MDedge Psychiatry

The Food and Drug Administration could expand the use of the Pfizer COVID-19 vaccine to teens early next week, The New York Times and CNN reported, both citing unnamed officials familiar with the agency’s plans.

In late March, Pfizer submitted data to the FDA showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12 to 15. Their vaccine  is already authorized for use teens and adults ages 16 and older.

The move would make about 17 million more Americans eligible for vaccination and would be a major step toward getting both adolescents and teens back into classrooms full time by next fall.

“Across the globe, we are longing for a normal life. This is especially true for our children. The initial results we have seen in the adolescent studies suggest that children are particularly well protected by vaccination, which is very encouraging given the trends we have seen in recent weeks regarding the spread of the B.1.1.7 U.K. variant,” Ugur Sahin, CEO and co-founder of Pfizer partner BioNTech, said in a March 31 press release.

Getting schools fully reopened for in-person learning has been a goal of both the Trump and Biden administrations, but it has been tricky to pull off, as some parents and teachers have been reluctant to return to classrooms with so much uncertainty about the risk and the role of children in spreading the virus.

A recent study of roughly 150,000 school-aged children in Israel found that while kids under age 10 were unlikely to catch or spread the virus as they reentered classrooms. Older children, though, were a different story. The study found that children ages 10-19 had risks of catching the virus that were as high as adults ages 20-60.

The risk for severe illness and death from COVID-19 rises with age.

Children and teens are at relatively low risk from severe outcomes after a COVID-19 infection compared to adults, but they can catch it and some will get really sick with it, especially if they have an underlying health condition, like obesity or asthma that makes them more vulnerable.

Beyond the initial infection, children can get a rare late complication called MIS-C, that while treatable, can be severe and requires hospitalization. Emerging reports also suggest there are some kids that become long haulers in much the same way adults do, dealing with lingering problems for months after they first get sick.

As new variants of the coronavirus circulate in the United States, some states have seen big increases in the number of children and teens with COVID. In Michigan, for example, which recently dealt with a spring surge of cases dominated by the B.1.1.7 variant, cases in children and teens quadrupled in April compared to February.

Beyond individual protection, vaccinating children and teens has been seen as important to achieving strong community protection, or herd immunity, against the new coronavirus.

If the FDA expands the authorization for the Pfizer vaccine, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will likely meet to review data on the safety and efficacy of the vaccine. The committee may then vote on new recommendations for use of the vaccine in the United States.

Not everyone agrees with the idea that American adolescents, who are at relatively low risk of bad outcomes, could get access to COVID vaccines ahead of vulnerable essential workers and seniors in other parts of the world that are still fighting the pandemic with little access to vaccines.

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

The Food and Drug Administration could expand the use of the Pfizer COVID-19 vaccine to teens early next week, The New York Times and CNN reported, both citing unnamed officials familiar with the agency’s plans.

In late March, Pfizer submitted data to the FDA showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12 to 15. Their vaccine  is already authorized for use teens and adults ages 16 and older.

The move would make about 17 million more Americans eligible for vaccination and would be a major step toward getting both adolescents and teens back into classrooms full time by next fall.

“Across the globe, we are longing for a normal life. This is especially true for our children. The initial results we have seen in the adolescent studies suggest that children are particularly well protected by vaccination, which is very encouraging given the trends we have seen in recent weeks regarding the spread of the B.1.1.7 U.K. variant,” Ugur Sahin, CEO and co-founder of Pfizer partner BioNTech, said in a March 31 press release.

Getting schools fully reopened for in-person learning has been a goal of both the Trump and Biden administrations, but it has been tricky to pull off, as some parents and teachers have been reluctant to return to classrooms with so much uncertainty about the risk and the role of children in spreading the virus.

A recent study of roughly 150,000 school-aged children in Israel found that while kids under age 10 were unlikely to catch or spread the virus as they reentered classrooms. Older children, though, were a different story. The study found that children ages 10-19 had risks of catching the virus that were as high as adults ages 20-60.

The risk for severe illness and death from COVID-19 rises with age.

Children and teens are at relatively low risk from severe outcomes after a COVID-19 infection compared to adults, but they can catch it and some will get really sick with it, especially if they have an underlying health condition, like obesity or asthma that makes them more vulnerable.

Beyond the initial infection, children can get a rare late complication called MIS-C, that while treatable, can be severe and requires hospitalization. Emerging reports also suggest there are some kids that become long haulers in much the same way adults do, dealing with lingering problems for months after they first get sick.

As new variants of the coronavirus circulate in the United States, some states have seen big increases in the number of children and teens with COVID. In Michigan, for example, which recently dealt with a spring surge of cases dominated by the B.1.1.7 variant, cases in children and teens quadrupled in April compared to February.

Beyond individual protection, vaccinating children and teens has been seen as important to achieving strong community protection, or herd immunity, against the new coronavirus.

If the FDA expands the authorization for the Pfizer vaccine, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will likely meet to review data on the safety and efficacy of the vaccine. The committee may then vote on new recommendations for use of the vaccine in the United States.

Not everyone agrees with the idea that American adolescents, who are at relatively low risk of bad outcomes, could get access to COVID vaccines ahead of vulnerable essential workers and seniors in other parts of the world that are still fighting the pandemic with little access to vaccines.

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

The Food and Drug Administration could expand the use of the Pfizer COVID-19 vaccine to teens early next week, The New York Times and CNN reported, both citing unnamed officials familiar with the agency’s plans.

In late March, Pfizer submitted data to the FDA showing its mRNA vaccine was 100% effective at preventing COVID-19 infection in children ages 12 to 15. Their vaccine  is already authorized for use teens and adults ages 16 and older.

The move would make about 17 million more Americans eligible for vaccination and would be a major step toward getting both adolescents and teens back into classrooms full time by next fall.

“Across the globe, we are longing for a normal life. This is especially true for our children. The initial results we have seen in the adolescent studies suggest that children are particularly well protected by vaccination, which is very encouraging given the trends we have seen in recent weeks regarding the spread of the B.1.1.7 U.K. variant,” Ugur Sahin, CEO and co-founder of Pfizer partner BioNTech, said in a March 31 press release.

Getting schools fully reopened for in-person learning has been a goal of both the Trump and Biden administrations, but it has been tricky to pull off, as some parents and teachers have been reluctant to return to classrooms with so much uncertainty about the risk and the role of children in spreading the virus.

A recent study of roughly 150,000 school-aged children in Israel found that while kids under age 10 were unlikely to catch or spread the virus as they reentered classrooms. Older children, though, were a different story. The study found that children ages 10-19 had risks of catching the virus that were as high as adults ages 20-60.

The risk for severe illness and death from COVID-19 rises with age.

Children and teens are at relatively low risk from severe outcomes after a COVID-19 infection compared to adults, but they can catch it and some will get really sick with it, especially if they have an underlying health condition, like obesity or asthma that makes them more vulnerable.

Beyond the initial infection, children can get a rare late complication called MIS-C, that while treatable, can be severe and requires hospitalization. Emerging reports also suggest there are some kids that become long haulers in much the same way adults do, dealing with lingering problems for months after they first get sick.

As new variants of the coronavirus circulate in the United States, some states have seen big increases in the number of children and teens with COVID. In Michigan, for example, which recently dealt with a spring surge of cases dominated by the B.1.1.7 variant, cases in children and teens quadrupled in April compared to February.

Beyond individual protection, vaccinating children and teens has been seen as important to achieving strong community protection, or herd immunity, against the new coronavirus.

If the FDA expands the authorization for the Pfizer vaccine, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will likely meet to review data on the safety and efficacy of the vaccine. The committee may then vote on new recommendations for use of the vaccine in the United States.

Not everyone agrees with the idea that American adolescents, who are at relatively low risk of bad outcomes, could get access to COVID vaccines ahead of vulnerable essential workers and seniors in other parts of the world that are still fighting the pandemic with little access to vaccines.

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

Concern and anxiety around COVID-19 remains high among Americans, with more people reporting mental health effects from the pandemic this year than last, and parents concerned about the mental health of their children, results of a new poll by the American Psychiatric Association show. Although the overall level of anxiety has decreased from last year’s APA poll, “the degree to which anxiety still reigns is concerning,” APA President Jeffrey Geller, MD, MPH, told this news organization.

The results of the latest poll were presented at the American Psychiatric Association 2021 annual meeting and based on an online survey conducted March 26 to April 5 among a sample of 1,000 adults aged 18 years or older.

Serious mental health hit

In the new poll, about 4 in 10 Americans (41%) report they are more anxious than last year, down from just over 60%.

Young adults aged 18-29 years (49%) and Hispanic/Latinos (50%) are more likely to report being more anxious now than a year ago. Those 65 or older (30%) are less apt to say they feel more anxious than last year.

The latest poll also shows that Americans are more anxious about family and loved ones getting COVID-19 (64%) than about catching the virus themselves (49%). 

Concern about family and loved ones contracting COVID-19 has increased since last year’s poll (conducted September 2020), rising from 56% then to 64% now. Hispanic/Latinx individuals (73%) and African American/Black individuals (76%) are more anxious about COVID-19 than White people (59%).

In the new poll, 43% of adults report the pandemic has had a serious impact on their mental health, up from 37% in 2020. Younger adults are more apt than older adults to report serious mental health effects.

Slightly fewer Americans report the pandemic is affecting their day-to-day life now as compared to a year ago, in ways such as problems sleeping (19% down from 22%), difficulty concentrating (18% down from 20%), and fighting more with loved ones (16% down from 17%).

The percentage of adults consuming more alcohol or other substances/drugs than normal increased slightly since last year (14%-17%). Additionally, 33% of adults (40% of women) report gaining weight during the pandemic.

Call to action

More than half of adults (53%) with children report they are concerned about the mental state of their children and almost half (48%) report the pandemic has caused mental health problems for one or more of their children, including minor problems for 29% and major problems for 19%.

More than a quarter (26%) of parents have sought professional mental health help for their children because of the pandemic.

Nearly half (49%) of parents of children younger than 18 years say their child received help from a mental health professional since the start of the pandemic; 23% received help from a primary care professional, 18% from a psychiatrist, 15% from a psychologist, 13% from a therapist, 10% from a social worker, and 10% from a school counselor or school psychologist.

More than 1 in 5 parents reported difficulty scheduling appointments for their child with a mental health professional.

“This poll shows that, even as vaccines become more widespread, Americans are still worried about the mental state of their children,” Dr. Geller said in a news release.

“This is a call to action for policymakers, who need to remember that, in our COVID-19 recovery, there’s no health without mental health,” he added.

Just over three-quarters (76%) of those surveyed say they have been or intend to get vaccinated; 22% say they don’t intend to get vaccinated; and 2% didn’t know.

For those who do not intend to get vaccinated, the primary concern (53%) is about side effects of the vaccine. Other reasons for not getting vaccinated include believing the vaccine is not effective (31%), believing the makers of the vaccine aren’t being honest about what’s in it (27%), and fear/anxiety about needles (12%).

Resiliency a finite resource

Reached for comment, Samoon Ahmad, MD, professor in the department of psychiatry, New York University, said it’s not surprising that Americans are still suffering more anxiety than normal.

“The Census Bureau’s Household Pulse Survey has shown that anxiety and depression levels have remained higher than normal since the pandemic began. That 43% of adults now say that the pandemic has had a serious impact on their mental health seems in line with what that survey has been reporting for over a year,” Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York, said in an interview.

He believes there are several reasons why anxiety levels remain high. One reason is something he’s noticed among his patients for years. “Most people struggle with anxiety especially at night when the noise and distractions of contemporary life fade away. This is the time of introspection,” he explained.

“Quarantine has been kind of like a protracted night because the distractions that are common in the so-called ‘rat race’ have been relatively muted for the past 14 months. I believe this has caused what you might call ‘forced introspection,’ and that this is giving rise to feelings of anxiety as people use their time alone to reassess their careers and their social lives and really begin to fret about some of the decisions that have led them to this point in their lives,” said Dr. Ahmad.

The other finding in the APA survey – that people are more concerned about their loved ones catching the virus than they were a year ago – is also not surprising, Dr. Ahmad said.

“Even though we seem to have turned a corner in the United States and the worst of the pandemic is behind us, the surge that went from roughly November through March of this year was more wide-reaching geographically than previous waves, and I think this made the severity of the virus far more real to people who lived in communities that had been spared severe outbreaks during the surges that we saw in the spring and summer of 2020,” Dr. Ahmad told this news organization.

“There’s also heightened concern over variants and the efficacy of the vaccine in treating these variants. Those who have families in other countries where the virus is surging, such as India or parts of Latin America, are likely experiencing additional stress and anxiety too,” he noted.

While the new APA poll findings are not surprising, they still are “deeply concerning,” Dr. Ahmad said.

“Resiliency is a finite resource, and people can only take so much stress before their mental health begins to suffer. For most people, this is not going to lead to some kind of overdramatic nervous breakdown. Instead, one may notice that they are more irritable than they once were, that they’re not sleeping particularly well, or that they have a nagging sense of discomfort and stress when doing activities that they used to think of as normal,” like taking a trip to the grocery store, meeting up with friends, or going to work, Dr. Ahmad said.

“Overcoming this kind of anxiety and reacclimating ourselves to social situations is going to take more time for some people than others, and that is perfectly natural,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York.

“I don’t think it’s wise to try to put a limit on what constitutes a normal amount of time to readjust, and I think everyone in the field of mental health needs to avoid pathologizing any lingering sense of unease. No one needs to be medicated or diagnosed with a mental illness because they are nervous about going into public spaces in the immediate aftermath of a pandemic. We need to show a lot of patience and encourage people to readjust at their own pace for the foreseeable future,” Dr. Ahmad said.

Dr. Geller and Dr. Ahmad have disclosed no relevant financial relationships.

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

Concern and anxiety around COVID-19 remains high among Americans, with more people reporting mental health effects from the pandemic this year than last, and parents concerned about the mental health of their children, results of a new poll by the American Psychiatric Association show. Although the overall level of anxiety has decreased from last year’s APA poll, “the degree to which anxiety still reigns is concerning,” APA President Jeffrey Geller, MD, MPH, told this news organization.

The results of the latest poll were presented at the American Psychiatric Association 2021 annual meeting and based on an online survey conducted March 26 to April 5 among a sample of 1,000 adults aged 18 years or older.

Serious mental health hit

In the new poll, about 4 in 10 Americans (41%) report they are more anxious than last year, down from just over 60%.

Young adults aged 18-29 years (49%) and Hispanic/Latinos (50%) are more likely to report being more anxious now than a year ago. Those 65 or older (30%) are less apt to say they feel more anxious than last year.

The latest poll also shows that Americans are more anxious about family and loved ones getting COVID-19 (64%) than about catching the virus themselves (49%). 

Concern about family and loved ones contracting COVID-19 has increased since last year’s poll (conducted September 2020), rising from 56% then to 64% now. Hispanic/Latinx individuals (73%) and African American/Black individuals (76%) are more anxious about COVID-19 than White people (59%).

In the new poll, 43% of adults report the pandemic has had a serious impact on their mental health, up from 37% in 2020. Younger adults are more apt than older adults to report serious mental health effects.

Slightly fewer Americans report the pandemic is affecting their day-to-day life now as compared to a year ago, in ways such as problems sleeping (19% down from 22%), difficulty concentrating (18% down from 20%), and fighting more with loved ones (16% down from 17%).

The percentage of adults consuming more alcohol or other substances/drugs than normal increased slightly since last year (14%-17%). Additionally, 33% of adults (40% of women) report gaining weight during the pandemic.

Call to action

More than half of adults (53%) with children report they are concerned about the mental state of their children and almost half (48%) report the pandemic has caused mental health problems for one or more of their children, including minor problems for 29% and major problems for 19%.

More than a quarter (26%) of parents have sought professional mental health help for their children because of the pandemic.

Nearly half (49%) of parents of children younger than 18 years say their child received help from a mental health professional since the start of the pandemic; 23% received help from a primary care professional, 18% from a psychiatrist, 15% from a psychologist, 13% from a therapist, 10% from a social worker, and 10% from a school counselor or school psychologist.

More than 1 in 5 parents reported difficulty scheduling appointments for their child with a mental health professional.

“This poll shows that, even as vaccines become more widespread, Americans are still worried about the mental state of their children,” Dr. Geller said in a news release.

“This is a call to action for policymakers, who need to remember that, in our COVID-19 recovery, there’s no health without mental health,” he added.

Just over three-quarters (76%) of those surveyed say they have been or intend to get vaccinated; 22% say they don’t intend to get vaccinated; and 2% didn’t know.

For those who do not intend to get vaccinated, the primary concern (53%) is about side effects of the vaccine. Other reasons for not getting vaccinated include believing the vaccine is not effective (31%), believing the makers of the vaccine aren’t being honest about what’s in it (27%), and fear/anxiety about needles (12%).

Resiliency a finite resource

Reached for comment, Samoon Ahmad, MD, professor in the department of psychiatry, New York University, said it’s not surprising that Americans are still suffering more anxiety than normal.

“The Census Bureau’s Household Pulse Survey has shown that anxiety and depression levels have remained higher than normal since the pandemic began. That 43% of adults now say that the pandemic has had a serious impact on their mental health seems in line with what that survey has been reporting for over a year,” Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York, said in an interview.

He believes there are several reasons why anxiety levels remain high. One reason is something he’s noticed among his patients for years. “Most people struggle with anxiety especially at night when the noise and distractions of contemporary life fade away. This is the time of introspection,” he explained.

“Quarantine has been kind of like a protracted night because the distractions that are common in the so-called ‘rat race’ have been relatively muted for the past 14 months. I believe this has caused what you might call ‘forced introspection,’ and that this is giving rise to feelings of anxiety as people use their time alone to reassess their careers and their social lives and really begin to fret about some of the decisions that have led them to this point in their lives,” said Dr. Ahmad.

The other finding in the APA survey – that people are more concerned about their loved ones catching the virus than they were a year ago – is also not surprising, Dr. Ahmad said.

“Even though we seem to have turned a corner in the United States and the worst of the pandemic is behind us, the surge that went from roughly November through March of this year was more wide-reaching geographically than previous waves, and I think this made the severity of the virus far more real to people who lived in communities that had been spared severe outbreaks during the surges that we saw in the spring and summer of 2020,” Dr. Ahmad told this news organization.

“There’s also heightened concern over variants and the efficacy of the vaccine in treating these variants. Those who have families in other countries where the virus is surging, such as India or parts of Latin America, are likely experiencing additional stress and anxiety too,” he noted.

While the new APA poll findings are not surprising, they still are “deeply concerning,” Dr. Ahmad said.

“Resiliency is a finite resource, and people can only take so much stress before their mental health begins to suffer. For most people, this is not going to lead to some kind of overdramatic nervous breakdown. Instead, one may notice that they are more irritable than they once were, that they’re not sleeping particularly well, or that they have a nagging sense of discomfort and stress when doing activities that they used to think of as normal,” like taking a trip to the grocery store, meeting up with friends, or going to work, Dr. Ahmad said.

“Overcoming this kind of anxiety and reacclimating ourselves to social situations is going to take more time for some people than others, and that is perfectly natural,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York.

“I don’t think it’s wise to try to put a limit on what constitutes a normal amount of time to readjust, and I think everyone in the field of mental health needs to avoid pathologizing any lingering sense of unease. No one needs to be medicated or diagnosed with a mental illness because they are nervous about going into public spaces in the immediate aftermath of a pandemic. We need to show a lot of patience and encourage people to readjust at their own pace for the foreseeable future,” Dr. Ahmad said.

Dr. Geller and Dr. Ahmad have disclosed no relevant financial relationships.

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

Concern and anxiety around COVID-19 remains high among Americans, with more people reporting mental health effects from the pandemic this year than last, and parents concerned about the mental health of their children, results of a new poll by the American Psychiatric Association show. Although the overall level of anxiety has decreased from last year’s APA poll, “the degree to which anxiety still reigns is concerning,” APA President Jeffrey Geller, MD, MPH, told this news organization.

The results of the latest poll were presented at the American Psychiatric Association 2021 annual meeting and based on an online survey conducted March 26 to April 5 among a sample of 1,000 adults aged 18 years or older.

Serious mental health hit

In the new poll, about 4 in 10 Americans (41%) report they are more anxious than last year, down from just over 60%.

Young adults aged 18-29 years (49%) and Hispanic/Latinos (50%) are more likely to report being more anxious now than a year ago. Those 65 or older (30%) are less apt to say they feel more anxious than last year.

The latest poll also shows that Americans are more anxious about family and loved ones getting COVID-19 (64%) than about catching the virus themselves (49%). 

Concern about family and loved ones contracting COVID-19 has increased since last year’s poll (conducted September 2020), rising from 56% then to 64% now. Hispanic/Latinx individuals (73%) and African American/Black individuals (76%) are more anxious about COVID-19 than White people (59%).

In the new poll, 43% of adults report the pandemic has had a serious impact on their mental health, up from 37% in 2020. Younger adults are more apt than older adults to report serious mental health effects.

Slightly fewer Americans report the pandemic is affecting their day-to-day life now as compared to a year ago, in ways such as problems sleeping (19% down from 22%), difficulty concentrating (18% down from 20%), and fighting more with loved ones (16% down from 17%).

The percentage of adults consuming more alcohol or other substances/drugs than normal increased slightly since last year (14%-17%). Additionally, 33% of adults (40% of women) report gaining weight during the pandemic.

Call to action

More than half of adults (53%) with children report they are concerned about the mental state of their children and almost half (48%) report the pandemic has caused mental health problems for one or more of their children, including minor problems for 29% and major problems for 19%.

More than a quarter (26%) of parents have sought professional mental health help for their children because of the pandemic.

Nearly half (49%) of parents of children younger than 18 years say their child received help from a mental health professional since the start of the pandemic; 23% received help from a primary care professional, 18% from a psychiatrist, 15% from a psychologist, 13% from a therapist, 10% from a social worker, and 10% from a school counselor or school psychologist.

More than 1 in 5 parents reported difficulty scheduling appointments for their child with a mental health professional.

“This poll shows that, even as vaccines become more widespread, Americans are still worried about the mental state of their children,” Dr. Geller said in a news release.

“This is a call to action for policymakers, who need to remember that, in our COVID-19 recovery, there’s no health without mental health,” he added.

Just over three-quarters (76%) of those surveyed say they have been or intend to get vaccinated; 22% say they don’t intend to get vaccinated; and 2% didn’t know.

For those who do not intend to get vaccinated, the primary concern (53%) is about side effects of the vaccine. Other reasons for not getting vaccinated include believing the vaccine is not effective (31%), believing the makers of the vaccine aren’t being honest about what’s in it (27%), and fear/anxiety about needles (12%).

Resiliency a finite resource

Reached for comment, Samoon Ahmad, MD, professor in the department of psychiatry, New York University, said it’s not surprising that Americans are still suffering more anxiety than normal.

“The Census Bureau’s Household Pulse Survey has shown that anxiety and depression levels have remained higher than normal since the pandemic began. That 43% of adults now say that the pandemic has had a serious impact on their mental health seems in line with what that survey has been reporting for over a year,” Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York, said in an interview.

He believes there are several reasons why anxiety levels remain high. One reason is something he’s noticed among his patients for years. “Most people struggle with anxiety especially at night when the noise and distractions of contemporary life fade away. This is the time of introspection,” he explained.

“Quarantine has been kind of like a protracted night because the distractions that are common in the so-called ‘rat race’ have been relatively muted for the past 14 months. I believe this has caused what you might call ‘forced introspection,’ and that this is giving rise to feelings of anxiety as people use their time alone to reassess their careers and their social lives and really begin to fret about some of the decisions that have led them to this point in their lives,” said Dr. Ahmad.

The other finding in the APA survey – that people are more concerned about their loved ones catching the virus than they were a year ago – is also not surprising, Dr. Ahmad said.

“Even though we seem to have turned a corner in the United States and the worst of the pandemic is behind us, the surge that went from roughly November through March of this year was more wide-reaching geographically than previous waves, and I think this made the severity of the virus far more real to people who lived in communities that had been spared severe outbreaks during the surges that we saw in the spring and summer of 2020,” Dr. Ahmad told this news organization.

“There’s also heightened concern over variants and the efficacy of the vaccine in treating these variants. Those who have families in other countries where the virus is surging, such as India or parts of Latin America, are likely experiencing additional stress and anxiety too,” he noted.

While the new APA poll findings are not surprising, they still are “deeply concerning,” Dr. Ahmad said.

“Resiliency is a finite resource, and people can only take so much stress before their mental health begins to suffer. For most people, this is not going to lead to some kind of overdramatic nervous breakdown. Instead, one may notice that they are more irritable than they once were, that they’re not sleeping particularly well, or that they have a nagging sense of discomfort and stress when doing activities that they used to think of as normal,” like taking a trip to the grocery store, meeting up with friends, or going to work, Dr. Ahmad said.

“Overcoming this kind of anxiety and reacclimating ourselves to social situations is going to take more time for some people than others, and that is perfectly natural,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York.

“I don’t think it’s wise to try to put a limit on what constitutes a normal amount of time to readjust, and I think everyone in the field of mental health needs to avoid pathologizing any lingering sense of unease. No one needs to be medicated or diagnosed with a mental illness because they are nervous about going into public spaces in the immediate aftermath of a pandemic. We need to show a lot of patience and encourage people to readjust at their own pace for the foreseeable future,” Dr. Ahmad said.

Dr. Geller and Dr. Ahmad have disclosed no relevant financial relationships.

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

Young Black adults who witness or experience police violence have significantly elevated levels of anxiety, new research shows.

In the first study to quantify the impact of police contact anxiety, investigators found it was associated with moderately severe anxiety levels in this group of individuals, highlighting the need to screen for exposure to police violence in this patient population, study investigator Robert O. Motley Jr, PhD, manager of the Race & Opportunity Lab at Washington University in St. Louis, said in an interview.

“If you’re working in an institution and providing clinical care, mental health care, or behavior health care, these additional measures should be included to get a much more holistic view of the exposure of these individuals in terms of traumatic events. These assessments can inform your decisions around care,” Dr. Motley added.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

‘Alarming’ rates of exposure

Evidence shows anxiety disorders are among the most prevalent conditions for Black people aged 18-29 years – an age group described as “emergent adulthood” because these individuals haven’t yet taken on full responsibilities of adulthood.

Research shows Black emergent adults are three to four times more likely than other ethnic groups to be exposed to actual or threatened nonfatal police violence, said Dr. Motley. “So they didn’t die, but were exposed to force, which could be things like police yelling at them, hitting or kicking them, pointing a gun at them, or tasing them.”

These individuals are also two to three times more likely to experience exposure to fatal police violence, and to be unarmed and killed, said Dr. Motley.

Evidence shows a clear link between exposure to stressful or traumatic events and anxiety disorders, but there has been little research examining the relationship between exposure to police violence and anxiety disorders among Black emergent adults, he said.

To assess the prevalence and correlates of “police contact anxiety” the investigators used computer-assisted surveys to collect data from 300 young Black college students in St. Louis who had been exposed to police violence at some point in their lives. The mean age of the sample was 20.4 years and included an equal number of men and women.

Work status for the previous year showed almost one-quarter (23.6%) were unemployed and about half worked part time. Almost two-thirds (62.6%) had an annual income of less than $10,000.

Respondents reported they had personally experienced police violence almost twice (a mean of 1.89) during their lifetime. The mean number of times they witnessed police using force against someone else was 7.82. Respondents also reported they had watched videos showing police use of force on the internet or television an average of 34.5 times.

This, said Dr. Motley, isn’t surprising given the growing number of young adults – of all races – who are using social media platforms to upload and share videos.

The researchers also looked at witnessing community violence, unrelated to police violence. Here, respondents had an average of 10.9 exposures.

“These results tell me these individuals are exposed to high levels of violence in their lifetime, which should be alarming,” said Dr. Motley.
 

Protectors or predators?

To examine the impact of police contact anxiety caused either by direct experience, or as a result of witnessing, or seeing a video of police use of violence in the past 30 days, the researchers created a “police contact anxiety” scale.

Respondents were asked six questions pertaining specifically to experiences during, or in anticipation of, police contact and its effects on anxiety levels.

For each of the six questions, participants rated the severity of anxiety on a scale of 0 (least severe) to 3 (most severe) for each exposure type. The final score had a potential range of 0-24.

Results showed police contact anxiety was moderately severe for all three exposure types with scores ranging from 13 to 14.

Ordinary least square regression analyses showed that, compared with unemployed participants, those who worked full time were less likely to have higher police contact anxiety as a result of seeing a video of police use of force (P < .05) – a finding Dr. Motley said was not surprising.

Employment, he noted, promotes individual self-efficacy, social participation, and mental health, which may provide a “buffer” to the effects of watching videos of police violence.

Dr. Motley noted that police officers “have been entrusted to serve and protect” the community, but “rarely face consequences when they use force against Black emergent adults; they’re rarely held accountable.”

These young Black adults “may perceive police officers as more of a threat to personal safety instead of a protector of it.”

Additional bivariate analyses showed that males had significantly higher scores than females for police contact anxiety because of witnessing police use of force.

This, too, was not surprising since males are exposed to more violence in general, said Dr. Motley.

It’s important to replicate the findings using a much larger and more diverse sample, he said. His next research project will be to collect data from a nationally representative sample of emerging adults across different ethnic groups and examining a range of different variables.

Commenting on the findings, Jeffrey Borenstein, MD, president and CEO of the Brain & Behavior Research Foundation and editor in chief of Psychiatric News, called it “outstanding.”

“This is a very important issue,” said Dr. Borenstein, who moderated a press briefing that featured the study.

“We know anxiety is an extremely important condition and symptom, across the board for all groups, and often anxiety isn’t evaluated in the way that it needs to be. This is a great study that will lead to further research in this important area,” he added.

The study was funded by the National Institute on Minority Health and Health Disparities. Dr. Motley and Dr. Borenstein have disclosed no relevant financial relationships.

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

Young Black adults who witness or experience police violence have significantly elevated levels of anxiety, new research shows.

In the first study to quantify the impact of police contact anxiety, investigators found it was associated with moderately severe anxiety levels in this group of individuals, highlighting the need to screen for exposure to police violence in this patient population, study investigator Robert O. Motley Jr, PhD, manager of the Race & Opportunity Lab at Washington University in St. Louis, said in an interview.

“If you’re working in an institution and providing clinical care, mental health care, or behavior health care, these additional measures should be included to get a much more holistic view of the exposure of these individuals in terms of traumatic events. These assessments can inform your decisions around care,” Dr. Motley added.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

‘Alarming’ rates of exposure

Evidence shows anxiety disorders are among the most prevalent conditions for Black people aged 18-29 years – an age group described as “emergent adulthood” because these individuals haven’t yet taken on full responsibilities of adulthood.

Research shows Black emergent adults are three to four times more likely than other ethnic groups to be exposed to actual or threatened nonfatal police violence, said Dr. Motley. “So they didn’t die, but were exposed to force, which could be things like police yelling at them, hitting or kicking them, pointing a gun at them, or tasing them.”

These individuals are also two to three times more likely to experience exposure to fatal police violence, and to be unarmed and killed, said Dr. Motley.

Evidence shows a clear link between exposure to stressful or traumatic events and anxiety disorders, but there has been little research examining the relationship between exposure to police violence and anxiety disorders among Black emergent adults, he said.

To assess the prevalence and correlates of “police contact anxiety” the investigators used computer-assisted surveys to collect data from 300 young Black college students in St. Louis who had been exposed to police violence at some point in their lives. The mean age of the sample was 20.4 years and included an equal number of men and women.

Work status for the previous year showed almost one-quarter (23.6%) were unemployed and about half worked part time. Almost two-thirds (62.6%) had an annual income of less than $10,000.

Respondents reported they had personally experienced police violence almost twice (a mean of 1.89) during their lifetime. The mean number of times they witnessed police using force against someone else was 7.82. Respondents also reported they had watched videos showing police use of force on the internet or television an average of 34.5 times.

This, said Dr. Motley, isn’t surprising given the growing number of young adults – of all races – who are using social media platforms to upload and share videos.

The researchers also looked at witnessing community violence, unrelated to police violence. Here, respondents had an average of 10.9 exposures.

“These results tell me these individuals are exposed to high levels of violence in their lifetime, which should be alarming,” said Dr. Motley.
 

Protectors or predators?

To examine the impact of police contact anxiety caused either by direct experience, or as a result of witnessing, or seeing a video of police use of violence in the past 30 days, the researchers created a “police contact anxiety” scale.

Respondents were asked six questions pertaining specifically to experiences during, or in anticipation of, police contact and its effects on anxiety levels.

For each of the six questions, participants rated the severity of anxiety on a scale of 0 (least severe) to 3 (most severe) for each exposure type. The final score had a potential range of 0-24.

Results showed police contact anxiety was moderately severe for all three exposure types with scores ranging from 13 to 14.

Ordinary least square regression analyses showed that, compared with unemployed participants, those who worked full time were less likely to have higher police contact anxiety as a result of seeing a video of police use of force (P < .05) – a finding Dr. Motley said was not surprising.

Employment, he noted, promotes individual self-efficacy, social participation, and mental health, which may provide a “buffer” to the effects of watching videos of police violence.

Dr. Motley noted that police officers “have been entrusted to serve and protect” the community, but “rarely face consequences when they use force against Black emergent adults; they’re rarely held accountable.”

These young Black adults “may perceive police officers as more of a threat to personal safety instead of a protector of it.”

Additional bivariate analyses showed that males had significantly higher scores than females for police contact anxiety because of witnessing police use of force.

This, too, was not surprising since males are exposed to more violence in general, said Dr. Motley.

It’s important to replicate the findings using a much larger and more diverse sample, he said. His next research project will be to collect data from a nationally representative sample of emerging adults across different ethnic groups and examining a range of different variables.

Commenting on the findings, Jeffrey Borenstein, MD, president and CEO of the Brain & Behavior Research Foundation and editor in chief of Psychiatric News, called it “outstanding.”

“This is a very important issue,” said Dr. Borenstein, who moderated a press briefing that featured the study.

“We know anxiety is an extremely important condition and symptom, across the board for all groups, and often anxiety isn’t evaluated in the way that it needs to be. This is a great study that will lead to further research in this important area,” he added.

The study was funded by the National Institute on Minority Health and Health Disparities. Dr. Motley and Dr. Borenstein have disclosed no relevant financial relationships.

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

Young Black adults who witness or experience police violence have significantly elevated levels of anxiety, new research shows.

In the first study to quantify the impact of police contact anxiety, investigators found it was associated with moderately severe anxiety levels in this group of individuals, highlighting the need to screen for exposure to police violence in this patient population, study investigator Robert O. Motley Jr, PhD, manager of the Race & Opportunity Lab at Washington University in St. Louis, said in an interview.

“If you’re working in an institution and providing clinical care, mental health care, or behavior health care, these additional measures should be included to get a much more holistic view of the exposure of these individuals in terms of traumatic events. These assessments can inform your decisions around care,” Dr. Motley added.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

‘Alarming’ rates of exposure

Evidence shows anxiety disorders are among the most prevalent conditions for Black people aged 18-29 years – an age group described as “emergent adulthood” because these individuals haven’t yet taken on full responsibilities of adulthood.

Research shows Black emergent adults are three to four times more likely than other ethnic groups to be exposed to actual or threatened nonfatal police violence, said Dr. Motley. “So they didn’t die, but were exposed to force, which could be things like police yelling at them, hitting or kicking them, pointing a gun at them, or tasing them.”

These individuals are also two to three times more likely to experience exposure to fatal police violence, and to be unarmed and killed, said Dr. Motley.

Evidence shows a clear link between exposure to stressful or traumatic events and anxiety disorders, but there has been little research examining the relationship between exposure to police violence and anxiety disorders among Black emergent adults, he said.

To assess the prevalence and correlates of “police contact anxiety” the investigators used computer-assisted surveys to collect data from 300 young Black college students in St. Louis who had been exposed to police violence at some point in their lives. The mean age of the sample was 20.4 years and included an equal number of men and women.

Work status for the previous year showed almost one-quarter (23.6%) were unemployed and about half worked part time. Almost two-thirds (62.6%) had an annual income of less than $10,000.

Respondents reported they had personally experienced police violence almost twice (a mean of 1.89) during their lifetime. The mean number of times they witnessed police using force against someone else was 7.82. Respondents also reported they had watched videos showing police use of force on the internet or television an average of 34.5 times.

This, said Dr. Motley, isn’t surprising given the growing number of young adults – of all races – who are using social media platforms to upload and share videos.

The researchers also looked at witnessing community violence, unrelated to police violence. Here, respondents had an average of 10.9 exposures.

“These results tell me these individuals are exposed to high levels of violence in their lifetime, which should be alarming,” said Dr. Motley.
 

Protectors or predators?

To examine the impact of police contact anxiety caused either by direct experience, or as a result of witnessing, or seeing a video of police use of violence in the past 30 days, the researchers created a “police contact anxiety” scale.

Respondents were asked six questions pertaining specifically to experiences during, or in anticipation of, police contact and its effects on anxiety levels.

For each of the six questions, participants rated the severity of anxiety on a scale of 0 (least severe) to 3 (most severe) for each exposure type. The final score had a potential range of 0-24.

Results showed police contact anxiety was moderately severe for all three exposure types with scores ranging from 13 to 14.

Ordinary least square regression analyses showed that, compared with unemployed participants, those who worked full time were less likely to have higher police contact anxiety as a result of seeing a video of police use of force (P < .05) – a finding Dr. Motley said was not surprising.

Employment, he noted, promotes individual self-efficacy, social participation, and mental health, which may provide a “buffer” to the effects of watching videos of police violence.

Dr. Motley noted that police officers “have been entrusted to serve and protect” the community, but “rarely face consequences when they use force against Black emergent adults; they’re rarely held accountable.”

These young Black adults “may perceive police officers as more of a threat to personal safety instead of a protector of it.”

Additional bivariate analyses showed that males had significantly higher scores than females for police contact anxiety because of witnessing police use of force.

This, too, was not surprising since males are exposed to more violence in general, said Dr. Motley.

It’s important to replicate the findings using a much larger and more diverse sample, he said. His next research project will be to collect data from a nationally representative sample of emerging adults across different ethnic groups and examining a range of different variables.

Commenting on the findings, Jeffrey Borenstein, MD, president and CEO of the Brain & Behavior Research Foundation and editor in chief of Psychiatric News, called it “outstanding.”

“This is a very important issue,” said Dr. Borenstein, who moderated a press briefing that featured the study.

“We know anxiety is an extremely important condition and symptom, across the board for all groups, and often anxiety isn’t evaluated in the way that it needs to be. This is a great study that will lead to further research in this important area,” he added.

The study was funded by the National Institute on Minority Health and Health Disparities. Dr. Motley and Dr. Borenstein have disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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.

LPETTET/Getty Images

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.

“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.

“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.”

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.

LPETTET/Getty Images

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.

“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.

“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.”

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.

LPETTET/Getty Images

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.

“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.

“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.”

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.

Cigarette smoking is common among patients with schizophrenia, mood disorders, anxiety disorders,^1-3 substance use disorders (SUDs),⁴ and other psychiatric disorders. Research suggests that compared with the general population, patients with SUDs consume more nicotine products and are more vulnerable to the effects of smoking.⁵ Despite the availability of effective treatments, many mental health professionals are reluctant to identify and treat tobacco use disorder,^6-8 or they prioritize other disorders over tobacco use. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illness.

Cotinine is a biomarker that can be used to detect tobacco use. It can be measured in routine clinical practice by collecting urinary, serum, or salivary specimens, and used to monitor psychiatric patients’ tobacco use. Monitoring cotinine levels is similar to using other biomarkers to assess medication adherence or identify illicit substance use. A growing body of evidence supports the utility of cotinine screening as a part of a comprehensive substance use disorder treatment plan,^5,9,10 especially for:

• patients who have comorbid conditions that can be exacerbated by tobacco use, such as chronic obstructive pulmonary disease
• patients who are pregnant^11,12
• patients who are less reliable in self-report or who require objective testing for validation.

Routine clinical screening of tobacco use is recommended for all patients and early detection may facilitate earlier treatment. Several FDA-approved medications are available for smoking cessation¹³; however, discussion of treatment options is beyond the scope of this review. In this article, we describe how cotinine is measured and analyzed, 3 case vignettes that illustrate its potential clinical utility, and limitations to its use as a biomarker of tobacco use.

Methods of measuring cotinine

Cigarette smoking is associated with the absorption of nicotine, which is mainly metabolized by cytochrome P450 (CYP) 2A6 to 6 primary metabolites: cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine oxide, and nicotine oxide.^14,15 Cotinine is the biomarker of choice for detecting use of tobacco/nicotine products due to its stability (it is not influenced by dietary or environmental factors), extended half-life (16 to 19 hours, compared with 2 hours for nicotine), and stable concentration throughout the day. Samples from saliva, urine, or blood can be analyzed through radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and gas/liquid chromatography.¹⁶ The specificity of cotinine for tobacco use is excellent, except for persons who are taking medications that contain nicotine.¹⁷

An advantage of cotinine over other biomarkers for smoking (such as carbon monoxide in expired air) is that the optimal cut-off points for cotinine are relatively uninfluenced by the prevalence of smoking in the population. The optimal cut-off levels used to detect current tobacco use may vary based on the sample or test used (saliva, urine, or plasma) and certain patient-specific factors (Box 1^11,16,18-21). However, for plasma or saliva cotinine, 16 ng/mL is the generally accepted cut-off level for detecting current tobacco use. A urinary cotinine cut-off level of 50 ng/mL is likely appropriate for most circumstances.¹⁷ Users of electronic nicotine delivery systems (electronic cigarettes) have been found to have cotinine levels similar to those of cigarette smokers.²²

Box 1

Assessment of cotinine levels in saliva may be considered for outpatient monitoring due to its noninvasive nature, tolerability, and the ability to collect multiple samples over a limited period.²³ Saliva cotinine levels correlate closely with blood concentrations. Urine cotinine levels offer some advantage because concentrations are 6 times higher in urine than in blood or saliva. For this reason, urine cotinine is the most widely used biomarker in individuals who use tobacco due to its high sensitivity, specificity, reliability, and noninvasive collection.²³ By using a lower urinary cut-off of ≥2.47 ng/mL, ELISA kits detect the highest sensitivity and specificity, which is useful for monitoring daily tobacco use.²⁴ This cut-off value was associated with 100% sensitivity and specificity, and these numbers declined with increases in the cut-off threshold.²³

Impact of cigarette smoking

The following 3 clinical vignettes illustrate the impact of tobacco use disorder on patients, and how cotinine might help with their treatment.

Continue to: Vignette 1

Mr. D, age 44, has a history of schizophrenia and has smoked 1 pack of cigarettes per day for the last 15 years. He was recently discharged from an inpatient psychiatric facility after his symptoms were stabilized. During his hospitalization, Mr. D used a nicotine-replacement product to comply with the hospital’s smoke-free policy. Unfortunately, since discharge, Mr. D reports worsening auditory hallucinations despite adherence with his antipsychotic medication, clozapine, 600 mg at bedtime. Collateral information gathered from Mr. D’s mother confirms that he has been adherent with the discharge medication regimen; however, Mr. D has resumed smoking 1 pack of cigarettes daily. The treatment team suspects that his worsening psychosis is related to the decrease of blood clozapine level due to CYP induction by cigarette smoke.

Cotinine and smoking-related drug interactions

Vignette 1 illustrates the significant impact tobacco smoke can have on the effectiveness of a psychotropic medication. This is caused by polycyclic aromatic hydrocarbons induction of hepatic CYP1A2 isoenzymes. Clinicians should routinely screen patients for smoking status due to the potential for drug interactions. Common major CYP1A2 substrates include clozapine, olanzapine, duloxetine, and mirtazapine. Common minor CYP1A2 substrates include asenapine, chlorpromazine, haloperidol, perphenazine, ziprasidone, and zolpidem.²⁵ This case also highlights the potential advantage of collecting collateral information, and the utility of objective laboratory testing (such as cotinine monitoring) for optimal treatment because patient self-report can be unreliable and incomplete.^12,26

Vignette 2

Mr. B, age 34, has a history of cocaine use disorder and tobacco use disorder. He is referred to a treatment program and participates in a contingency management program for his substance use disorders. Biomarkers, including salivary cotinine, are used to assess Mr. B’s exposure to tobacco use. Mr. B and other participants in his program are eligible for prize draws if they are found to have samples that are negative for tobacco and other substances. There are other incentives in place for patients who show a reduced cotinine concentration.

Cotinine monitoring and contingency management

Clinicians can incorporate cotinine monitoring into existing SUD treatment. This is similar to the utilization of other biomarkers that are commonly used to identify recent illicit substance use or monitor adherence to treatment medications. For example, benzoylecgonine, a metabolite of cocaine, is frequently used to monitor abstinence from cocaine.²⁷ In addition, buprenorphine metabolites are used to monitor medication adherence and the possibility of diversion among patients being treated for opioid use disorder.²⁸ Smoking cessation may be associated with a decreased risk of relapse to illicit substances.²⁹

Treatments based on contingency management principles involve giving patients tangible rewards to reinforce desired (positive) behaviors. Smoking cessation can be confirmed by monitoring cotinine levels. Gayman et al⁹ found twice-weekly salivary testing was compatible with monitoring and promoting abstinence in a prize-based contingency management smoking cessation program. Most prior studies used urine cotinine measures to verify abstinence. Although highly reliable, urine samples require close monitoring to ensure sample validity, which can be a burden on staff and unpleasant for patients.⁹ It is also important to note that the rate of elimination of cotinine from saliva and urine are comparable. The half-life of cotinine is approximately 18 hours, and therefore the specificity of salivary test strips may be impacted during the first 4 to 5 days of abstinence. In the first few days of smoking cessation, a more intensive approach, such as quantifying urine cotinine levels and monitoring decline, may be appropriate.²³

Continue to: Vignette 3

Vignette 3

Ms. C, age 34 and pregnant, is admitted to an outpatient treatment program for alcohol use disorder. She also has generalized anxiety disorder and tobacco use disorder. In addition to attending group therapy sessions and self-reporting any recent alcohol consumption, Ms. C also undergoes alcohol breathalyzer tests and urine studies of alcohol metabolites to monitor abstinence from alcohol. She says that the regular laboratory screening for alcohol use gives her a sense of accountability and tangible evidence of change that positively impacts her treatment. When the treating psychiatrist recommends that Ms. C also consider addressing her tobacco use disorder, she asks if there is some way to include laboratory testing to monitor her smoking cessation.

Cotinine as a predictor of smoking status

Smoking abstinence rates during pregnancy are lower than that for other substances, and pregnant women may not be aware of the impact of smoking on fetal development.³⁰ Cotinine can be used to verify self-report of smoking status and severity.^10,31,32

Salivary cotinine tests are commercially available, relatively economical, and convenient to use when frequent monitoring is required.³² In general, based on established cut-off values that are unique to the specimen collected, the overall high specificity and sensitivity of salivary testing allows clinicians to predict smoker vs nonsmoker status with confidence. For example, a 2008 study reported a salivary cotinine cut-off level of 12 ng/mL for smokers.²¹ The sensitivity and specificity of this cut-off value for distinguishing cigarette smokers from never smokers were 96.7% and 96.9%, respectively.²¹

Additionally, some studies suggest that cotinine levels may be predictive of treatment outcomes and retention in SUD treatment programs.^33,34 One study of smoking cessation using nicotine replacement products found that compared with patients with lower baseline cotinine levels prior to treatment, patients with higher baseline cotinine plasma levels had lower smoking cessation success rates.³⁴

A few caveats

There are several limitations to quantitative measures of cotinine (Box 2^21,23). These include (but are not limited to) potential errors related to sample collection, storage, shipping, and analysis.²³ Compared with other methods, point-of-care cotinine measurement in saliva is noninvasive, simple, and requires less training to properly use.²³

Box 2

Continue to: Confirmation of smoking cessation...

Confirmation of smoking cessation can be monitored reliably within the clinical setting using cotinine monitoring. However, this is not a routine test, and there are no guidelines or consensus on how or when it should be used. The clinical feasibility of cotinine monitoring for psychiatric patients will depend on the cost of testing, methods used, amount of reimbursement for performing the tests, and how clinicians value such testing.³⁵

Bottom Line

Cotinine is a biomarker that can be used to detect tobacco use. Cotinine measurement can be used to monitor tobacco use and smoking cessation in psychiatric patients. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illnesses. However, cotinine measurement is not a routine test, and there are no guidelines on how or when this test should be used.

Related Resources

• Peckham E, Brabyn S, Cook L, et al. Smoking cessation in severe mental ill health: what works? An updated systematic review and meta-analysis. BMC Psychiatry. 2017;17(1):252.
• Tidey JW, Miller ME. Smoking cessation and reduction in people with chronic mental illness. BMJ. 2015;351:h4065. doi: 10.1136/bmj.h4065

Drug Brand Names

Asenapine • Saphris
Buprenorphine • Sublocade
Clozapine • Clozaril
Duloxetine • Cymbalta
Haloperidol • Haldol
Mirtazapine • Remeron
Olanzapine • Zyprexa
Ziprasidone • Geodon
Zolpidem • Ambien

Cigarette smoking is common among patients with schizophrenia, mood disorders, anxiety disorders,^1-3 substance use disorders (SUDs),⁴ and other psychiatric disorders. Research suggests that compared with the general population, patients with SUDs consume more nicotine products and are more vulnerable to the effects of smoking.⁵ Despite the availability of effective treatments, many mental health professionals are reluctant to identify and treat tobacco use disorder,^6-8 or they prioritize other disorders over tobacco use. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illness.

Cotinine is a biomarker that can be used to detect tobacco use. It can be measured in routine clinical practice by collecting urinary, serum, or salivary specimens, and used to monitor psychiatric patients’ tobacco use. Monitoring cotinine levels is similar to using other biomarkers to assess medication adherence or identify illicit substance use. A growing body of evidence supports the utility of cotinine screening as a part of a comprehensive substance use disorder treatment plan,^5,9,10 especially for:

• patients who have comorbid conditions that can be exacerbated by tobacco use, such as chronic obstructive pulmonary disease
• patients who are pregnant^11,12
• patients who are less reliable in self-report or who require objective testing for validation.

Routine clinical screening of tobacco use is recommended for all patients and early detection may facilitate earlier treatment. Several FDA-approved medications are available for smoking cessation¹³; however, discussion of treatment options is beyond the scope of this review. In this article, we describe how cotinine is measured and analyzed, 3 case vignettes that illustrate its potential clinical utility, and limitations to its use as a biomarker of tobacco use.

Methods of measuring cotinine

Cigarette smoking is associated with the absorption of nicotine, which is mainly metabolized by cytochrome P450 (CYP) 2A6 to 6 primary metabolites: cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine oxide, and nicotine oxide.^14,15 Cotinine is the biomarker of choice for detecting use of tobacco/nicotine products due to its stability (it is not influenced by dietary or environmental factors), extended half-life (16 to 19 hours, compared with 2 hours for nicotine), and stable concentration throughout the day. Samples from saliva, urine, or blood can be analyzed through radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and gas/liquid chromatography.¹⁶ The specificity of cotinine for tobacco use is excellent, except for persons who are taking medications that contain nicotine.¹⁷

An advantage of cotinine over other biomarkers for smoking (such as carbon monoxide in expired air) is that the optimal cut-off points for cotinine are relatively uninfluenced by the prevalence of smoking in the population. The optimal cut-off levels used to detect current tobacco use may vary based on the sample or test used (saliva, urine, or plasma) and certain patient-specific factors (Box 1^11,16,18-21). However, for plasma or saliva cotinine, 16 ng/mL is the generally accepted cut-off level for detecting current tobacco use. A urinary cotinine cut-off level of 50 ng/mL is likely appropriate for most circumstances.¹⁷ Users of electronic nicotine delivery systems (electronic cigarettes) have been found to have cotinine levels similar to those of cigarette smokers.²²

Box 1

Assessment of cotinine levels in saliva may be considered for outpatient monitoring due to its noninvasive nature, tolerability, and the ability to collect multiple samples over a limited period.²³ Saliva cotinine levels correlate closely with blood concentrations. Urine cotinine levels offer some advantage because concentrations are 6 times higher in urine than in blood or saliva. For this reason, urine cotinine is the most widely used biomarker in individuals who use tobacco due to its high sensitivity, specificity, reliability, and noninvasive collection.²³ By using a lower urinary cut-off of ≥2.47 ng/mL, ELISA kits detect the highest sensitivity and specificity, which is useful for monitoring daily tobacco use.²⁴ This cut-off value was associated with 100% sensitivity and specificity, and these numbers declined with increases in the cut-off threshold.²³

Impact of cigarette smoking

The following 3 clinical vignettes illustrate the impact of tobacco use disorder on patients, and how cotinine might help with their treatment.

Continue to: Vignette 1

Mr. D, age 44, has a history of schizophrenia and has smoked 1 pack of cigarettes per day for the last 15 years. He was recently discharged from an inpatient psychiatric facility after his symptoms were stabilized. During his hospitalization, Mr. D used a nicotine-replacement product to comply with the hospital’s smoke-free policy. Unfortunately, since discharge, Mr. D reports worsening auditory hallucinations despite adherence with his antipsychotic medication, clozapine, 600 mg at bedtime. Collateral information gathered from Mr. D’s mother confirms that he has been adherent with the discharge medication regimen; however, Mr. D has resumed smoking 1 pack of cigarettes daily. The treatment team suspects that his worsening psychosis is related to the decrease of blood clozapine level due to CYP induction by cigarette smoke.

Cotinine and smoking-related drug interactions

Vignette 1 illustrates the significant impact tobacco smoke can have on the effectiveness of a psychotropic medication. This is caused by polycyclic aromatic hydrocarbons induction of hepatic CYP1A2 isoenzymes. Clinicians should routinely screen patients for smoking status due to the potential for drug interactions. Common major CYP1A2 substrates include clozapine, olanzapine, duloxetine, and mirtazapine. Common minor CYP1A2 substrates include asenapine, chlorpromazine, haloperidol, perphenazine, ziprasidone, and zolpidem.²⁵ This case also highlights the potential advantage of collecting collateral information, and the utility of objective laboratory testing (such as cotinine monitoring) for optimal treatment because patient self-report can be unreliable and incomplete.^12,26

Vignette 2

Mr. B, age 34, has a history of cocaine use disorder and tobacco use disorder. He is referred to a treatment program and participates in a contingency management program for his substance use disorders. Biomarkers, including salivary cotinine, are used to assess Mr. B’s exposure to tobacco use. Mr. B and other participants in his program are eligible for prize draws if they are found to have samples that are negative for tobacco and other substances. There are other incentives in place for patients who show a reduced cotinine concentration.

Cotinine monitoring and contingency management

Clinicians can incorporate cotinine monitoring into existing SUD treatment. This is similar to the utilization of other biomarkers that are commonly used to identify recent illicit substance use or monitor adherence to treatment medications. For example, benzoylecgonine, a metabolite of cocaine, is frequently used to monitor abstinence from cocaine.²⁷ In addition, buprenorphine metabolites are used to monitor medication adherence and the possibility of diversion among patients being treated for opioid use disorder.²⁸ Smoking cessation may be associated with a decreased risk of relapse to illicit substances.²⁹

Treatments based on contingency management principles involve giving patients tangible rewards to reinforce desired (positive) behaviors. Smoking cessation can be confirmed by monitoring cotinine levels. Gayman et al⁹ found twice-weekly salivary testing was compatible with monitoring and promoting abstinence in a prize-based contingency management smoking cessation program. Most prior studies used urine cotinine measures to verify abstinence. Although highly reliable, urine samples require close monitoring to ensure sample validity, which can be a burden on staff and unpleasant for patients.⁹ It is also important to note that the rate of elimination of cotinine from saliva and urine are comparable. The half-life of cotinine is approximately 18 hours, and therefore the specificity of salivary test strips may be impacted during the first 4 to 5 days of abstinence. In the first few days of smoking cessation, a more intensive approach, such as quantifying urine cotinine levels and monitoring decline, may be appropriate.²³

Continue to: Vignette 3

Vignette 3

Ms. C, age 34 and pregnant, is admitted to an outpatient treatment program for alcohol use disorder. She also has generalized anxiety disorder and tobacco use disorder. In addition to attending group therapy sessions and self-reporting any recent alcohol consumption, Ms. C also undergoes alcohol breathalyzer tests and urine studies of alcohol metabolites to monitor abstinence from alcohol. She says that the regular laboratory screening for alcohol use gives her a sense of accountability and tangible evidence of change that positively impacts her treatment. When the treating psychiatrist recommends that Ms. C also consider addressing her tobacco use disorder, she asks if there is some way to include laboratory testing to monitor her smoking cessation.

Cotinine as a predictor of smoking status

Smoking abstinence rates during pregnancy are lower than that for other substances, and pregnant women may not be aware of the impact of smoking on fetal development.³⁰ Cotinine can be used to verify self-report of smoking status and severity.^10,31,32

Salivary cotinine tests are commercially available, relatively economical, and convenient to use when frequent monitoring is required.³² In general, based on established cut-off values that are unique to the specimen collected, the overall high specificity and sensitivity of salivary testing allows clinicians to predict smoker vs nonsmoker status with confidence. For example, a 2008 study reported a salivary cotinine cut-off level of 12 ng/mL for smokers.²¹ The sensitivity and specificity of this cut-off value for distinguishing cigarette smokers from never smokers were 96.7% and 96.9%, respectively.²¹

Additionally, some studies suggest that cotinine levels may be predictive of treatment outcomes and retention in SUD treatment programs.^33,34 One study of smoking cessation using nicotine replacement products found that compared with patients with lower baseline cotinine levels prior to treatment, patients with higher baseline cotinine plasma levels had lower smoking cessation success rates.³⁴

A few caveats

There are several limitations to quantitative measures of cotinine (Box 2^21,23). These include (but are not limited to) potential errors related to sample collection, storage, shipping, and analysis.²³ Compared with other methods, point-of-care cotinine measurement in saliva is noninvasive, simple, and requires less training to properly use.²³

Box 2

Continue to: Confirmation of smoking cessation...

Confirmation of smoking cessation can be monitored reliably within the clinical setting using cotinine monitoring. However, this is not a routine test, and there are no guidelines or consensus on how or when it should be used. The clinical feasibility of cotinine monitoring for psychiatric patients will depend on the cost of testing, methods used, amount of reimbursement for performing the tests, and how clinicians value such testing.³⁵

Bottom Line

Cotinine is a biomarker that can be used to detect tobacco use. Cotinine measurement can be used to monitor tobacco use and smoking cessation in psychiatric patients. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illnesses. However, cotinine measurement is not a routine test, and there are no guidelines on how or when this test should be used.

Related Resources

• Peckham E, Brabyn S, Cook L, et al. Smoking cessation in severe mental ill health: what works? An updated systematic review and meta-analysis. BMC Psychiatry. 2017;17(1):252.
• Tidey JW, Miller ME. Smoking cessation and reduction in people with chronic mental illness. BMJ. 2015;351:h4065. doi: 10.1136/bmj.h4065

Drug Brand Names

Asenapine • Saphris
Buprenorphine • Sublocade
Clozapine • Clozaril
Duloxetine • Cymbalta
Haloperidol • Haldol
Mirtazapine • Remeron
Olanzapine • Zyprexa
Ziprasidone • Geodon
Zolpidem • Ambien

Cigarette smoking is common among patients with schizophrenia, mood disorders, anxiety disorders,^1-3 substance use disorders (SUDs),⁴ and other psychiatric disorders. Research suggests that compared with the general population, patients with SUDs consume more nicotine products and are more vulnerable to the effects of smoking.⁵ Despite the availability of effective treatments, many mental health professionals are reluctant to identify and treat tobacco use disorder,^6-8 or they prioritize other disorders over tobacco use. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illness.

Cotinine is a biomarker that can be used to detect tobacco use. It can be measured in routine clinical practice by collecting urinary, serum, or salivary specimens, and used to monitor psychiatric patients’ tobacco use. Monitoring cotinine levels is similar to using other biomarkers to assess medication adherence or identify illicit substance use. A growing body of evidence supports the utility of cotinine screening as a part of a comprehensive substance use disorder treatment plan,^5,9,10 especially for:

• patients who have comorbid conditions that can be exacerbated by tobacco use, such as chronic obstructive pulmonary disease
• patients who are pregnant^11,12
• patients who are less reliable in self-report or who require objective testing for validation.

Routine clinical screening of tobacco use is recommended for all patients and early detection may facilitate earlier treatment. Several FDA-approved medications are available for smoking cessation¹³; however, discussion of treatment options is beyond the scope of this review. In this article, we describe how cotinine is measured and analyzed, 3 case vignettes that illustrate its potential clinical utility, and limitations to its use as a biomarker of tobacco use.

Methods of measuring cotinine

Cigarette smoking is associated with the absorption of nicotine, which is mainly metabolized by cytochrome P450 (CYP) 2A6 to 6 primary metabolites: cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine oxide, and nicotine oxide.^14,15 Cotinine is the biomarker of choice for detecting use of tobacco/nicotine products due to its stability (it is not influenced by dietary or environmental factors), extended half-life (16 to 19 hours, compared with 2 hours for nicotine), and stable concentration throughout the day. Samples from saliva, urine, or blood can be analyzed through radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and gas/liquid chromatography.¹⁶ The specificity of cotinine for tobacco use is excellent, except for persons who are taking medications that contain nicotine.¹⁷

An advantage of cotinine over other biomarkers for smoking (such as carbon monoxide in expired air) is that the optimal cut-off points for cotinine are relatively uninfluenced by the prevalence of smoking in the population. The optimal cut-off levels used to detect current tobacco use may vary based on the sample or test used (saliva, urine, or plasma) and certain patient-specific factors (Box 1^11,16,18-21). However, for plasma or saliva cotinine, 16 ng/mL is the generally accepted cut-off level for detecting current tobacco use. A urinary cotinine cut-off level of 50 ng/mL is likely appropriate for most circumstances.¹⁷ Users of electronic nicotine delivery systems (electronic cigarettes) have been found to have cotinine levels similar to those of cigarette smokers.²²

Box 1

Assessment of cotinine levels in saliva may be considered for outpatient monitoring due to its noninvasive nature, tolerability, and the ability to collect multiple samples over a limited period.²³ Saliva cotinine levels correlate closely with blood concentrations. Urine cotinine levels offer some advantage because concentrations are 6 times higher in urine than in blood or saliva. For this reason, urine cotinine is the most widely used biomarker in individuals who use tobacco due to its high sensitivity, specificity, reliability, and noninvasive collection.²³ By using a lower urinary cut-off of ≥2.47 ng/mL, ELISA kits detect the highest sensitivity and specificity, which is useful for monitoring daily tobacco use.²⁴ This cut-off value was associated with 100% sensitivity and specificity, and these numbers declined with increases in the cut-off threshold.²³

Impact of cigarette smoking

The following 3 clinical vignettes illustrate the impact of tobacco use disorder on patients, and how cotinine might help with their treatment.

Continue to: Vignette 1

Mr. D, age 44, has a history of schizophrenia and has smoked 1 pack of cigarettes per day for the last 15 years. He was recently discharged from an inpatient psychiatric facility after his symptoms were stabilized. During his hospitalization, Mr. D used a nicotine-replacement product to comply with the hospital’s smoke-free policy. Unfortunately, since discharge, Mr. D reports worsening auditory hallucinations despite adherence with his antipsychotic medication, clozapine, 600 mg at bedtime. Collateral information gathered from Mr. D’s mother confirms that he has been adherent with the discharge medication regimen; however, Mr. D has resumed smoking 1 pack of cigarettes daily. The treatment team suspects that his worsening psychosis is related to the decrease of blood clozapine level due to CYP induction by cigarette smoke.

Cotinine and smoking-related drug interactions

Vignette 1 illustrates the significant impact tobacco smoke can have on the effectiveness of a psychotropic medication. This is caused by polycyclic aromatic hydrocarbons induction of hepatic CYP1A2 isoenzymes. Clinicians should routinely screen patients for smoking status due to the potential for drug interactions. Common major CYP1A2 substrates include clozapine, olanzapine, duloxetine, and mirtazapine. Common minor CYP1A2 substrates include asenapine, chlorpromazine, haloperidol, perphenazine, ziprasidone, and zolpidem.²⁵ This case also highlights the potential advantage of collecting collateral information, and the utility of objective laboratory testing (such as cotinine monitoring) for optimal treatment because patient self-report can be unreliable and incomplete.^12,26

Vignette 2

Mr. B, age 34, has a history of cocaine use disorder and tobacco use disorder. He is referred to a treatment program and participates in a contingency management program for his substance use disorders. Biomarkers, including salivary cotinine, are used to assess Mr. B’s exposure to tobacco use. Mr. B and other participants in his program are eligible for prize draws if they are found to have samples that are negative for tobacco and other substances. There are other incentives in place for patients who show a reduced cotinine concentration.

Cotinine monitoring and contingency management

Clinicians can incorporate cotinine monitoring into existing SUD treatment. This is similar to the utilization of other biomarkers that are commonly used to identify recent illicit substance use or monitor adherence to treatment medications. For example, benzoylecgonine, a metabolite of cocaine, is frequently used to monitor abstinence from cocaine.²⁷ In addition, buprenorphine metabolites are used to monitor medication adherence and the possibility of diversion among patients being treated for opioid use disorder.²⁸ Smoking cessation may be associated with a decreased risk of relapse to illicit substances.²⁹

Treatments based on contingency management principles involve giving patients tangible rewards to reinforce desired (positive) behaviors. Smoking cessation can be confirmed by monitoring cotinine levels. Gayman et al⁹ found twice-weekly salivary testing was compatible with monitoring and promoting abstinence in a prize-based contingency management smoking cessation program. Most prior studies used urine cotinine measures to verify abstinence. Although highly reliable, urine samples require close monitoring to ensure sample validity, which can be a burden on staff and unpleasant for patients.⁹ It is also important to note that the rate of elimination of cotinine from saliva and urine are comparable. The half-life of cotinine is approximately 18 hours, and therefore the specificity of salivary test strips may be impacted during the first 4 to 5 days of abstinence. In the first few days of smoking cessation, a more intensive approach, such as quantifying urine cotinine levels and monitoring decline, may be appropriate.²³

Continue to: Vignette 3

Vignette 3

Ms. C, age 34 and pregnant, is admitted to an outpatient treatment program for alcohol use disorder. She also has generalized anxiety disorder and tobacco use disorder. In addition to attending group therapy sessions and self-reporting any recent alcohol consumption, Ms. C also undergoes alcohol breathalyzer tests and urine studies of alcohol metabolites to monitor abstinence from alcohol. She says that the regular laboratory screening for alcohol use gives her a sense of accountability and tangible evidence of change that positively impacts her treatment. When the treating psychiatrist recommends that Ms. C also consider addressing her tobacco use disorder, she asks if there is some way to include laboratory testing to monitor her smoking cessation.

Cotinine as a predictor of smoking status

Smoking abstinence rates during pregnancy are lower than that for other substances, and pregnant women may not be aware of the impact of smoking on fetal development.³⁰ Cotinine can be used to verify self-report of smoking status and severity.^10,31,32

Salivary cotinine tests are commercially available, relatively economical, and convenient to use when frequent monitoring is required.³² In general, based on established cut-off values that are unique to the specimen collected, the overall high specificity and sensitivity of salivary testing allows clinicians to predict smoker vs nonsmoker status with confidence. For example, a 2008 study reported a salivary cotinine cut-off level of 12 ng/mL for smokers.²¹ The sensitivity and specificity of this cut-off value for distinguishing cigarette smokers from never smokers were 96.7% and 96.9%, respectively.²¹

Additionally, some studies suggest that cotinine levels may be predictive of treatment outcomes and retention in SUD treatment programs.^33,34 One study of smoking cessation using nicotine replacement products found that compared with patients with lower baseline cotinine levels prior to treatment, patients with higher baseline cotinine plasma levels had lower smoking cessation success rates.³⁴

A few caveats

There are several limitations to quantitative measures of cotinine (Box 2^21,23). These include (but are not limited to) potential errors related to sample collection, storage, shipping, and analysis.²³ Compared with other methods, point-of-care cotinine measurement in saliva is noninvasive, simple, and requires less training to properly use.²³

Box 2

Continue to: Confirmation of smoking cessation...

Confirmation of smoking cessation can be monitored reliably within the clinical setting using cotinine monitoring. However, this is not a routine test, and there are no guidelines or consensus on how or when it should be used. The clinical feasibility of cotinine monitoring for psychiatric patients will depend on the cost of testing, methods used, amount of reimbursement for performing the tests, and how clinicians value such testing.³⁵

Bottom Line

Cotinine is a biomarker that can be used to detect tobacco use. Cotinine measurement can be used to monitor tobacco use and smoking cessation in psychiatric patients. Early detection and treatment of tobacco use disorder can improve patients’ health and reduce the incidence of acute and chronic illnesses. However, cotinine measurement is not a routine test, and there are no guidelines on how or when this test should be used.

Related Resources

• Peckham E, Brabyn S, Cook L, et al. Smoking cessation in severe mental ill health: what works? An updated systematic review and meta-analysis. BMC Psychiatry. 2017;17(1):252.
• Tidey JW, Miller ME. Smoking cessation and reduction in people with chronic mental illness. BMJ. 2015;351:h4065. doi: 10.1136/bmj.h4065

Drug Brand Names

Asenapine • Saphris
Buprenorphine • Sublocade
Clozapine • Clozaril
Duloxetine • Cymbalta
Haloperidol • Haldol
Mirtazapine • Remeron
Olanzapine • Zyprexa
Ziprasidone • Geodon
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Emerging data demonstrate that untreated perinatal anxiety is associated with negative outcomes, including an increased risk for suicide.¹ A 2017 systematic review and meta-analysis that included 102 studies with a total of 221,974 women from 34 countries found that the prevalence of self-reported anxiety symptoms and any anxiety disorder was 22.9% and 15.2%, respectively, across the 3 trimesters.¹ During pregnancy, anxiety disorders (eg, generalized anxiety disorder) and anxiety-related disorders (eg, obsessive-compulsive disorder [OCD] and posttraumatic stress disorder [PTSD]) can present as new illnesses or as a reoccurrence of an existing illness. Patients with pre-existing OCD may notice that the nature of their obsessions is changing. Women with pre-existing PTSD may have their symptoms triggered by pregnancy or delivery or may develop PTSD as a result of a traumatic delivery. Anxiety is frequently comorbid with depression, and high anxiety during pregnancy is one of the strongest risk factors for depression.^1,2

In light of this data, awareness and recognition of perinatal anxiety is critical. In this article, we describe how to accurately assess perinatal anxiety by avoiding assumptions and asking key questions during the clinical interview.

Avoid these common assumptions

Assessment begins with avoiding assumptions typically associated with maternal mental health. One common assumption is that pregnancy is a joyous occasion for all women. Pregnancy can be a stressful time that has its own unique difficulties, including the potential to develop or have a relapse of a mental illness. Another assumption is that the only concern is “postpartum depression.” In actuality, a significant percentage of women will experience depression during their pregnancy (not just in the postpartum period), and many other psychiatric illnesses are common during the perinatal period, including anxiety disorders.

Conduct a focused interview

Risk factors associated with antenatal anxiety include²:

• previous history of mental illness (particularly a history of anxiety and depression and a history of psychiatric treatment)
• lack of partner or social support
• history of abuse or domestic violence
• unplanned or unwanted pregnancy
• adverse events in life and high perceived stress
• present/past pregnancy complications
• pregnancy loss.

Symptoms of anxiety. The presence of anxiety or worrying does not necessarily mean a mother has an anxiety disorder. Using the DSM-5 as a guide, we should use the questions outlined in the following sections to inquire about all of the symptoms related to a particular illness, the pervasiveness of these symptoms, and to what extent these symptoms impair a woman’s ability to function and carry out her usual activities.³

Past psychiatric history. Ask your patient the following: Have you previously experienced anxiety and/or depressive symptoms? Were those symptoms limited only to times when you were pregnant or postpartum? Were your symptoms severe enough to disrupt your life (job, school, relationships, ability to complete daily tasks)? What treatments were effective for your symptoms? What treatments were ineffective?³

Social factors. Learn more about your patient’s support systems by asking: Who do you consider to be part of your social support? How is your relationship with your social support? Are there challenges in your relationship with your friends, family, or partner? If yes, what are those challenges? Are there other children in the home, and do you have support for them? Is your home environment safe? Do you feel that you have what you need for the baby? What stressors are you currently experiencing? Do you attend support groups for expectant mothers? Are you engaged in perinatal care?³

Continue to: Given the high prevalence...

Given the high prevalence of interpersonal violence in women of reproductive age, all patients should be screened for this. The American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women recommends screening for interpersonal violence at the first visit during the perinatal period, during each trimester, and at the postpartum visit (at minimum).⁴ Potential screening questions include (but are not limited to): Have you and/or your children ever been threatened by or felt afraid of your partner? When you argue with your partner, do either of you get physical? Has your partner ever physically hurt you (eg, hit, choked)? Do you feel safe at home? Do you have a safe place to go with resources you and your children will need in case of an emergency?^4-6

Feelings toward pregnancy, past/current pregnancy complications, and pregnancy loss. Ask your patient: Was this pregnancy planned? How do you feel about your pregnancy? How do you see yourself as a mother? Do you currently have pregnancy complications and/or have had them in the past, and, if so, what are/were they? Have you lost a pregnancy? If so, what was that like? Do you have fears related to childbirth, and, if so, what are they?³

Intrusive thoughts about harming the baby. Intrusive thoughts are common in postpartum women with anxiety disorders, including OCD.⁷ Merely asking patients if they’ve had thoughts of harming their baby is incomplete and insufficient to assess for intrusive thoughts. This question does not distinguish between intrusive thoughts and homicidal ideation; this distinction is absolutely necessary given the difference in potential risk to the infant.

Intrusive thoughts are generally associated with a low risk of mothers acting on their thoughts. These thoughts are typically ego dystonic and, in the most severe form, can be distressing to an extent that they cause behavioral changes, such as avoiding bathing the infant, avoiding diaper changes, avoiding knives, or separating themselves from the infant.⁷ On the contrary, having homicidal ideation carries a higher risk for harm to the infant. Homicidal ideation may be seen in patients with co-occurring psychosis, poor reality testing, and delusions.^5,7

Questions such as “Do you worry about harm coming to your baby?” “Do you worry about you causing harm to your baby?” and “Have you had an upsetting thought about harming your baby?” are more likely to reveal intrusive thoughts and prompt further exploration. Statements such as “Some people tell me that they have distressing thoughts about harm coming to their baby” can gently open the door to a having a dialogue about such thoughts. This dialogue is significantly important in making informed assessments as we develop comprehensive treatment plans.

Emerging data demonstrate that untreated perinatal anxiety is associated with negative outcomes, including an increased risk for suicide.¹ A 2017 systematic review and meta-analysis that included 102 studies with a total of 221,974 women from 34 countries found that the prevalence of self-reported anxiety symptoms and any anxiety disorder was 22.9% and 15.2%, respectively, across the 3 trimesters.¹ During pregnancy, anxiety disorders (eg, generalized anxiety disorder) and anxiety-related disorders (eg, obsessive-compulsive disorder [OCD] and posttraumatic stress disorder [PTSD]) can present as new illnesses or as a reoccurrence of an existing illness. Patients with pre-existing OCD may notice that the nature of their obsessions is changing. Women with pre-existing PTSD may have their symptoms triggered by pregnancy or delivery or may develop PTSD as a result of a traumatic delivery. Anxiety is frequently comorbid with depression, and high anxiety during pregnancy is one of the strongest risk factors for depression.^1,2

In light of this data, awareness and recognition of perinatal anxiety is critical. In this article, we describe how to accurately assess perinatal anxiety by avoiding assumptions and asking key questions during the clinical interview.

Avoid these common assumptions

Assessment begins with avoiding assumptions typically associated with maternal mental health. One common assumption is that pregnancy is a joyous occasion for all women. Pregnancy can be a stressful time that has its own unique difficulties, including the potential to develop or have a relapse of a mental illness. Another assumption is that the only concern is “postpartum depression.” In actuality, a significant percentage of women will experience depression during their pregnancy (not just in the postpartum period), and many other psychiatric illnesses are common during the perinatal period, including anxiety disorders.

Conduct a focused interview

Risk factors associated with antenatal anxiety include²:

• previous history of mental illness (particularly a history of anxiety and depression and a history of psychiatric treatment)
• lack of partner or social support
• history of abuse or domestic violence
• unplanned or unwanted pregnancy
• adverse events in life and high perceived stress
• present/past pregnancy complications
• pregnancy loss.

Symptoms of anxiety. The presence of anxiety or worrying does not necessarily mean a mother has an anxiety disorder. Using the DSM-5 as a guide, we should use the questions outlined in the following sections to inquire about all of the symptoms related to a particular illness, the pervasiveness of these symptoms, and to what extent these symptoms impair a woman’s ability to function and carry out her usual activities.³

Past psychiatric history. Ask your patient the following: Have you previously experienced anxiety and/or depressive symptoms? Were those symptoms limited only to times when you were pregnant or postpartum? Were your symptoms severe enough to disrupt your life (job, school, relationships, ability to complete daily tasks)? What treatments were effective for your symptoms? What treatments were ineffective?³

Social factors. Learn more about your patient’s support systems by asking: Who do you consider to be part of your social support? How is your relationship with your social support? Are there challenges in your relationship with your friends, family, or partner? If yes, what are those challenges? Are there other children in the home, and do you have support for them? Is your home environment safe? Do you feel that you have what you need for the baby? What stressors are you currently experiencing? Do you attend support groups for expectant mothers? Are you engaged in perinatal care?³

Continue to: Given the high prevalence...

Given the high prevalence of interpersonal violence in women of reproductive age, all patients should be screened for this. The American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women recommends screening for interpersonal violence at the first visit during the perinatal period, during each trimester, and at the postpartum visit (at minimum).⁴ Potential screening questions include (but are not limited to): Have you and/or your children ever been threatened by or felt afraid of your partner? When you argue with your partner, do either of you get physical? Has your partner ever physically hurt you (eg, hit, choked)? Do you feel safe at home? Do you have a safe place to go with resources you and your children will need in case of an emergency?^4-6

Feelings toward pregnancy, past/current pregnancy complications, and pregnancy loss. Ask your patient: Was this pregnancy planned? How do you feel about your pregnancy? How do you see yourself as a mother? Do you currently have pregnancy complications and/or have had them in the past, and, if so, what are/were they? Have you lost a pregnancy? If so, what was that like? Do you have fears related to childbirth, and, if so, what are they?³

Intrusive thoughts about harming the baby. Intrusive thoughts are common in postpartum women with anxiety disorders, including OCD.⁷ Merely asking patients if they’ve had thoughts of harming their baby is incomplete and insufficient to assess for intrusive thoughts. This question does not distinguish between intrusive thoughts and homicidal ideation; this distinction is absolutely necessary given the difference in potential risk to the infant.

Intrusive thoughts are generally associated with a low risk of mothers acting on their thoughts. These thoughts are typically ego dystonic and, in the most severe form, can be distressing to an extent that they cause behavioral changes, such as avoiding bathing the infant, avoiding diaper changes, avoiding knives, or separating themselves from the infant.⁷ On the contrary, having homicidal ideation carries a higher risk for harm to the infant. Homicidal ideation may be seen in patients with co-occurring psychosis, poor reality testing, and delusions.^5,7

Questions such as “Do you worry about harm coming to your baby?” “Do you worry about you causing harm to your baby?” and “Have you had an upsetting thought about harming your baby?” are more likely to reveal intrusive thoughts and prompt further exploration. Statements such as “Some people tell me that they have distressing thoughts about harm coming to their baby” can gently open the door to a having a dialogue about such thoughts. This dialogue is significantly important in making informed assessments as we develop comprehensive treatment plans.

Emerging data demonstrate that untreated perinatal anxiety is associated with negative outcomes, including an increased risk for suicide.¹ A 2017 systematic review and meta-analysis that included 102 studies with a total of 221,974 women from 34 countries found that the prevalence of self-reported anxiety symptoms and any anxiety disorder was 22.9% and 15.2%, respectively, across the 3 trimesters.¹ During pregnancy, anxiety disorders (eg, generalized anxiety disorder) and anxiety-related disorders (eg, obsessive-compulsive disorder [OCD] and posttraumatic stress disorder [PTSD]) can present as new illnesses or as a reoccurrence of an existing illness. Patients with pre-existing OCD may notice that the nature of their obsessions is changing. Women with pre-existing PTSD may have their symptoms triggered by pregnancy or delivery or may develop PTSD as a result of a traumatic delivery. Anxiety is frequently comorbid with depression, and high anxiety during pregnancy is one of the strongest risk factors for depression.^1,2

In light of this data, awareness and recognition of perinatal anxiety is critical. In this article, we describe how to accurately assess perinatal anxiety by avoiding assumptions and asking key questions during the clinical interview.

Avoid these common assumptions

Assessment begins with avoiding assumptions typically associated with maternal mental health. One common assumption is that pregnancy is a joyous occasion for all women. Pregnancy can be a stressful time that has its own unique difficulties, including the potential to develop or have a relapse of a mental illness. Another assumption is that the only concern is “postpartum depression.” In actuality, a significant percentage of women will experience depression during their pregnancy (not just in the postpartum period), and many other psychiatric illnesses are common during the perinatal period, including anxiety disorders.

Conduct a focused interview

Risk factors associated with antenatal anxiety include²:

• previous history of mental illness (particularly a history of anxiety and depression and a history of psychiatric treatment)
• lack of partner or social support
• history of abuse or domestic violence
• unplanned or unwanted pregnancy
• adverse events in life and high perceived stress
• present/past pregnancy complications
• pregnancy loss.

Symptoms of anxiety. The presence of anxiety or worrying does not necessarily mean a mother has an anxiety disorder. Using the DSM-5 as a guide, we should use the questions outlined in the following sections to inquire about all of the symptoms related to a particular illness, the pervasiveness of these symptoms, and to what extent these symptoms impair a woman’s ability to function and carry out her usual activities.³

Past psychiatric history. Ask your patient the following: Have you previously experienced anxiety and/or depressive symptoms? Were those symptoms limited only to times when you were pregnant or postpartum? Were your symptoms severe enough to disrupt your life (job, school, relationships, ability to complete daily tasks)? What treatments were effective for your symptoms? What treatments were ineffective?³

Social factors. Learn more about your patient’s support systems by asking: Who do you consider to be part of your social support? How is your relationship with your social support? Are there challenges in your relationship with your friends, family, or partner? If yes, what are those challenges? Are there other children in the home, and do you have support for them? Is your home environment safe? Do you feel that you have what you need for the baby? What stressors are you currently experiencing? Do you attend support groups for expectant mothers? Are you engaged in perinatal care?³

Continue to: Given the high prevalence...

Given the high prevalence of interpersonal violence in women of reproductive age, all patients should be screened for this. The American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women recommends screening for interpersonal violence at the first visit during the perinatal period, during each trimester, and at the postpartum visit (at minimum).⁴ Potential screening questions include (but are not limited to): Have you and/or your children ever been threatened by or felt afraid of your partner? When you argue with your partner, do either of you get physical? Has your partner ever physically hurt you (eg, hit, choked)? Do you feel safe at home? Do you have a safe place to go with resources you and your children will need in case of an emergency?^4-6

Feelings toward pregnancy, past/current pregnancy complications, and pregnancy loss. Ask your patient: Was this pregnancy planned? How do you feel about your pregnancy? How do you see yourself as a mother? Do you currently have pregnancy complications and/or have had them in the past, and, if so, what are/were they? Have you lost a pregnancy? If so, what was that like? Do you have fears related to childbirth, and, if so, what are they?³

Intrusive thoughts about harming the baby. Intrusive thoughts are common in postpartum women with anxiety disorders, including OCD.⁷ Merely asking patients if they’ve had thoughts of harming their baby is incomplete and insufficient to assess for intrusive thoughts. This question does not distinguish between intrusive thoughts and homicidal ideation; this distinction is absolutely necessary given the difference in potential risk to the infant.

Intrusive thoughts are generally associated with a low risk of mothers acting on their thoughts. These thoughts are typically ego dystonic and, in the most severe form, can be distressing to an extent that they cause behavioral changes, such as avoiding bathing the infant, avoiding diaper changes, avoiding knives, or separating themselves from the infant.⁷ On the contrary, having homicidal ideation carries a higher risk for harm to the infant. Homicidal ideation may be seen in patients with co-occurring psychosis, poor reality testing, and delusions.^5,7

Questions such as “Do you worry about harm coming to your baby?” “Do you worry about you causing harm to your baby?” and “Have you had an upsetting thought about harming your baby?” are more likely to reveal intrusive thoughts and prompt further exploration. Statements such as “Some people tell me that they have distressing thoughts about harm coming to their baby” can gently open the door to a having a dialogue about such thoughts. This dialogue is significantly important in making informed assessments as we develop comprehensive treatment plans.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.