), peanuts (54%), and soy (51%). Food allergies are also on the uptick in countries with rising EoE rates, suggesting that the two trends may be interrelated.

From a genetic standpoint, EoE is more likely to develop in those with first-degree relatives with the disease than in the general population. Thirty independent genes thought to be associated with EoE have been identified. EoE is also significantly more common in men than in women.

3. Diagnosis requires knowing the symptoms, excluding other disorders, and performing biopsy.

EoE can occur early in life, with approximately one third of children with the disease presenting under age 5 years. The prevalence rises with age, eventually peaking in those aged 35-45 years. 

The presentation of EoE can be quite variable depending on patient age. Pediatric patients are significantly more likely to experience failure to thrive, vomiting, and heartburn, whereas their adult counterparts more often present with food impaction and dysphagia. 

At the 2018 AGREE international consensus conference, researchers defined diagnostic criteria as presence of esophageal dysfunction symptoms; exclusion of non-EoE disorders, such as gastroesophageal reflux disease and achalasia; and esophageal biopsy findings of at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm²). 

Endoscopic findings can also be crucial in diagnosing EoE because patients with this disease often present with inflammatory patterns recognizable in the form of exudates, furrows, and edema and/or fibrotic phenotypes such as the presence of rings and stenosis. Clinicians are advised to refer to the Endoscopic Reference Score proposed by Hirano and colleagues. 

4. Treatment approaches rely on the ‘3 Ds.’

Although there is currently no leading strategy for the primary treatment of EoE, clinicians can avail themselves of suggested pathways. 

The lack of a treatment hierarchy means that patients typically are very involved in selecting the therapy that works best for them. Physicians should be aware that patients researching EoE on their own might not find the information they need. A recent study found that the artificial intelligence tool ChatGPT was highly inaccurate when it came to providing answers about EoE.

The treatment strategies that clinicians and their patients can choose from revolve around the “3 Ds”: diet, drugs, and dilation. 

Diet:

Three dietary interventions are available for EoE treatment: 

• Elemental diet, in which patients consume only an amino-acid based formula that does not include any intact proteins
• Empiric elimination diet, which removes foods more commonly associated with food allergy regardless of whether there has been a positive allergy testing result
• Allergy testing-directed food elimination, which involves avoidance of all foods for which specific antibodies were detected or that tested positive on skin-prick tests

Each of these dietary interventions has clear advantages and drawbacks that should be discussed with patients. Elemental diets achieve robust histologic responses, yet their highly restrictive nature makes compliance difficult and can greatly impair patients’ quality of life. 

Empiric elimination diets are the most popular choice and have shown high response rates. A common approach is to begin by removing six common foods (milk, wheat, egg, soy, nuts, and fish/seafood), which are then gradually reintroduced to identify the culprits. However, patients must be motivated to follow this process, and the likelihood it will be successful is greatly enhanced with assistance from a dietitian, which may not always be possible.

Last, allergy testing-guided food elimination diets have been reported to produce remissions rates of just under 50%, and the skin allergy tests they primarily rely on have been criticized for being unreliable. 

Drugs:

The treatment of EoE experienced a significant advance in 2022 when dupilumab, a monoclonal antibody that binds to the interleukin (IL)–4 receptor alpha, became the first drug approved by the US Food and Drug Administration (FDA) for treating EoE in adults and pediatric patients aged 12 years or older. The drug was approved by the European Commission in 2023. In late January 2024, the FDA expanded dupilumab’s approval to children aged 1-11 years and weighing ≥ 15 kg after positive histologic remission and safety results were reported in the two-part phase 3 EoE KIDS trial. 

In addition, the FDA approved budesonide, the first oral treatment for EoE, in February 2024. 

These approvals have expanded treatment options beyond proton pump inhibitors (PPIs) and topical glucocorticosteroids, both of which received only nuanced recommendations for use under US and UK clinical guidelines. 

A recent meta-analysis found that PPIs, off-label and EoE-specific topical steroids, and biologics had greater efficacy than did placebo in achieving histological remission. However, significant heterogeneity in the included studies’ eligibility criteria and outcome measures prevented development of a “solid therapeutic hierarchy,” the authors noted. 

In addition, researchers are investigating therapies targeting IL-5 (eg, mepolizumab, reslizumab, and benralizumab) and other key inflammatory mediators in EoE, such as Siglec-8 (lirentelimab), IL-13 (cendakimab), and the sphingosine 1–phosphate receptor (etrasimod). 

Dilation:

Finally, patients with significant strictures can benefit from dilation performed via through-the-scope balloons or Savary-Gilliard bougies, which can significantly and immediately improve symptoms even if they cannot address the underlying inflammation. Concerns that dilation would lead to increased complications, such as perforation and mucosal tears, do not appear to be borne out by recent data. 

5. Reducing diagnosis delays is crucial for limiting EoE-associated morbidity.

Despite efforts to bring attention to EoE, evidence suggests that delays between symptom onset and diagnosis are common, and result in treatment delays. One study found a median lag time of 6 years. 

The longer the delay in treatment, the more likely patients are to develop esophageal rings, a long narrowing in the esophageal caliber, or focal strictures. For example, diagnostic delays of more than 20 years result in prevalence rates of 70.8% for esophageal strictures, compared with 17.2% with delays of 0-2 years. 

Simply put, the sooner one can identify EoE and begin treatment, the more likely patients are to be spared its worst effects. 
 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

A noteworthy shift recently occurred in the field of hepatology, but it didn’t stem from a clinical trial or medical finding. Instead, the change arose from a matter of semantics.

In a special article published online in the journal Hepatology, a diverse international consensus group introduced new terminology for one of the world’s most rapidly growing diseases.

The term nonalcoholic fatty liver disease (NAFLD) was to be officially retired, replaced with a more precise and descriptive term – metabolic dysfunction–associated steatotic liver disease (MASLD).

In addition, steatotic liver disease (SLD) would be used as an umbrella term encompassing both MASLD and a new subcategory, MetALD, for individuals with MASLD whose alcohol consumption ranges from 140 to 350 g/wk for women and from 210 to 420 g/wk for men. Nonalcoholic steatohepatitis (NASH) would be known as metabolic dysfunction-associated steatohepatitis (MASH).

The new terminology represents small changes with significant implications, especially for patients with MetALD, said the NAFLD nomenclature consensus group’s co-lead, Mary E. Rinella, MD, professor of medicine at University of Chicago and director of the metabolic and fatty liver program at University of Chicago Hospitals.

“The only really new thing we did is identify a group of people who meet criteria for MASLD and also drink more than the allowable limit,” she said. “There are tons of these patients who were not being considered before. Now they’re in a category by themselves, where they are going to be able to be studied and better understood.”
 

Why make a change?

The unveiling of the new nomenclature marked the culmination of 3 years of dedicated work that was built upon decades of growing understanding about the pathophysiologic underpinnings of these disease states.

The terms NAFLD and NASH emerged in 1980 to describe patients with chronic liver disease who denied excessive alcohol consumption. However, in the past 2 decades, it became increasingly evident that the existing terminology was inadequate, the consensus group’s co-lead, Philip Newsome, PhD, said in an interview.

“There was a strong desire for a name that describes what the condition is, rather than what it isn’t; avoiding use of stigmatizing terms, such as fatty and alcoholic; and finally, a nomenclature that could recognize the coexistence of conditions,” said Dr. Newsome, former secretary general of the European Association for the Study of the Liver (EASL), and director of the Centre for Liver and Gastrointestinal Research at the University of Birmingham, England.

These forces, combined with the recognition that NAFLD and alcohol-related liver disease shared biological processes, created momentum for change.

The idea gained traction with a 2020 article that proposed “MAFLD” as a more suitable term because it would link the disease with its known cardiometabolic risks, Dr. Rinella explained.

“We thought that paper was going to be the beginning of a conversation, but what happened instead is it became a full-court press,” Dr. Rinella said.

Dr. Rinella and Dr. Newsome then spearheaded a study to determine whether content experts and patients supported change. The process was led by three prominent international liver societies: EASL, the American Association for the Study of Liver Diseases (AASLD), and the Asociación Latinoamericana para el Estudio del Hígado. The organizations received input from 236 panelists from 56 countries, reflecting the diverse voices essential for addressing a disease with an expanding global prevalence rate.

In this globalized world, you cannot make a decision from on high and then expect everybody to just adopt it, Dr. Rinella noted.

The panel utilized a modified Delphi consensus approach, necessitating a supermajority of respondents (67%) to vote in favor of the changes. Seventy-four percent felt that the current nomenclature was sufficiently flawed to consider a name change, and 89% preferred terminology that describes the underlying cause of the disease. A supermajority felt that having “metabolic disease or dysfunction” in the name would help patients better understand their disease (72%) and help health care professionals better explain or understand the disease (80%).

The participants settled on the new terminology, and the study resulted in a conclusion: “The new nomenclature and diagnostic criteria are widely supported, nonstigmatizing, and can improve awareness and patient identification.”

It was by no means a simple or straightforward task, according to Dr. Rinella. “Anytime you have a contentious issue and you engage a broad range of stakeholders, many of which you know are in disagreement, you’re going to have a difficult time reaching consensus,” she said.
 

Reassuring reluctant adopters

The backing of international liver societies will be crucial to ensuring the smooth and relatively swift adoption of the new nomenclature. The AASLD announced in July that it would begin this process by holding conversations with key stakeholders, including the Food and Drug Administration, patient organizations, and pharmaceutical industry representatives.

“By engaging external groups, we have gained valuable insights into potential roadblocks or barriers that may impede the full implementation of the new MASLD nomenclature,” AASLD President Norah Terrault, MD, MPH, FAASLD, told this news organization. “Knowing the types of issues they face will allow us to build an implementation plan that will help guide the field through adoption.”

Even with buy-in from key stakeholders, implementing the changes will be no small feat. It’s a “vast undertaking” that may result in short-term frustrations for some groups, Dr. Terrault said.

“For instance, researchers whose work commenced under the old nomenclature may not be able to alter their research papers and will need to publish under the old nomenclature, which may impact which journals their research could be published in,” she said. “Some patient advocacy groups may have the old nomenclature in their names, resulting in a need to rebrand and revise their educational resources. Patient materials need to be updated. Primary care professionals need to be educated. The list goes on.”

These changes demand both patience and time, Dr. Terrault said. This applies to those tasked with persuading colleagues and patients, as well as clinicians, many of whom have already expressed some resistance to the updated terminology.

The panel anticipated pushback from clinicians who still advocate for NAFLD. However, Dr. Rinella countered that a diagnosis of MASLD requires only one cardiometabolic risk factor and has 99% overlap in most populations. In contrast, the MAFLD diagnostic criteria put forward in 2020 proposed even more restrictive cardiometabolic criteria and greater tolerance for alcohol consumption and would alter the disease natural history, she said.

Concerns have also been raised that replacing NAFLD with MASLD might complicate the value of prior research efforts. However, this should not be a cause for concern, as extensive examination across multiple populations has demonstrated near complete overlap between the two definitions, Dr. Rinella said. Biomarker development, natural history studies, and drug development research will remain unaffected, she said.

Some detractors argue that the term “fatty” is sufficiently descriptive and not stigmatizing. However, Dr. Newsome contends that the panel’s research unequivocally disproves this notion.

“Our Delphi process demonstrated very clearly that over 50% felt it was stigmatizing, and in particular, there were clear supportive views for this change from many patient groups,” he noted. “The new nomenclature empowers patients to explain what the condition means without the use of emotional language.”
 

An opportunity to improve care

One compelling way to persuade reluctant adopters of the new nomenclature’s value is to highlight the opportunities it presents.

The updated terminology opens avenues for research and clinical improvements for patients who meet MASLD criteria and consume alcohol at higher levels (MetALD), Dr. Newsome said.

“There are questions about the relative contribution of these two factors to liver injury, and I see this as an opportunity to explore this area further,” he said.

Hepatologists should embrace this change as a means of increasing awareness regarding the metabolic origins of the disease, Dr. Rinella said. This, in turn, will help identify more patients who require treatment but who are currently overlooked by the existing system, she noted.

“Right now, only around 1% of people with advanced disease are being identified by primary care physicians,” she said. “Hopefully, by elevating the role of metabolic disease, primary care physicians, endocrinologists, and gastroenterologists will be able to identify more patients and bring them to care before they develop cirrhosis.”

Such an outcome would signify much more than a mere semantic shift; it would represent a major advancement in the diagnosis and management of the disease.

A version of this article appeared on Medscape.com.

A noteworthy shift recently occurred in the field of hepatology, but it didn’t stem from a clinical trial or medical finding. Instead, the change arose from a matter of semantics.

In a special article published online in the journal Hepatology, a diverse international consensus group introduced new terminology for one of the world’s most rapidly growing diseases.

The term nonalcoholic fatty liver disease (NAFLD) was to be officially retired, replaced with a more precise and descriptive term – metabolic dysfunction–associated steatotic liver disease (MASLD).

In addition, steatotic liver disease (SLD) would be used as an umbrella term encompassing both MASLD and a new subcategory, MetALD, for individuals with MASLD whose alcohol consumption ranges from 140 to 350 g/wk for women and from 210 to 420 g/wk for men. Nonalcoholic steatohepatitis (NASH) would be known as metabolic dysfunction-associated steatohepatitis (MASH).

The new terminology represents small changes with significant implications, especially for patients with MetALD, said the NAFLD nomenclature consensus group’s co-lead, Mary E. Rinella, MD, professor of medicine at University of Chicago and director of the metabolic and fatty liver program at University of Chicago Hospitals.

“The only really new thing we did is identify a group of people who meet criteria for MASLD and also drink more than the allowable limit,” she said. “There are tons of these patients who were not being considered before. Now they’re in a category by themselves, where they are going to be able to be studied and better understood.”
 

Why make a change?

The unveiling of the new nomenclature marked the culmination of 3 years of dedicated work that was built upon decades of growing understanding about the pathophysiologic underpinnings of these disease states.

The terms NAFLD and NASH emerged in 1980 to describe patients with chronic liver disease who denied excessive alcohol consumption. However, in the past 2 decades, it became increasingly evident that the existing terminology was inadequate, the consensus group’s co-lead, Philip Newsome, PhD, said in an interview.

“There was a strong desire for a name that describes what the condition is, rather than what it isn’t; avoiding use of stigmatizing terms, such as fatty and alcoholic; and finally, a nomenclature that could recognize the coexistence of conditions,” said Dr. Newsome, former secretary general of the European Association for the Study of the Liver (EASL), and director of the Centre for Liver and Gastrointestinal Research at the University of Birmingham, England.

These forces, combined with the recognition that NAFLD and alcohol-related liver disease shared biological processes, created momentum for change.

The idea gained traction with a 2020 article that proposed “MAFLD” as a more suitable term because it would link the disease with its known cardiometabolic risks, Dr. Rinella explained.

“We thought that paper was going to be the beginning of a conversation, but what happened instead is it became a full-court press,” Dr. Rinella said.

Dr. Rinella and Dr. Newsome then spearheaded a study to determine whether content experts and patients supported change. The process was led by three prominent international liver societies: EASL, the American Association for the Study of Liver Diseases (AASLD), and the Asociación Latinoamericana para el Estudio del Hígado. The organizations received input from 236 panelists from 56 countries, reflecting the diverse voices essential for addressing a disease with an expanding global prevalence rate.

In this globalized world, you cannot make a decision from on high and then expect everybody to just adopt it, Dr. Rinella noted.

The panel utilized a modified Delphi consensus approach, necessitating a supermajority of respondents (67%) to vote in favor of the changes. Seventy-four percent felt that the current nomenclature was sufficiently flawed to consider a name change, and 89% preferred terminology that describes the underlying cause of the disease. A supermajority felt that having “metabolic disease or dysfunction” in the name would help patients better understand their disease (72%) and help health care professionals better explain or understand the disease (80%).

The participants settled on the new terminology, and the study resulted in a conclusion: “The new nomenclature and diagnostic criteria are widely supported, nonstigmatizing, and can improve awareness and patient identification.”

It was by no means a simple or straightforward task, according to Dr. Rinella. “Anytime you have a contentious issue and you engage a broad range of stakeholders, many of which you know are in disagreement, you’re going to have a difficult time reaching consensus,” she said.
 

Reassuring reluctant adopters

The backing of international liver societies will be crucial to ensuring the smooth and relatively swift adoption of the new nomenclature. The AASLD announced in July that it would begin this process by holding conversations with key stakeholders, including the Food and Drug Administration, patient organizations, and pharmaceutical industry representatives.

“By engaging external groups, we have gained valuable insights into potential roadblocks or barriers that may impede the full implementation of the new MASLD nomenclature,” AASLD President Norah Terrault, MD, MPH, FAASLD, told this news organization. “Knowing the types of issues they face will allow us to build an implementation plan that will help guide the field through adoption.”

Even with buy-in from key stakeholders, implementing the changes will be no small feat. It’s a “vast undertaking” that may result in short-term frustrations for some groups, Dr. Terrault said.

“For instance, researchers whose work commenced under the old nomenclature may not be able to alter their research papers and will need to publish under the old nomenclature, which may impact which journals their research could be published in,” she said. “Some patient advocacy groups may have the old nomenclature in their names, resulting in a need to rebrand and revise their educational resources. Patient materials need to be updated. Primary care professionals need to be educated. The list goes on.”

These changes demand both patience and time, Dr. Terrault said. This applies to those tasked with persuading colleagues and patients, as well as clinicians, many of whom have already expressed some resistance to the updated terminology.

The panel anticipated pushback from clinicians who still advocate for NAFLD. However, Dr. Rinella countered that a diagnosis of MASLD requires only one cardiometabolic risk factor and has 99% overlap in most populations. In contrast, the MAFLD diagnostic criteria put forward in 2020 proposed even more restrictive cardiometabolic criteria and greater tolerance for alcohol consumption and would alter the disease natural history, she said.

Concerns have also been raised that replacing NAFLD with MASLD might complicate the value of prior research efforts. However, this should not be a cause for concern, as extensive examination across multiple populations has demonstrated near complete overlap between the two definitions, Dr. Rinella said. Biomarker development, natural history studies, and drug development research will remain unaffected, she said.

Some detractors argue that the term “fatty” is sufficiently descriptive and not stigmatizing. However, Dr. Newsome contends that the panel’s research unequivocally disproves this notion.

“Our Delphi process demonstrated very clearly that over 50% felt it was stigmatizing, and in particular, there were clear supportive views for this change from many patient groups,” he noted. “The new nomenclature empowers patients to explain what the condition means without the use of emotional language.”
 

An opportunity to improve care

One compelling way to persuade reluctant adopters of the new nomenclature’s value is to highlight the opportunities it presents.

The updated terminology opens avenues for research and clinical improvements for patients who meet MASLD criteria and consume alcohol at higher levels (MetALD), Dr. Newsome said.

“There are questions about the relative contribution of these two factors to liver injury, and I see this as an opportunity to explore this area further,” he said.

Hepatologists should embrace this change as a means of increasing awareness regarding the metabolic origins of the disease, Dr. Rinella said. This, in turn, will help identify more patients who require treatment but who are currently overlooked by the existing system, she noted.

“Right now, only around 1% of people with advanced disease are being identified by primary care physicians,” she said. “Hopefully, by elevating the role of metabolic disease, primary care physicians, endocrinologists, and gastroenterologists will be able to identify more patients and bring them to care before they develop cirrhosis.”

Such an outcome would signify much more than a mere semantic shift; it would represent a major advancement in the diagnosis and management of the disease.

A version of this article appeared on Medscape.com.

A noteworthy shift recently occurred in the field of hepatology, but it didn’t stem from a clinical trial or medical finding. Instead, the change arose from a matter of semantics.

In a special article published online in the journal Hepatology, a diverse international consensus group introduced new terminology for one of the world’s most rapidly growing diseases.

The term nonalcoholic fatty liver disease (NAFLD) was to be officially retired, replaced with a more precise and descriptive term – metabolic dysfunction–associated steatotic liver disease (MASLD).

In addition, steatotic liver disease (SLD) would be used as an umbrella term encompassing both MASLD and a new subcategory, MetALD, for individuals with MASLD whose alcohol consumption ranges from 140 to 350 g/wk for women and from 210 to 420 g/wk for men. Nonalcoholic steatohepatitis (NASH) would be known as metabolic dysfunction-associated steatohepatitis (MASH).

The new terminology represents small changes with significant implications, especially for patients with MetALD, said the NAFLD nomenclature consensus group’s co-lead, Mary E. Rinella, MD, professor of medicine at University of Chicago and director of the metabolic and fatty liver program at University of Chicago Hospitals.

“The only really new thing we did is identify a group of people who meet criteria for MASLD and also drink more than the allowable limit,” she said. “There are tons of these patients who were not being considered before. Now they’re in a category by themselves, where they are going to be able to be studied and better understood.”
 

Why make a change?

The unveiling of the new nomenclature marked the culmination of 3 years of dedicated work that was built upon decades of growing understanding about the pathophysiologic underpinnings of these disease states.

The terms NAFLD and NASH emerged in 1980 to describe patients with chronic liver disease who denied excessive alcohol consumption. However, in the past 2 decades, it became increasingly evident that the existing terminology was inadequate, the consensus group’s co-lead, Philip Newsome, PhD, said in an interview.

“There was a strong desire for a name that describes what the condition is, rather than what it isn’t; avoiding use of stigmatizing terms, such as fatty and alcoholic; and finally, a nomenclature that could recognize the coexistence of conditions,” said Dr. Newsome, former secretary general of the European Association for the Study of the Liver (EASL), and director of the Centre for Liver and Gastrointestinal Research at the University of Birmingham, England.

These forces, combined with the recognition that NAFLD and alcohol-related liver disease shared biological processes, created momentum for change.

The idea gained traction with a 2020 article that proposed “MAFLD” as a more suitable term because it would link the disease with its known cardiometabolic risks, Dr. Rinella explained.

“We thought that paper was going to be the beginning of a conversation, but what happened instead is it became a full-court press,” Dr. Rinella said.

Dr. Rinella and Dr. Newsome then spearheaded a study to determine whether content experts and patients supported change. The process was led by three prominent international liver societies: EASL, the American Association for the Study of Liver Diseases (AASLD), and the Asociación Latinoamericana para el Estudio del Hígado. The organizations received input from 236 panelists from 56 countries, reflecting the diverse voices essential for addressing a disease with an expanding global prevalence rate.

In this globalized world, you cannot make a decision from on high and then expect everybody to just adopt it, Dr. Rinella noted.

The panel utilized a modified Delphi consensus approach, necessitating a supermajority of respondents (67%) to vote in favor of the changes. Seventy-four percent felt that the current nomenclature was sufficiently flawed to consider a name change, and 89% preferred terminology that describes the underlying cause of the disease. A supermajority felt that having “metabolic disease or dysfunction” in the name would help patients better understand their disease (72%) and help health care professionals better explain or understand the disease (80%).

The participants settled on the new terminology, and the study resulted in a conclusion: “The new nomenclature and diagnostic criteria are widely supported, nonstigmatizing, and can improve awareness and patient identification.”

It was by no means a simple or straightforward task, according to Dr. Rinella. “Anytime you have a contentious issue and you engage a broad range of stakeholders, many of which you know are in disagreement, you’re going to have a difficult time reaching consensus,” she said.
 

Reassuring reluctant adopters

The backing of international liver societies will be crucial to ensuring the smooth and relatively swift adoption of the new nomenclature. The AASLD announced in July that it would begin this process by holding conversations with key stakeholders, including the Food and Drug Administration, patient organizations, and pharmaceutical industry representatives.

“By engaging external groups, we have gained valuable insights into potential roadblocks or barriers that may impede the full implementation of the new MASLD nomenclature,” AASLD President Norah Terrault, MD, MPH, FAASLD, told this news organization. “Knowing the types of issues they face will allow us to build an implementation plan that will help guide the field through adoption.”

Even with buy-in from key stakeholders, implementing the changes will be no small feat. It’s a “vast undertaking” that may result in short-term frustrations for some groups, Dr. Terrault said.

“For instance, researchers whose work commenced under the old nomenclature may not be able to alter their research papers and will need to publish under the old nomenclature, which may impact which journals their research could be published in,” she said. “Some patient advocacy groups may have the old nomenclature in their names, resulting in a need to rebrand and revise their educational resources. Patient materials need to be updated. Primary care professionals need to be educated. The list goes on.”

These changes demand both patience and time, Dr. Terrault said. This applies to those tasked with persuading colleagues and patients, as well as clinicians, many of whom have already expressed some resistance to the updated terminology.

The panel anticipated pushback from clinicians who still advocate for NAFLD. However, Dr. Rinella countered that a diagnosis of MASLD requires only one cardiometabolic risk factor and has 99% overlap in most populations. In contrast, the MAFLD diagnostic criteria put forward in 2020 proposed even more restrictive cardiometabolic criteria and greater tolerance for alcohol consumption and would alter the disease natural history, she said.

Concerns have also been raised that replacing NAFLD with MASLD might complicate the value of prior research efforts. However, this should not be a cause for concern, as extensive examination across multiple populations has demonstrated near complete overlap between the two definitions, Dr. Rinella said. Biomarker development, natural history studies, and drug development research will remain unaffected, she said.

Some detractors argue that the term “fatty” is sufficiently descriptive and not stigmatizing. However, Dr. Newsome contends that the panel’s research unequivocally disproves this notion.

“Our Delphi process demonstrated very clearly that over 50% felt it was stigmatizing, and in particular, there were clear supportive views for this change from many patient groups,” he noted. “The new nomenclature empowers patients to explain what the condition means without the use of emotional language.”
 

An opportunity to improve care

One compelling way to persuade reluctant adopters of the new nomenclature’s value is to highlight the opportunities it presents.

The updated terminology opens avenues for research and clinical improvements for patients who meet MASLD criteria and consume alcohol at higher levels (MetALD), Dr. Newsome said.

“There are questions about the relative contribution of these two factors to liver injury, and I see this as an opportunity to explore this area further,” he said.

Hepatologists should embrace this change as a means of increasing awareness regarding the metabolic origins of the disease, Dr. Rinella said. This, in turn, will help identify more patients who require treatment but who are currently overlooked by the existing system, she noted.

“Right now, only around 1% of people with advanced disease are being identified by primary care physicians,” she said. “Hopefully, by elevating the role of metabolic disease, primary care physicians, endocrinologists, and gastroenterologists will be able to identify more patients and bring them to care before they develop cirrhosis.”

Such an outcome would signify much more than a mere semantic shift; it would represent a major advancement in the diagnosis and management of the disease.

A version of this article appeared on Medscape.com.

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Grant_Jon_IL_web.jpg

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Grant_Jon_IL_web.jpg

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Grant_Jon_IL_web.jpg

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

Antibiotics are among the most commonly prescribed medications in both outpatient and hospital settings. Global efforts at curbing antibiotic-resistant strains have prompted clinicians to pursue better stewardship, whereby they limit their prescribing of such medications to those who truly need them.

Yet there’s another possible means of addressing antibiotic resistance – using dietary interventions to reduce the gastrointestinal complaints that so often accompany the use of antibiotics: vomiting, nausea, diarrhea, bloating/indigestion, abdominal pain, and loss of appetite. Far from being a mere nuisance, these complications can have major ramifications.

“Often [these side effects] will result in people stopping an antibiotic they need or taking a second- or third-generation one, which potentially causes even more problems with resistance,” explained Daniel J. Merenstein, MD, a professor of family medicine at Georgetown University, Washington, who has conducted multiple trials on antibiotic stewardship and probiotics.

And it’s not just clinicians who would like to find a way around these common complaints. On lifestyle blogs such as Livestrong and Goop, medical news websites, and via academic institutions, patients can learn how the right probiotic supplement or certain fermented or high-fiber foods, for example, might spare them the upset stomach that often accompanies a course of antibiotics.

Yet according to experts in the field, there are notable questions to be answered about whether there’s evidence to support this approach.

The cost of GI discomfort

Pinpointing the exact manner by which antibiotics upend GI tracts is a complex task, according to Gail Cresci, PhD, RD, a microbiome researcher in the department of pediatric gastroenterology, hepatology, and nutrition and director of nutrition research at the Cleveland Clinic.

“A lot of different mechanisms can go awry,” Dr. Cresci said. “But normally, the good microbes are there to help keep the balance, so when that balance is gone, the pathogens can take over and lead to this disruption.”

According to Lynne V. McFarland, PhD, a recently retired infectious disease epidemiologist who now serves as a private consultant, such complications can have substantial ramifications for patients and health care systems.

“If you’re an inpatient and develop antibiotic-associated diarrhea, it usually increases the length of stay from 8 to 20 days. It also increases the cost of care. And small children who have this can get severely dehydrated, which can become life threatening.”

Proponents of probiotics

Several of the researchers who were interviewed believe there’s convincing evidence supporting probiotics for the treatment of common antibiotic-related GI complaints. In many instances, they were involved in the studies themselves.

During Dr. McFarland’s 4-decade career in probiotics research, she has participated in early animal studies with strains such as Saccharomyces boulardii and was involved in meta-analyses of their role in Clostridioides difficile infection and associated diarrhea and even as a potential GI intervention for COVID-19 patients (Antibiotics (Basel). 2021 Apr 9;10(4):408).

In mouse model studies from 2013 and 2018, Dr. Cresci and colleagues showed that the probiotic strains Lactobacillus GG and Faecalibacterium prausnitzii reduced the structural gut changes that lead to antibiotic-associated diarrhea and minimized the risk of C. difficile infection.

In a 2021 randomized controlled trial led by Merenstein, healthy participants were given a trial of amoxicillin/clavulanate (days 1-7) in conjunction with either yogurt containing the probiotic Bifidobacterium animalis subsp lactis BB-12 or control yogurt (days 1-14). After assessing feces samples over a 30-day period, they found that those who received the probiotic yogurt had a significantly smaller decrease in short-chain fatty acid levels and a more stable taxonomic microbiota profile than control persons.

Dr. Merenstein said that, on the basis of results such as these and others, he’s comfortable being relatively definitive about the value of probiotics.

“I believe it’s close to standard of care that if you’re prescribing antibiotics, especially for more than 7 days, you really need to put people on probiotics that have been studied, simply because the evidence is robust enough now,” he said.

Even for proponents, there are caveats

However, all the researchers recommending the use of probiotics did so with caveats. First and foremost, they advise clinicians that the term “probiotics” is an imprecise catchall and is essentially meaningless.

“A lot of products label themselves as probiotic. It’s a great marketing scheme, but many of the products out there aren’t really probiotics; they’re not proven with randomized control trials and don’t have the scientific background,” said Dr. McFarland. “We’ve found that the efficacy is extremely strain specific and disease specific. A strain may work for one disease and not work for another.”

In 2018, Dr. McFarland coauthored an evidence-based practical guide to help clinicians and patients identify the specific strain that works in certain indications. Dr. Cresci recommends that clinicians consult websites such as Probiotics.org or the National Institutes of Health’s database to find the strains that have been proven to work in well-designed clinical trials.

There was also agreement that, to date, the most robust data support probiotics for the treatment of antibiotic-associated diarrhea.

Although the optimal timing of probiotics is a subject of debate, most proponents agreed that the general rule is “the sooner the better.”

Dr. McFarland recommended incorporating probiotics within 24 hours of starting an antibiotic “because the damage done to your GI tract microbiome is pretty quick, and the probiotics work best if they’re established before major disruption occurs.” She added that patients should continue taking probiotics for 2-8 weeks after stopping antibiotics.

“It takes a long time for your normal flora to get restored,” she said. “It’s best to cover your bases.”

For others, the evidence is not definitive

Opinions on the value of probiotics to combat antibiotic-related GI side effects are divergent, though.

“I would not recommend the routine use of probiotics, and certainly not in the prevention of C. difficile or antibiotic-related diarrhea,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, Norfolk. “I think the evidence does not support that, and I stand strongly on that recommendation.”

Dr. Johnson cited the 2020 guidelines from the American Gastroenterological Association, which offer only a conditional recommendation for the use of specific probiotics and only in preventing antibiotic-associated C. difficile infection.

Geoffrey A. Preidis, MD, PhD, an assistant professor of pediatrics in the section of gastroenterology, hepatology, and nutrition at Baylor College of Medicine, Houston, served as a coauthor of the AGA’s guidelines. He noted that after reviewing 39 published trials of approximately 10,000 patients given probiotics while receiving antibiotics, the authors “did find some evidence that specific probiotics might decrease the risk of C. difficile diarrhea, but the quality of that evidence was low.”

Dr. Preidis attributed this to the lack of well-designed multicenter trials that can isolate the effects of certain strains and determine their benefit in this application.

“The majority of published trials have not reported safety data as rigorously as these data are reported in pharmaceutical trials, so the risk of side effects could be higher than we think,” said Dr. Preidis. “As living microbes, probiotics can move from the intestines into the bloodstream, causing sepsis. Contamination in the manufacturing process has been reported. There might be other long-term effects that we are not yet aware of.”

When asked to characterize the available data on probiotics, Dr. Johnson replied, “I’d generally label it, ‘caveat emptor.’ ”

Dr. McFarland agreed that the field would benefit from better-designed studies and called out meta-analyses that pool outcomes with various strains for particular criticism.

“When researchers do that, it’s no longer valid and shouldn’t have been published, in my opinion,” she told this news organization.

‘Antibiotic diets’ as a possible approach

A compromise between the two sides may be the so-called antibiotic diet. The theory behind such diets is that foods and beverages with biome-boosting properties may be a risk-free intervention that patients can adopt to alleviate antibiotic-related side effects.

“You want your diet to include more soluble fibers to help support the good bacteria, particularly when you’re taking antibiotics,” said Dr. Cresci. “You can get this through eating fresh fruits and vegetables, whole grains, and foods that have more prebiotic, like potatoes. You can also eat fermented food, such as kefir, kombucha, kimchi, and yogurt, so you’re adding more beneficial bacteria into your intestinal tract.”

There is ample published evidence that such foods can boost microbiome diversity and decrease inflammation, including a July 2021 study in Cell. However, the protection this may confer while taking antibiotics isn’t known. Establishing a clear role for the efficacy of such interventions is made additionally difficult by the well-established limitations of conducting dietary clinical trials.

Dr. Merenstein said that there is no compelling evidence that antibiotic-related complications can be offset by changing what goes onto our dinner plates. He joked: “We can’t say, ‘Here’s amoxicillin for your ear infection, now make sure you increase your fermented food, fiber, and water.’ ”

Dr. Johnson said he’s intrigued by studies of prebiotics – fibers that boost beneficial bacteria in the GI system.

“I would love to have more findings about prebiotic identification; that is, things we could do in a healthy way to keep the gut balanced while it’s subject to a change with antibiotics,” he said. “We’re just not there yet.”

Dr. Johnson added that he generally recommends that patients taking antibiotics eat “a bland diet, avoiding things that may have been provocative in the past.”

If patients are already enjoying foods with microbiome-boosting reputations, Dr. Johnson sees “very little downside to continuing that [while on antibiotics].” However, he noted that the period in which you’re taking antibiotics isn’t ideal for trying new foods, given the lack of experience with how the gut bacteria will react.

There are data about foods to avoid while taking antibiotics, which generally fall in line with common dietary knowledge. Many patients may know not to drink grapefruit juice with certain medications, but it’s worth a reminder. Certain antibiotics may also require delaying or avoiding dairy products, although this does not apply to yogurt.

A fiber-deficient diet can aggravate microbiota collapse following antibiotics. In a 2020 study, researchers showed that people on a high-fat diet who were using antibiotics were 8.6 times more likely to have preinflammatory bowel disease than those eating low-fat foods and who had no recent history of antibiotic use. Mouse model data from the same study indicated that poor diet and antibiotics may have worked in conjunction to reduce oxygen in the gut.

Dr. McFarland noted that building a healthy microbiome is a lifelong pursuit and that several factors (for example, environmental or genetic) are out of individuals’ hands. The general public might want a quick fix – ironically, one of the main drivers behind their requesting and receiving antibiotics when they’re not indicated – but it’s likely not available to them.

“You can’t eat one salad and suddenly have a healthy gut, unfortunately.”

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

Antibiotics are among the most commonly prescribed medications in both outpatient and hospital settings. Global efforts at curbing antibiotic-resistant strains have prompted clinicians to pursue better stewardship, whereby they limit their prescribing of such medications to those who truly need them.

Yet there’s another possible means of addressing antibiotic resistance – using dietary interventions to reduce the gastrointestinal complaints that so often accompany the use of antibiotics: vomiting, nausea, diarrhea, bloating/indigestion, abdominal pain, and loss of appetite. Far from being a mere nuisance, these complications can have major ramifications.

“Often [these side effects] will result in people stopping an antibiotic they need or taking a second- or third-generation one, which potentially causes even more problems with resistance,” explained Daniel J. Merenstein, MD, a professor of family medicine at Georgetown University, Washington, who has conducted multiple trials on antibiotic stewardship and probiotics.

And it’s not just clinicians who would like to find a way around these common complaints. On lifestyle blogs such as Livestrong and Goop, medical news websites, and via academic institutions, patients can learn how the right probiotic supplement or certain fermented or high-fiber foods, for example, might spare them the upset stomach that often accompanies a course of antibiotics.

Yet according to experts in the field, there are notable questions to be answered about whether there’s evidence to support this approach.

The cost of GI discomfort

Pinpointing the exact manner by which antibiotics upend GI tracts is a complex task, according to Gail Cresci, PhD, RD, a microbiome researcher in the department of pediatric gastroenterology, hepatology, and nutrition and director of nutrition research at the Cleveland Clinic.

“A lot of different mechanisms can go awry,” Dr. Cresci said. “But normally, the good microbes are there to help keep the balance, so when that balance is gone, the pathogens can take over and lead to this disruption.”

According to Lynne V. McFarland, PhD, a recently retired infectious disease epidemiologist who now serves as a private consultant, such complications can have substantial ramifications for patients and health care systems.

“If you’re an inpatient and develop antibiotic-associated diarrhea, it usually increases the length of stay from 8 to 20 days. It also increases the cost of care. And small children who have this can get severely dehydrated, which can become life threatening.”

Proponents of probiotics

Several of the researchers who were interviewed believe there’s convincing evidence supporting probiotics for the treatment of common antibiotic-related GI complaints. In many instances, they were involved in the studies themselves.

During Dr. McFarland’s 4-decade career in probiotics research, she has participated in early animal studies with strains such as Saccharomyces boulardii and was involved in meta-analyses of their role in Clostridioides difficile infection and associated diarrhea and even as a potential GI intervention for COVID-19 patients (Antibiotics (Basel). 2021 Apr 9;10(4):408).

In mouse model studies from 2013 and 2018, Dr. Cresci and colleagues showed that the probiotic strains Lactobacillus GG and Faecalibacterium prausnitzii reduced the structural gut changes that lead to antibiotic-associated diarrhea and minimized the risk of C. difficile infection.

In a 2021 randomized controlled trial led by Merenstein, healthy participants were given a trial of amoxicillin/clavulanate (days 1-7) in conjunction with either yogurt containing the probiotic Bifidobacterium animalis subsp lactis BB-12 or control yogurt (days 1-14). After assessing feces samples over a 30-day period, they found that those who received the probiotic yogurt had a significantly smaller decrease in short-chain fatty acid levels and a more stable taxonomic microbiota profile than control persons.

Dr. Merenstein said that, on the basis of results such as these and others, he’s comfortable being relatively definitive about the value of probiotics.

“I believe it’s close to standard of care that if you’re prescribing antibiotics, especially for more than 7 days, you really need to put people on probiotics that have been studied, simply because the evidence is robust enough now,” he said.

Even for proponents, there are caveats

However, all the researchers recommending the use of probiotics did so with caveats. First and foremost, they advise clinicians that the term “probiotics” is an imprecise catchall and is essentially meaningless.

“A lot of products label themselves as probiotic. It’s a great marketing scheme, but many of the products out there aren’t really probiotics; they’re not proven with randomized control trials and don’t have the scientific background,” said Dr. McFarland. “We’ve found that the efficacy is extremely strain specific and disease specific. A strain may work for one disease and not work for another.”

In 2018, Dr. McFarland coauthored an evidence-based practical guide to help clinicians and patients identify the specific strain that works in certain indications. Dr. Cresci recommends that clinicians consult websites such as Probiotics.org or the National Institutes of Health’s database to find the strains that have been proven to work in well-designed clinical trials.

There was also agreement that, to date, the most robust data support probiotics for the treatment of antibiotic-associated diarrhea.

Although the optimal timing of probiotics is a subject of debate, most proponents agreed that the general rule is “the sooner the better.”

Dr. McFarland recommended incorporating probiotics within 24 hours of starting an antibiotic “because the damage done to your GI tract microbiome is pretty quick, and the probiotics work best if they’re established before major disruption occurs.” She added that patients should continue taking probiotics for 2-8 weeks after stopping antibiotics.

“It takes a long time for your normal flora to get restored,” she said. “It’s best to cover your bases.”

For others, the evidence is not definitive

Opinions on the value of probiotics to combat antibiotic-related GI side effects are divergent, though.

“I would not recommend the routine use of probiotics, and certainly not in the prevention of C. difficile or antibiotic-related diarrhea,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, Norfolk. “I think the evidence does not support that, and I stand strongly on that recommendation.”

Dr. Johnson cited the 2020 guidelines from the American Gastroenterological Association, which offer only a conditional recommendation for the use of specific probiotics and only in preventing antibiotic-associated C. difficile infection.

Geoffrey A. Preidis, MD, PhD, an assistant professor of pediatrics in the section of gastroenterology, hepatology, and nutrition at Baylor College of Medicine, Houston, served as a coauthor of the AGA’s guidelines. He noted that after reviewing 39 published trials of approximately 10,000 patients given probiotics while receiving antibiotics, the authors “did find some evidence that specific probiotics might decrease the risk of C. difficile diarrhea, but the quality of that evidence was low.”

Dr. Preidis attributed this to the lack of well-designed multicenter trials that can isolate the effects of certain strains and determine their benefit in this application.

“The majority of published trials have not reported safety data as rigorously as these data are reported in pharmaceutical trials, so the risk of side effects could be higher than we think,” said Dr. Preidis. “As living microbes, probiotics can move from the intestines into the bloodstream, causing sepsis. Contamination in the manufacturing process has been reported. There might be other long-term effects that we are not yet aware of.”

When asked to characterize the available data on probiotics, Dr. Johnson replied, “I’d generally label it, ‘caveat emptor.’ ”

Dr. McFarland agreed that the field would benefit from better-designed studies and called out meta-analyses that pool outcomes with various strains for particular criticism.

“When researchers do that, it’s no longer valid and shouldn’t have been published, in my opinion,” she told this news organization.

‘Antibiotic diets’ as a possible approach

A compromise between the two sides may be the so-called antibiotic diet. The theory behind such diets is that foods and beverages with biome-boosting properties may be a risk-free intervention that patients can adopt to alleviate antibiotic-related side effects.

“You want your diet to include more soluble fibers to help support the good bacteria, particularly when you’re taking antibiotics,” said Dr. Cresci. “You can get this through eating fresh fruits and vegetables, whole grains, and foods that have more prebiotic, like potatoes. You can also eat fermented food, such as kefir, kombucha, kimchi, and yogurt, so you’re adding more beneficial bacteria into your intestinal tract.”

There is ample published evidence that such foods can boost microbiome diversity and decrease inflammation, including a July 2021 study in Cell. However, the protection this may confer while taking antibiotics isn’t known. Establishing a clear role for the efficacy of such interventions is made additionally difficult by the well-established limitations of conducting dietary clinical trials.

Dr. Merenstein said that there is no compelling evidence that antibiotic-related complications can be offset by changing what goes onto our dinner plates. He joked: “We can’t say, ‘Here’s amoxicillin for your ear infection, now make sure you increase your fermented food, fiber, and water.’ ”

Dr. Johnson said he’s intrigued by studies of prebiotics – fibers that boost beneficial bacteria in the GI system.

“I would love to have more findings about prebiotic identification; that is, things we could do in a healthy way to keep the gut balanced while it’s subject to a change with antibiotics,” he said. “We’re just not there yet.”

Dr. Johnson added that he generally recommends that patients taking antibiotics eat “a bland diet, avoiding things that may have been provocative in the past.”

If patients are already enjoying foods with microbiome-boosting reputations, Dr. Johnson sees “very little downside to continuing that [while on antibiotics].” However, he noted that the period in which you’re taking antibiotics isn’t ideal for trying new foods, given the lack of experience with how the gut bacteria will react.

There are data about foods to avoid while taking antibiotics, which generally fall in line with common dietary knowledge. Many patients may know not to drink grapefruit juice with certain medications, but it’s worth a reminder. Certain antibiotics may also require delaying or avoiding dairy products, although this does not apply to yogurt.

A fiber-deficient diet can aggravate microbiota collapse following antibiotics. In a 2020 study, researchers showed that people on a high-fat diet who were using antibiotics were 8.6 times more likely to have preinflammatory bowel disease than those eating low-fat foods and who had no recent history of antibiotic use. Mouse model data from the same study indicated that poor diet and antibiotics may have worked in conjunction to reduce oxygen in the gut.

Dr. McFarland noted that building a healthy microbiome is a lifelong pursuit and that several factors (for example, environmental or genetic) are out of individuals’ hands. The general public might want a quick fix – ironically, one of the main drivers behind their requesting and receiving antibiotics when they’re not indicated – but it’s likely not available to them.

“You can’t eat one salad and suddenly have a healthy gut, unfortunately.”

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

Antibiotics are among the most commonly prescribed medications in both outpatient and hospital settings. Global efforts at curbing antibiotic-resistant strains have prompted clinicians to pursue better stewardship, whereby they limit their prescribing of such medications to those who truly need them.

Yet there’s another possible means of addressing antibiotic resistance – using dietary interventions to reduce the gastrointestinal complaints that so often accompany the use of antibiotics: vomiting, nausea, diarrhea, bloating/indigestion, abdominal pain, and loss of appetite. Far from being a mere nuisance, these complications can have major ramifications.

“Often [these side effects] will result in people stopping an antibiotic they need or taking a second- or third-generation one, which potentially causes even more problems with resistance,” explained Daniel J. Merenstein, MD, a professor of family medicine at Georgetown University, Washington, who has conducted multiple trials on antibiotic stewardship and probiotics.

And it’s not just clinicians who would like to find a way around these common complaints. On lifestyle blogs such as Livestrong and Goop, medical news websites, and via academic institutions, patients can learn how the right probiotic supplement or certain fermented or high-fiber foods, for example, might spare them the upset stomach that often accompanies a course of antibiotics.

Yet according to experts in the field, there are notable questions to be answered about whether there’s evidence to support this approach.

The cost of GI discomfort

Pinpointing the exact manner by which antibiotics upend GI tracts is a complex task, according to Gail Cresci, PhD, RD, a microbiome researcher in the department of pediatric gastroenterology, hepatology, and nutrition and director of nutrition research at the Cleveland Clinic.

“A lot of different mechanisms can go awry,” Dr. Cresci said. “But normally, the good microbes are there to help keep the balance, so when that balance is gone, the pathogens can take over and lead to this disruption.”

According to Lynne V. McFarland, PhD, a recently retired infectious disease epidemiologist who now serves as a private consultant, such complications can have substantial ramifications for patients and health care systems.

“If you’re an inpatient and develop antibiotic-associated diarrhea, it usually increases the length of stay from 8 to 20 days. It also increases the cost of care. And small children who have this can get severely dehydrated, which can become life threatening.”

Proponents of probiotics

Several of the researchers who were interviewed believe there’s convincing evidence supporting probiotics for the treatment of common antibiotic-related GI complaints. In many instances, they were involved in the studies themselves.

During Dr. McFarland’s 4-decade career in probiotics research, she has participated in early animal studies with strains such as Saccharomyces boulardii and was involved in meta-analyses of their role in Clostridioides difficile infection and associated diarrhea and even as a potential GI intervention for COVID-19 patients (Antibiotics (Basel). 2021 Apr 9;10(4):408).

In mouse model studies from 2013 and 2018, Dr. Cresci and colleagues showed that the probiotic strains Lactobacillus GG and Faecalibacterium prausnitzii reduced the structural gut changes that lead to antibiotic-associated diarrhea and minimized the risk of C. difficile infection.

In a 2021 randomized controlled trial led by Merenstein, healthy participants were given a trial of amoxicillin/clavulanate (days 1-7) in conjunction with either yogurt containing the probiotic Bifidobacterium animalis subsp lactis BB-12 or control yogurt (days 1-14). After assessing feces samples over a 30-day period, they found that those who received the probiotic yogurt had a significantly smaller decrease in short-chain fatty acid levels and a more stable taxonomic microbiota profile than control persons.

Dr. Merenstein said that, on the basis of results such as these and others, he’s comfortable being relatively definitive about the value of probiotics.

“I believe it’s close to standard of care that if you’re prescribing antibiotics, especially for more than 7 days, you really need to put people on probiotics that have been studied, simply because the evidence is robust enough now,” he said.

Even for proponents, there are caveats

However, all the researchers recommending the use of probiotics did so with caveats. First and foremost, they advise clinicians that the term “probiotics” is an imprecise catchall and is essentially meaningless.

“A lot of products label themselves as probiotic. It’s a great marketing scheme, but many of the products out there aren’t really probiotics; they’re not proven with randomized control trials and don’t have the scientific background,” said Dr. McFarland. “We’ve found that the efficacy is extremely strain specific and disease specific. A strain may work for one disease and not work for another.”

In 2018, Dr. McFarland coauthored an evidence-based practical guide to help clinicians and patients identify the specific strain that works in certain indications. Dr. Cresci recommends that clinicians consult websites such as Probiotics.org or the National Institutes of Health’s database to find the strains that have been proven to work in well-designed clinical trials.

There was also agreement that, to date, the most robust data support probiotics for the treatment of antibiotic-associated diarrhea.

Although the optimal timing of probiotics is a subject of debate, most proponents agreed that the general rule is “the sooner the better.”

Dr. McFarland recommended incorporating probiotics within 24 hours of starting an antibiotic “because the damage done to your GI tract microbiome is pretty quick, and the probiotics work best if they’re established before major disruption occurs.” She added that patients should continue taking probiotics for 2-8 weeks after stopping antibiotics.

“It takes a long time for your normal flora to get restored,” she said. “It’s best to cover your bases.”

For others, the evidence is not definitive

Opinions on the value of probiotics to combat antibiotic-related GI side effects are divergent, though.

“I would not recommend the routine use of probiotics, and certainly not in the prevention of C. difficile or antibiotic-related diarrhea,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, Norfolk. “I think the evidence does not support that, and I stand strongly on that recommendation.”

Dr. Johnson cited the 2020 guidelines from the American Gastroenterological Association, which offer only a conditional recommendation for the use of specific probiotics and only in preventing antibiotic-associated C. difficile infection.

Geoffrey A. Preidis, MD, PhD, an assistant professor of pediatrics in the section of gastroenterology, hepatology, and nutrition at Baylor College of Medicine, Houston, served as a coauthor of the AGA’s guidelines. He noted that after reviewing 39 published trials of approximately 10,000 patients given probiotics while receiving antibiotics, the authors “did find some evidence that specific probiotics might decrease the risk of C. difficile diarrhea, but the quality of that evidence was low.”

Dr. Preidis attributed this to the lack of well-designed multicenter trials that can isolate the effects of certain strains and determine their benefit in this application.

“The majority of published trials have not reported safety data as rigorously as these data are reported in pharmaceutical trials, so the risk of side effects could be higher than we think,” said Dr. Preidis. “As living microbes, probiotics can move from the intestines into the bloodstream, causing sepsis. Contamination in the manufacturing process has been reported. There might be other long-term effects that we are not yet aware of.”

When asked to characterize the available data on probiotics, Dr. Johnson replied, “I’d generally label it, ‘caveat emptor.’ ”

Dr. McFarland agreed that the field would benefit from better-designed studies and called out meta-analyses that pool outcomes with various strains for particular criticism.

“When researchers do that, it’s no longer valid and shouldn’t have been published, in my opinion,” she told this news organization.

‘Antibiotic diets’ as a possible approach

A compromise between the two sides may be the so-called antibiotic diet. The theory behind such diets is that foods and beverages with biome-boosting properties may be a risk-free intervention that patients can adopt to alleviate antibiotic-related side effects.

“You want your diet to include more soluble fibers to help support the good bacteria, particularly when you’re taking antibiotics,” said Dr. Cresci. “You can get this through eating fresh fruits and vegetables, whole grains, and foods that have more prebiotic, like potatoes. You can also eat fermented food, such as kefir, kombucha, kimchi, and yogurt, so you’re adding more beneficial bacteria into your intestinal tract.”

There is ample published evidence that such foods can boost microbiome diversity and decrease inflammation, including a July 2021 study in Cell. However, the protection this may confer while taking antibiotics isn’t known. Establishing a clear role for the efficacy of such interventions is made additionally difficult by the well-established limitations of conducting dietary clinical trials.

Dr. Merenstein said that there is no compelling evidence that antibiotic-related complications can be offset by changing what goes onto our dinner plates. He joked: “We can’t say, ‘Here’s amoxicillin for your ear infection, now make sure you increase your fermented food, fiber, and water.’ ”

Dr. Johnson said he’s intrigued by studies of prebiotics – fibers that boost beneficial bacteria in the GI system.

“I would love to have more findings about prebiotic identification; that is, things we could do in a healthy way to keep the gut balanced while it’s subject to a change with antibiotics,” he said. “We’re just not there yet.”

Dr. Johnson added that he generally recommends that patients taking antibiotics eat “a bland diet, avoiding things that may have been provocative in the past.”

If patients are already enjoying foods with microbiome-boosting reputations, Dr. Johnson sees “very little downside to continuing that [while on antibiotics].” However, he noted that the period in which you’re taking antibiotics isn’t ideal for trying new foods, given the lack of experience with how the gut bacteria will react.

There are data about foods to avoid while taking antibiotics, which generally fall in line with common dietary knowledge. Many patients may know not to drink grapefruit juice with certain medications, but it’s worth a reminder. Certain antibiotics may also require delaying or avoiding dairy products, although this does not apply to yogurt.

A fiber-deficient diet can aggravate microbiota collapse following antibiotics. In a 2020 study, researchers showed that people on a high-fat diet who were using antibiotics were 8.6 times more likely to have preinflammatory bowel disease than those eating low-fat foods and who had no recent history of antibiotic use. Mouse model data from the same study indicated that poor diet and antibiotics may have worked in conjunction to reduce oxygen in the gut.

Dr. McFarland noted that building a healthy microbiome is a lifelong pursuit and that several factors (for example, environmental or genetic) are out of individuals’ hands. The general public might want a quick fix – ironically, one of the main drivers behind their requesting and receiving antibiotics when they’re not indicated – but it’s likely not available to them.

“You can’t eat one salad and suddenly have a healthy gut, unfortunately.”

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

When holiday shoppers recently went to their local liquor stores in search of some liquid spirit, many were instead greeted by the sight of increasingly barren shelves.

alcohol_wineglasses_web.jpg

Although partly a result of global supply chain issues, this was also yet more evidence of the rising demand for alcohol among adults during these difficult COVID years. It’s a trend that has led to concerns of an echo pandemic of alcohol-related morbidity, which has begun to play out in the form of rising rates of gastrointestinal and liver disease, hospital admissions for alcoholic hepatitis, and alcohol-related incidents of domestic violence.

Those who imbibe alcohol in low to moderate levels may not see themselves reflected in such stories of drinking’s hefty tolls. They’re instead following established health guidance that a little bit of alcohol now and then actually has robust health benefits. Yet the past few of years have seen a notable fraying of this idea, as emerging data calls into question whether alcohol in moderation should really continue to be just what the doctor ordered. 
 

Behind the curve: Alcohol’s diminishing cardioprotective value

Perhaps the most resonant argument for the benefits of light to moderate alcohol consumption – usually defined as between one to two drinks a day – has been its proposed cardioprotective value. In this way, alcohol differs from tobacco, which is unsafe at any level. Alcohol’s proposed cardioprotective effects are often represented as a J-shaped curve, with moderate drinking occupying the sweet spot between teetotaling and heavy/binge drinking when it comes to reduced mortality.

In reality, this association is more likely “a statistical artifact” largely derived from low-quality observational studies, according to Christopher Labos, MD, CM, MSc, an epidemiologist and cardiologist at the Queen Elizabeth Health Complex in Montreal.

“When you look at studies that correct for things like reverse causation, or the fact that some people who drink zero alcohol are former drinkers who used to drink alcohol, then you realize that the protective benefit of alcohol is either minimal or nonexistent and that alcohol does more harm than good to our society,” said Dr. Labos, who detailed the reasons underpinning alcohol’s unearned cardioprotective reputation in a 2020 Medscape commentary.

This statistical limitation was on display in July 2021 when BMC Medicine published results from meta-analyses suggesting that current drinkers need not stop consuming small amounts of alcohol for the secondary prevention of cardiovascular disease (CVD). The study’s own investigators noted that it likely overestimated the reduced risk of CVD by including former heavy drinkers as nondrinkers.

Even if the J-shaped curve exists, its simplicity is deceiving. CVD risk increases alongside alcohol consumption owning to a complicated array of genetic and lifestyle factors. The curve also presents something of a catch-22. If you like alcohol enough to drink it every day, staying at the nadir of the curve where you’d gain the most benefits may prove challenging.

Another factor dimming alcohol’s cardioprotective reputation came via recent data that atrial fibrillation episodes can be triggered by acute alcohol use. A randomized, controlled trial published in the New England Journal of Medicine concluded that abstinence reduced arrhythmia recurrences in regular drinkers with atrial fibrillation.

“If we can replicate that, I think we’ll find that reducing alcohol consumption might be a very effective way to prevent and treat atrial fibrillation,” said Dr. Labos.

However, J-curve proponents will note the publication of study data from the UK Biobank indicating that low levels of alcohol consumption confers the greatest reduction in atrial fibrillation risk.
 

An overlooked carcinogen no longer  

Surveys indicate that less than half of Americans realize alcohol increases cancer risk. That might have changed just a bit this year. In early 2021, an epidemiological analysis estimated that alcohol contributed to 4.8% of cancer cases and 3.2% of cancer deaths in the United States. Then the Lancet Oncology published the results of a high-profile, population-based study on the global burden of cancer as a result of alcoho. Although the main takeaway message was that 4% of new cancer cases worldwide in 2020 were attributable to alcohol, it was also noteworthy that moderate drinking accounted for 103,100 out of 741,300 of these projected annual cases.

“The risk of cancer increases even with low or moderate levels of drinking,” said the study’s lead author Harriet Rumgay, BSc, from the International Agency for Research on Cancer in Lyon, France. “Drinking less means you’ll have a lower risk of cancer than if you drink heavily, but there is no safe limit of alcohol consumption.”

The study linked alcohol consumption with an increased risk of at least seven different cancer types, including cancers of the oral cavity, pharynx, larynx, esophagus, colon, rectum, liver, and breast.

Although in North America men represented about two-thirds of the burden of cancer caused by alcohol, Ms. Rumgay added that “low and moderate levels of drinking [one or two alcoholic drinks per day] contributed relatively more cancer cases among women than among men.”

Yet more negative news for moderate alcohol drinkers arrived in August 2021, when a team of South Korean researchers published data in JAMA Network Open showing that, when it came to the risk of developing gastrointestinal cancers, even binge drinking may be preferable to continuous but moderate consumption.

Perhaps the changing perception of alcohol’s carcinogenic potential is best summed up by the American Cancer Society, who in updating its guidelines in 2020 after an 8-year interim offered this succinct piece of advice: “It is best not to drink alcohol.” 
 

Neurotoxic implications

There has similarly been a reconsideration of the effects of moderate alcohol consumption on brain health.

A recent report of multimodal MRI brain and cognitive testing data from over 25,000 participants in the UK Biobank study indicate that alcohol may have no safe dosage . Even moderate consumption reduced gray matter volume and functional connectivity, negative associations that were increased in those with higher blood pressure and body mass index.

Speaking with this news organization in May 2021, an investigator said: “The size of the effect is small, albeit greater than any other modifiable risk factor,” noting that the changes have been linked to decreased memory and dementia.

Louise Mewton, PhD, from the Center for Healthy Brain Aging at the University of New South Wales, Sydney, said that these results provide an interesting comparison with others into the association between alcohol and dementia.

“A recent study of over 1 million dementia cases in France indicated that problematic alcohol use (alcohol use disorders) were one of the strongest risk factors for dementia – even more so than things like high blood pressure and diabetes,” Dr. Mewton said in an interview. In comparison, “the most-recent reviews indicate that 4 drinks/week is associated with the lowest risk for dementia – so we’re talking about very low levels of alcohol use in terms of maintaining brain health.

“Understanding why very small amounts of alcohol appear to be protective in terms of dementia but damaging when we look at brain scans is something that would be really interesting to unpack.”

Dr. Mewton and colleagues recently published data suggesting that there are three periods when the brain might be particularly susceptible to alcohol’s neurotoxic effects: gestation (from conception to birth), later adolescence (15-19 years), and older adulthood (over 65 years). Directing behavioral interventions to patients in these stages may therefore be beneficial.

And there’s no time too soon to promote abstinence among those with alcohol use disorder, as brain damage is shown to still occur even in the immediate period after people cease drinking.

Although in one more argument for the J-shaped curve’s relevance, data from the Massachusetts General Brigham Biobank recently indicated that moderate alcohol use, unlike low and heavy use, lowered both stress-related neurobiological activity and major adverse cardiovascular events.
 

Getting patients to reconsider alcohol’s ‘benefits’

These new findings mean physicians will find themselves imparting a more nuanced message about the health impacts of moderate alcohol consumption than in prior years. To aid those efforts, Ms. Rumgay advised clinicians to consult a special issue of the journal Nutrients that features review articles of alcohol›s impact on various health outcomes.

Ms. Rumgay also supports broader policy changes.

“There is some evidence that adding cancer warnings to alcohol labels, similar to those used on cigarette packages, might deter people from purchasing alcohol products and increase awareness of the causal link with cancer,” she said. “But the most effective ways of reducing alcohol use in the population are through increasing the price of alcohol through higher taxes, limiting purchasing availability, and reducing marketing of alcohol brands to the public.”

Dr. Mewton recommended various interventions for patients who still find it difficult to curtail their drinking.

“For less severe, problematic use, things like cognitive-behavioral therapy and motivational therapy are very effective in reducing alcohol consumption,” she said in an interview.

For all the discussion about how the COVID-19 pandemic has exacerbated problematic drinking, it has also provided an opportunity for getting patients to reexamine their relationship to alcohol. And as Dr. Labos noted, emerging data on alcohol’s negative effects probably won’t be considered earth-shattering to most patients.

“Deep down, I think most people know that alcohol is not healthy, but it is part of our social culture and so we find ways to justify our own behavior,” he said in an interview.

Dr. Labos suggested that clinicians reframe alcohol in their patients’ minds for what it really is – “an indulgence that we shouldn’t have too much of very often.

“Just like junk food, that doesn’t mean we can’t enjoy small amounts occasionally, but we have to stop presenting that it is good for us, because it isn’t.”

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

When holiday shoppers recently went to their local liquor stores in search of some liquid spirit, many were instead greeted by the sight of increasingly barren shelves.

alcohol_wineglasses_web.jpg

Although partly a result of global supply chain issues, this was also yet more evidence of the rising demand for alcohol among adults during these difficult COVID years. It’s a trend that has led to concerns of an echo pandemic of alcohol-related morbidity, which has begun to play out in the form of rising rates of gastrointestinal and liver disease, hospital admissions for alcoholic hepatitis, and alcohol-related incidents of domestic violence.

Those who imbibe alcohol in low to moderate levels may not see themselves reflected in such stories of drinking’s hefty tolls. They’re instead following established health guidance that a little bit of alcohol now and then actually has robust health benefits. Yet the past few of years have seen a notable fraying of this idea, as emerging data calls into question whether alcohol in moderation should really continue to be just what the doctor ordered. 
 

Behind the curve: Alcohol’s diminishing cardioprotective value

Perhaps the most resonant argument for the benefits of light to moderate alcohol consumption – usually defined as between one to two drinks a day – has been its proposed cardioprotective value. In this way, alcohol differs from tobacco, which is unsafe at any level. Alcohol’s proposed cardioprotective effects are often represented as a J-shaped curve, with moderate drinking occupying the sweet spot between teetotaling and heavy/binge drinking when it comes to reduced mortality.

In reality, this association is more likely “a statistical artifact” largely derived from low-quality observational studies, according to Christopher Labos, MD, CM, MSc, an epidemiologist and cardiologist at the Queen Elizabeth Health Complex in Montreal.

“When you look at studies that correct for things like reverse causation, or the fact that some people who drink zero alcohol are former drinkers who used to drink alcohol, then you realize that the protective benefit of alcohol is either minimal or nonexistent and that alcohol does more harm than good to our society,” said Dr. Labos, who detailed the reasons underpinning alcohol’s unearned cardioprotective reputation in a 2020 Medscape commentary.

This statistical limitation was on display in July 2021 when BMC Medicine published results from meta-analyses suggesting that current drinkers need not stop consuming small amounts of alcohol for the secondary prevention of cardiovascular disease (CVD). The study’s own investigators noted that it likely overestimated the reduced risk of CVD by including former heavy drinkers as nondrinkers.

Even if the J-shaped curve exists, its simplicity is deceiving. CVD risk increases alongside alcohol consumption owning to a complicated array of genetic and lifestyle factors. The curve also presents something of a catch-22. If you like alcohol enough to drink it every day, staying at the nadir of the curve where you’d gain the most benefits may prove challenging.

Another factor dimming alcohol’s cardioprotective reputation came via recent data that atrial fibrillation episodes can be triggered by acute alcohol use. A randomized, controlled trial published in the New England Journal of Medicine concluded that abstinence reduced arrhythmia recurrences in regular drinkers with atrial fibrillation.

“If we can replicate that, I think we’ll find that reducing alcohol consumption might be a very effective way to prevent and treat atrial fibrillation,” said Dr. Labos.

However, J-curve proponents will note the publication of study data from the UK Biobank indicating that low levels of alcohol consumption confers the greatest reduction in atrial fibrillation risk.
 

An overlooked carcinogen no longer  

Surveys indicate that less than half of Americans realize alcohol increases cancer risk. That might have changed just a bit this year. In early 2021, an epidemiological analysis estimated that alcohol contributed to 4.8% of cancer cases and 3.2% of cancer deaths in the United States. Then the Lancet Oncology published the results of a high-profile, population-based study on the global burden of cancer as a result of alcoho. Although the main takeaway message was that 4% of new cancer cases worldwide in 2020 were attributable to alcohol, it was also noteworthy that moderate drinking accounted for 103,100 out of 741,300 of these projected annual cases.

“The risk of cancer increases even with low or moderate levels of drinking,” said the study’s lead author Harriet Rumgay, BSc, from the International Agency for Research on Cancer in Lyon, France. “Drinking less means you’ll have a lower risk of cancer than if you drink heavily, but there is no safe limit of alcohol consumption.”

The study linked alcohol consumption with an increased risk of at least seven different cancer types, including cancers of the oral cavity, pharynx, larynx, esophagus, colon, rectum, liver, and breast.

Although in North America men represented about two-thirds of the burden of cancer caused by alcohol, Ms. Rumgay added that “low and moderate levels of drinking [one or two alcoholic drinks per day] contributed relatively more cancer cases among women than among men.”

Yet more negative news for moderate alcohol drinkers arrived in August 2021, when a team of South Korean researchers published data in JAMA Network Open showing that, when it came to the risk of developing gastrointestinal cancers, even binge drinking may be preferable to continuous but moderate consumption.

Perhaps the changing perception of alcohol’s carcinogenic potential is best summed up by the American Cancer Society, who in updating its guidelines in 2020 after an 8-year interim offered this succinct piece of advice: “It is best not to drink alcohol.” 
 

Neurotoxic implications

There has similarly been a reconsideration of the effects of moderate alcohol consumption on brain health.

A recent report of multimodal MRI brain and cognitive testing data from over 25,000 participants in the UK Biobank study indicate that alcohol may have no safe dosage . Even moderate consumption reduced gray matter volume and functional connectivity, negative associations that were increased in those with higher blood pressure and body mass index.

Speaking with this news organization in May 2021, an investigator said: “The size of the effect is small, albeit greater than any other modifiable risk factor,” noting that the changes have been linked to decreased memory and dementia.

Louise Mewton, PhD, from the Center for Healthy Brain Aging at the University of New South Wales, Sydney, said that these results provide an interesting comparison with others into the association between alcohol and dementia.

“A recent study of over 1 million dementia cases in France indicated that problematic alcohol use (alcohol use disorders) were one of the strongest risk factors for dementia – even more so than things like high blood pressure and diabetes,” Dr. Mewton said in an interview. In comparison, “the most-recent reviews indicate that 4 drinks/week is associated with the lowest risk for dementia – so we’re talking about very low levels of alcohol use in terms of maintaining brain health.

“Understanding why very small amounts of alcohol appear to be protective in terms of dementia but damaging when we look at brain scans is something that would be really interesting to unpack.”

Dr. Mewton and colleagues recently published data suggesting that there are three periods when the brain might be particularly susceptible to alcohol’s neurotoxic effects: gestation (from conception to birth), later adolescence (15-19 years), and older adulthood (over 65 years). Directing behavioral interventions to patients in these stages may therefore be beneficial.

And there’s no time too soon to promote abstinence among those with alcohol use disorder, as brain damage is shown to still occur even in the immediate period after people cease drinking.

Although in one more argument for the J-shaped curve’s relevance, data from the Massachusetts General Brigham Biobank recently indicated that moderate alcohol use, unlike low and heavy use, lowered both stress-related neurobiological activity and major adverse cardiovascular events.
 

Getting patients to reconsider alcohol’s ‘benefits’

These new findings mean physicians will find themselves imparting a more nuanced message about the health impacts of moderate alcohol consumption than in prior years. To aid those efforts, Ms. Rumgay advised clinicians to consult a special issue of the journal Nutrients that features review articles of alcohol›s impact on various health outcomes.

Ms. Rumgay also supports broader policy changes.

“There is some evidence that adding cancer warnings to alcohol labels, similar to those used on cigarette packages, might deter people from purchasing alcohol products and increase awareness of the causal link with cancer,” she said. “But the most effective ways of reducing alcohol use in the population are through increasing the price of alcohol through higher taxes, limiting purchasing availability, and reducing marketing of alcohol brands to the public.”

Dr. Mewton recommended various interventions for patients who still find it difficult to curtail their drinking.

“For less severe, problematic use, things like cognitive-behavioral therapy and motivational therapy are very effective in reducing alcohol consumption,” she said in an interview.

For all the discussion about how the COVID-19 pandemic has exacerbated problematic drinking, it has also provided an opportunity for getting patients to reexamine their relationship to alcohol. And as Dr. Labos noted, emerging data on alcohol’s negative effects probably won’t be considered earth-shattering to most patients.

“Deep down, I think most people know that alcohol is not healthy, but it is part of our social culture and so we find ways to justify our own behavior,” he said in an interview.

Dr. Labos suggested that clinicians reframe alcohol in their patients’ minds for what it really is – “an indulgence that we shouldn’t have too much of very often.

“Just like junk food, that doesn’t mean we can’t enjoy small amounts occasionally, but we have to stop presenting that it is good for us, because it isn’t.”

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

When holiday shoppers recently went to their local liquor stores in search of some liquid spirit, many were instead greeted by the sight of increasingly barren shelves.

alcohol_wineglasses_web.jpg

Although partly a result of global supply chain issues, this was also yet more evidence of the rising demand for alcohol among adults during these difficult COVID years. It’s a trend that has led to concerns of an echo pandemic of alcohol-related morbidity, which has begun to play out in the form of rising rates of gastrointestinal and liver disease, hospital admissions for alcoholic hepatitis, and alcohol-related incidents of domestic violence.

Those who imbibe alcohol in low to moderate levels may not see themselves reflected in such stories of drinking’s hefty tolls. They’re instead following established health guidance that a little bit of alcohol now and then actually has robust health benefits. Yet the past few of years have seen a notable fraying of this idea, as emerging data calls into question whether alcohol in moderation should really continue to be just what the doctor ordered. 
 

Behind the curve: Alcohol’s diminishing cardioprotective value

Perhaps the most resonant argument for the benefits of light to moderate alcohol consumption – usually defined as between one to two drinks a day – has been its proposed cardioprotective value. In this way, alcohol differs from tobacco, which is unsafe at any level. Alcohol’s proposed cardioprotective effects are often represented as a J-shaped curve, with moderate drinking occupying the sweet spot between teetotaling and heavy/binge drinking when it comes to reduced mortality.

In reality, this association is more likely “a statistical artifact” largely derived from low-quality observational studies, according to Christopher Labos, MD, CM, MSc, an epidemiologist and cardiologist at the Queen Elizabeth Health Complex in Montreal.

“When you look at studies that correct for things like reverse causation, or the fact that some people who drink zero alcohol are former drinkers who used to drink alcohol, then you realize that the protective benefit of alcohol is either minimal or nonexistent and that alcohol does more harm than good to our society,” said Dr. Labos, who detailed the reasons underpinning alcohol’s unearned cardioprotective reputation in a 2020 Medscape commentary.

This statistical limitation was on display in July 2021 when BMC Medicine published results from meta-analyses suggesting that current drinkers need not stop consuming small amounts of alcohol for the secondary prevention of cardiovascular disease (CVD). The study’s own investigators noted that it likely overestimated the reduced risk of CVD by including former heavy drinkers as nondrinkers.

Even if the J-shaped curve exists, its simplicity is deceiving. CVD risk increases alongside alcohol consumption owning to a complicated array of genetic and lifestyle factors. The curve also presents something of a catch-22. If you like alcohol enough to drink it every day, staying at the nadir of the curve where you’d gain the most benefits may prove challenging.

Another factor dimming alcohol’s cardioprotective reputation came via recent data that atrial fibrillation episodes can be triggered by acute alcohol use. A randomized, controlled trial published in the New England Journal of Medicine concluded that abstinence reduced arrhythmia recurrences in regular drinkers with atrial fibrillation.

“If we can replicate that, I think we’ll find that reducing alcohol consumption might be a very effective way to prevent and treat atrial fibrillation,” said Dr. Labos.

However, J-curve proponents will note the publication of study data from the UK Biobank indicating that low levels of alcohol consumption confers the greatest reduction in atrial fibrillation risk.
 

An overlooked carcinogen no longer  

Surveys indicate that less than half of Americans realize alcohol increases cancer risk. That might have changed just a bit this year. In early 2021, an epidemiological analysis estimated that alcohol contributed to 4.8% of cancer cases and 3.2% of cancer deaths in the United States. Then the Lancet Oncology published the results of a high-profile, population-based study on the global burden of cancer as a result of alcoho. Although the main takeaway message was that 4% of new cancer cases worldwide in 2020 were attributable to alcohol, it was also noteworthy that moderate drinking accounted for 103,100 out of 741,300 of these projected annual cases.

“The risk of cancer increases even with low or moderate levels of drinking,” said the study’s lead author Harriet Rumgay, BSc, from the International Agency for Research on Cancer in Lyon, France. “Drinking less means you’ll have a lower risk of cancer than if you drink heavily, but there is no safe limit of alcohol consumption.”

The study linked alcohol consumption with an increased risk of at least seven different cancer types, including cancers of the oral cavity, pharynx, larynx, esophagus, colon, rectum, liver, and breast.

Although in North America men represented about two-thirds of the burden of cancer caused by alcohol, Ms. Rumgay added that “low and moderate levels of drinking [one or two alcoholic drinks per day] contributed relatively more cancer cases among women than among men.”

Yet more negative news for moderate alcohol drinkers arrived in August 2021, when a team of South Korean researchers published data in JAMA Network Open showing that, when it came to the risk of developing gastrointestinal cancers, even binge drinking may be preferable to continuous but moderate consumption.

Perhaps the changing perception of alcohol’s carcinogenic potential is best summed up by the American Cancer Society, who in updating its guidelines in 2020 after an 8-year interim offered this succinct piece of advice: “It is best not to drink alcohol.” 
 

Neurotoxic implications

There has similarly been a reconsideration of the effects of moderate alcohol consumption on brain health.

A recent report of multimodal MRI brain and cognitive testing data from over 25,000 participants in the UK Biobank study indicate that alcohol may have no safe dosage . Even moderate consumption reduced gray matter volume and functional connectivity, negative associations that were increased in those with higher blood pressure and body mass index.

Speaking with this news organization in May 2021, an investigator said: “The size of the effect is small, albeit greater than any other modifiable risk factor,” noting that the changes have been linked to decreased memory and dementia.

Louise Mewton, PhD, from the Center for Healthy Brain Aging at the University of New South Wales, Sydney, said that these results provide an interesting comparison with others into the association between alcohol and dementia.

“A recent study of over 1 million dementia cases in France indicated that problematic alcohol use (alcohol use disorders) were one of the strongest risk factors for dementia – even more so than things like high blood pressure and diabetes,” Dr. Mewton said in an interview. In comparison, “the most-recent reviews indicate that 4 drinks/week is associated with the lowest risk for dementia – so we’re talking about very low levels of alcohol use in terms of maintaining brain health.

“Understanding why very small amounts of alcohol appear to be protective in terms of dementia but damaging when we look at brain scans is something that would be really interesting to unpack.”

Dr. Mewton and colleagues recently published data suggesting that there are three periods when the brain might be particularly susceptible to alcohol’s neurotoxic effects: gestation (from conception to birth), later adolescence (15-19 years), and older adulthood (over 65 years). Directing behavioral interventions to patients in these stages may therefore be beneficial.

And there’s no time too soon to promote abstinence among those with alcohol use disorder, as brain damage is shown to still occur even in the immediate period after people cease drinking.

Although in one more argument for the J-shaped curve’s relevance, data from the Massachusetts General Brigham Biobank recently indicated that moderate alcohol use, unlike low and heavy use, lowered both stress-related neurobiological activity and major adverse cardiovascular events.
 

Getting patients to reconsider alcohol’s ‘benefits’

These new findings mean physicians will find themselves imparting a more nuanced message about the health impacts of moderate alcohol consumption than in prior years. To aid those efforts, Ms. Rumgay advised clinicians to consult a special issue of the journal Nutrients that features review articles of alcohol›s impact on various health outcomes.

Ms. Rumgay also supports broader policy changes.

“There is some evidence that adding cancer warnings to alcohol labels, similar to those used on cigarette packages, might deter people from purchasing alcohol products and increase awareness of the causal link with cancer,” she said. “But the most effective ways of reducing alcohol use in the population are through increasing the price of alcohol through higher taxes, limiting purchasing availability, and reducing marketing of alcohol brands to the public.”

Dr. Mewton recommended various interventions for patients who still find it difficult to curtail their drinking.

“For less severe, problematic use, things like cognitive-behavioral therapy and motivational therapy are very effective in reducing alcohol consumption,” she said in an interview.

For all the discussion about how the COVID-19 pandemic has exacerbated problematic drinking, it has also provided an opportunity for getting patients to reexamine their relationship to alcohol. And as Dr. Labos noted, emerging data on alcohol’s negative effects probably won’t be considered earth-shattering to most patients.

“Deep down, I think most people know that alcohol is not healthy, but it is part of our social culture and so we find ways to justify our own behavior,” he said in an interview.

Dr. Labos suggested that clinicians reframe alcohol in their patients’ minds for what it really is – “an indulgence that we shouldn’t have too much of very often.

“Just like junk food, that doesn’t mean we can’t enjoy small amounts occasionally, but we have to stop presenting that it is good for us, because it isn’t.”

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

Medical_marijuana_types_web.jpg

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

Martinez_Diana_NY_web.jpg

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

Wallace_Mark_CALIF_web.jpg

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

Freedman_Daniel_TEXAS_web.jpg

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

Medical_marijuana_types_web.jpg

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

Martinez_Diana_NY_web.jpg

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

Wallace_Mark_CALIF_web.jpg

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

Freedman_Daniel_TEXAS_web.jpg

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

Medical_marijuana_types_web.jpg

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

Martinez_Diana_NY_web.jpg

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

Wallace_Mark_CALIF_web.jpg

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

Freedman_Daniel_TEXAS_web.jpg

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.

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

During normal times, the U.K.-based charity No Panic offers itself as an easily accessible service to those with anxiety disorders and phobias. Visitors to the website who can receive immediate, remote support from trained volunteers. But this spring was anything but normal, as the reality of COVID-19’s worldwide spread became terrifyingly clear.

COVID-19 cases peaked in the United Kingdom in early April. Nationwide lockdown efforts contributed to a gradual but ultimately substantial decline in cases, yet, despite the favorable trend lines, No Panic has remained busier than ever.

Beyond the physical symptoms associated with COVID-19, the psychological outcomes are vast and, it seems, prolonged. Researchers have now formalized a definition of the long-term mental maladies associated with the pandemic, collectively deeming them “coronaphobia.”

The term is a catch-all phrase for the fear and the emotional and social strain experienced by the general public in response to COVID-19. Obsessive behaviors, distress, avoidance reaction, panic, anxiety, hoarding, paranoia, and depression are some of the responses associated with coronaphobia. On the surface, these appear to be normal, somewhat fitting reactions to this surreal and frightening moment in time. However, for those experiencing coronaphobia, they are distinctly maladaptive and harmful.

“We had a serious rise in the use of our services, notably the helpline and email enquiries,” explained Sarah Floyd, No Panic’s volunteer advisor and social media coordinator. “It has been up and down all along, but more of an up since lockdown is easing.”

The group’s experience offers yet more evidence that the anxieties and fears caused by this global pandemic don’t flatten alongside the curve but instead linger as chronic problems requiring ongoing care.

“Every week in my clinic, I’m seeing people who are experiencing more anxiety and hopelessness and having an emotional response that is perhaps out of proportion to what one would expect, which is directly related to what is going on in the world right now with coronavirus,” said Gregory Scott Brown, MD, founder and director of the Center for Green Psychiatry in West Lake Hills, Tex. “Simply put, I think what we are looking at is adjustment disorder. That is probably how the DSM would define it.”

Adjustment disorder is one of the most frequently diagnosed mental health conditions, although it is also relatively understudied. It is really a set of disorders that follow in the wake of a significant stressor, which can vary from serious illness or the death of a loved one to relocating or experiencing work problems. The resulting dysfunction and distress that the person experiences are considered out of proportion in duration or scale with what would normally be expected. Diagnosing an adjustment disorder is made difficult by the lack of a valid and reliable screening measure.

Recent literature suggests that coronaphobia may be likely to occur in those who feel vulnerable to disease, are predisposed to anxiety, or are intolerant of uncertainty. Preexisting mental health conditions can also be exacerbated by periods of quarantine, self-isolation, and lockdown, which can lead to panic attacks, chronophobia (fear of passing time), and suicidality.

Although imperfect comparisons, findings from earlier 21st century disease outbreaks, such as severe acute respiratory syndrome and the Ebola virus, signal that containment efforts themselves play a role in deteriorating mental health. A recent rapid review found that, in studies comparing persons who had previously undergone quarantines and those who had not, the former were significantly more likely to experience acute stress disorder, posttraumatic stress symptoms, and depression. Quarantine was found to result in long-term behavioral changes, such as avoiding crowds, among the general public and health care practitioners.

That tremendous psychological morbidity should accompany a global pandemic of this scale is not surprising, according to Amit Anand, MD, vice chair for research for the Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Life Span program at the Cleveland Clinic.

“The technical definition of anxiety is an impending sense of doom, and I think all of us are living with that,” Dr. Anand said. “The basic question then becomes, what is normal and when does it become abnormal?”

He added that most classifications of psychiatric disorders are set during periods of relative stability, which the current moment is most certainly not.

“This is such an unusual situation, so I think it will depend on case-by-case basis, keeping the whole context in mind as whether the patient is thinking or behaving with an abnormal amount of anxiety,” Dr. Anand said.

Investigators are currently trying to give clinicians the tools to better make that determination. In the first scientific study of this clinical condition, Sherman Lee, MD, reported that five symptoms – dizziness, sleep disturbances, tonic immobility, appetite loss, and nausea/abdominal distress – were strong factors for distinguishing coronaphobia from otherwise normal concerns about COVID-19 that did not result in functional impairment. Dr. Lee and colleagues have since published further evidence that coronaphobia “is a unique predictor of psychological distress during the COVID-19 crisis.” They are working on validating a self-reported mental health screener for this condition.

Having the tools to identify patients struggling with coronaphobia may go some ways toward addressing another area of declining health. At the outset of the COVID-19 pandemic, there was a question as to whether doctors would be beset by a surge of the “worried well” – persons mistakenly believing themselves to be infected. Now months into the pandemic, the converse phenomenon – a fear of contracting COVID-19 that is driving patients away from practitioners – appears to be the more valid concern.

In early spring, the pandemic’s first surge was accompanied by reports of approximately 40% and 60% drops in visits to EDs and ambulatory centers, respectively. Stories of acute stroke patients avoiding treatment began to appear in the press. Major U.S. cities saw noteworthy declines in 911 calls, indicating a hesitancy to be taken to a hospital. That COVID-19 has been accompanied by mass unemployment and subsequent loss of insurance complicates the notion that fear alone is keeping people from treatment. In other countries, it has been explicitly linked. Investigators in Singapore noted that coronaphobia played a role in reducing willingness to attend in-person visits among adolescents with eating disorders. Similarly, case reports in Israel suggest that coronaphobia has contributed to delays in diagnoses of common pediatric diseases.

There is also a concern, colloquially termed “reentry anxiety,” that mental health problems caused by the pandemic, the accompanying lockdown, self-isolation, and quarantine practices will prove alarmingly durable. Even after this challenging moment in history draws to a close, many people may face substantial stress in returning to the normal activities of life – social, professional, familial – once taken for granted.

“We are in the beginning phase of that now,” said Dr. Anand. “Lots of people are decompensating, getting depressed, and needing treatment. I think the longer it goes on for, the more difficult it will be.”

In the United States, that day may seem far away. Nonetheless, it is important to begin laying the therapeutic groundwork now, according to Dr. Brown.

“I am recommending unconventional therapies like meet-up groups, online forums,” he said. “Everything has shifted online, and so there are a lot of support groups that patients can participate to learn coping skills and really hear what other people are going through.”

Before reaching that stage, Dr. Brown recommends that clinicians first simply discuss such anxieties with their patients in order to normalize them.

“Realize that everyone essentially is going through some degree of this right now. The coronavirus pandemic is literally impacting every person on the face of the planet. Sometimes just pointing that out to people can really help,” he said.

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