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Dermatologists fear effects of Dobbs decision for patients on isotretinoin, methotrexate
More than 3 months after the Dobbs decision by the U.S. Supreme Court overturned Roe v. Wade and revoked the constitutional right to an abortion, Some have beefed up their already stringent instructions and lengthy conversations about avoiding pregnancy while on the medication.
The major fear is that a patient who is taking contraceptive precautions, in accordance with the isotretinoin risk-management program, iPLEDGE, but still becomes pregnant while on isotretinoin may find out about the pregnancy too late to undergo an abortion in her own state and may not be able to travel to another state – or the patient may live in a state where abortions are entirely prohibited and is unable to travel to another state.
Isotretinoin is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane; its former brand name was Accutane.
As of Oct. 7, a total of 14 states have banned most abortions, while 4 others have bans at 6, 15, 18, or 20 weeks. Attempts to restrict abortion on several other states are underway.
“To date, we don’t know of any specific effects of the Dobbs decision on isotretinoin prescribing, but with abortion access banned in many states, we anticipate that this could be a very real issue for individuals who accidentally become pregnant while taking isotretinoin,” said Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and chair of the American Academy of Dermatology Association’s iPLEDGE Workgroup.
The iPLEDGE REMS (Risk Evaluation and Mitigation Strategy) is the Food and Drug Administration–required safety program that is in place to manage the risk of isotretinoin teratogenicity and minimize fetal exposure. The work group meets with the FDA and isotretinoin manufacturers to keep the program safe and operating smoothly. The iPLEDGE workgroup has not yet issued any specific statements on the implications of the Dobbs decision on prescribing isotretinoin.
But work on the issue is ongoing by the American Academy of Dermatology. In a statement issued in September, Mark D. Kaufmann, MD, president of the AAD, said that the academy “is continuing to work with its Patient Guidance for State Regulations Regarding Reproductive Health Task Force to help dermatologists best navigate state laws about how care should be implemented for patients who are or might become pregnant, and have been exposed to teratogenic medications.”
The task force, working with the academy, is “in the process of developing resources to help members better assist patients and have a productive and caring dialogue with them,” according to the statement. No specific timeline was given for when those resources might be available.
Methotrexate prescriptions
Also of concern are prescriptions for methotrexate, which is prescribed for psoriasis, atopic dermatitis, and other skin diseases. Soon after the Dobbs decision was announced on June 24, pharmacies began to require pharmacists in states that banned abortions to verify that a prescription for methotrexate was not intended for an abortion, since methotrexate is used in combination with misoprostol for termination of an early pregnancy.
The action was taken, spokespersons for several major pharmacies said, to comply with state laws. According to Kara Page, a CVS spokesperson: “Pharmacists are caught in the middle on this issue.” Laws in some states, she told this news organization, “restrict the dispensing of medications for the purpose of inducing an abortion. These laws, some of which include criminal penalties, have forced us to require pharmacists in these states to validate that the intended indication is not to terminate a pregnancy before they can fill a prescription for methotrexate.”
“New laws in various states require additional steps for dispensing certain prescriptions and apply to all pharmacies, including Walgreens,” Fraser Engerman, a spokesperson for Walgreens, told this news organization. “In these states, our pharmacists work closely with prescribers as needed, to fill lawful, clinically appropriate prescriptions. We provide ongoing training and information to help our pharmacists understand the latest requirements in their area, and with these supports, the expectation is they are empowered to fill these prescriptions.”
The iPLEDGE program has numerous requirements before a patient can begin isotretinoin treatment. Patients capable of becoming pregnant must agree to use two effective forms of birth control during the entire treatment period, which typically lasts 4 or 5 months, as well as 1 month before and 1 month after treatment, or commit to total abstinence during that time.
Perspective: A Georgia dermatologist
Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, who sees patients regularly, practices in Georgia, where abortion is now banned at about 6 weeks of pregnancy. Dr. Yeung worries that some dermatologists in Georgia and elsewhere may not even want to take the risk of prescribing isotretinoin, although the results in treating resistant acne are well documented.
That isn’t his only concern. “Some may not want to prescribe it to a patient who reports they are abstinent and instead require them to go on two forms [of contraception].” Or some women who are not sexually active with anyone who can get them pregnant may also be asked to go on contraception, he said. Abstinence is an alternative option in iPLEDGE.
In the past, he said, well before the Dobbs decision, some doctors have argued that iPLEDGE should not include abstinence as an option. That 2020 report was challenged by others who pointed out that removing the abstinence option would pose ethical issues and may disproportionately affect minorities and others.
Before the Dobbs decision, Dr. Yeung noted, dermatologists prescribing isotretinoin focused on pregnancy prevention but knew that if pregnancy accidentally occurred, abortion was available as an option. “The reality after the decision is, it may or may not be available to all our patients.”
Of the 14 states banning most abortions, 10 are clustered within the South and Southeast. A woman living in Arkansas, which bans most abortions, for example, is surrounded by 6 other states that do the same.
Perspective: An Arizona dermatologist
Christina Kranc, MD, is a general dermatologist in Phoenix and Scottsdale. Arizona now bans most abortions. However, this has not changed her practice much when prescribing isotretinoin, she told this news organization, because when selecting appropriate candidates for the medication, she is strict on the contraceptive requirement, and only very rarely agrees to a patient relying on abstinence.
And if a patient capable of becoming pregnant was only having sex with another patient capable of becoming pregnant? Dr. Kranc said she would still require contraception unless it was impossible for pregnancy to occur.
Among the many scenarios a dermatologist might have to consider are a lesbian cisgender woman who is having, or has only had, sexual activity with another cisgender women.
Perspective: A Connecticut dermatologist
The concern is not only about isotretinoin but all teratogenic drugs, according to Jane M. Grant-Kels, MD, vice chair of dermatology and professor of dermatology, pathology, and pediatrics at the University of Connecticut, Farmington. She often prescribes methotrexate, which is also teratogenic.
Her advice for colleagues: “Whether you believe in abortion or not is irrelevant; it’s something you discuss with your patients.” She, too, fears that doctors in states banning abortions will stop prescribing these medications, “and that is very sad.”
For those practicing in states limiting or banning abortions, Dr. Grant-Kels said, “They need to have an even longer discussion with their patients about how serious this is.” Those doctors need to talk about not only two or three types of birth control, but also discuss with the patient about the potential need for travel, should pregnancy occur and abortion be the chosen option.
Although the newer biologics are an option for psoriasis, they are expensive. And, she said, many insurers require a step-therapy approach, and “want you to start with cheaper medications,” such as methotrexate. As a result, “in some states you won’t have access to the targeted therapies unless a patient fails something like methotrexate.”
Dr. Grant-Kels worries in particular about low-income women who may not have the means to travel to get an abortion.
Need for EC education
In a recent survey of 57 pediatric dermatologists who prescribe isotretinoin, only a third said they felt confident in their understanding of emergency contraception.
The authors of the study noted that the most common reasons for pregnancies during isotretinoin therapy reported to the FDA from 2011 to 2017 “included ineffective or inconsistent use” of contraceptives and “unsuccessful abstinence,” and recommended that physicians who prescribe isotretinoin update and increase their understanding of emergency contraception.
Dr. Yeung, Dr. Kranc, Dr. Grant-Kels, and Dr. Frieden reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
More than 3 months after the Dobbs decision by the U.S. Supreme Court overturned Roe v. Wade and revoked the constitutional right to an abortion, Some have beefed up their already stringent instructions and lengthy conversations about avoiding pregnancy while on the medication.
The major fear is that a patient who is taking contraceptive precautions, in accordance with the isotretinoin risk-management program, iPLEDGE, but still becomes pregnant while on isotretinoin may find out about the pregnancy too late to undergo an abortion in her own state and may not be able to travel to another state – or the patient may live in a state where abortions are entirely prohibited and is unable to travel to another state.
Isotretinoin is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane; its former brand name was Accutane.
As of Oct. 7, a total of 14 states have banned most abortions, while 4 others have bans at 6, 15, 18, or 20 weeks. Attempts to restrict abortion on several other states are underway.
“To date, we don’t know of any specific effects of the Dobbs decision on isotretinoin prescribing, but with abortion access banned in many states, we anticipate that this could be a very real issue for individuals who accidentally become pregnant while taking isotretinoin,” said Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and chair of the American Academy of Dermatology Association’s iPLEDGE Workgroup.
The iPLEDGE REMS (Risk Evaluation and Mitigation Strategy) is the Food and Drug Administration–required safety program that is in place to manage the risk of isotretinoin teratogenicity and minimize fetal exposure. The work group meets with the FDA and isotretinoin manufacturers to keep the program safe and operating smoothly. The iPLEDGE workgroup has not yet issued any specific statements on the implications of the Dobbs decision on prescribing isotretinoin.
But work on the issue is ongoing by the American Academy of Dermatology. In a statement issued in September, Mark D. Kaufmann, MD, president of the AAD, said that the academy “is continuing to work with its Patient Guidance for State Regulations Regarding Reproductive Health Task Force to help dermatologists best navigate state laws about how care should be implemented for patients who are or might become pregnant, and have been exposed to teratogenic medications.”
The task force, working with the academy, is “in the process of developing resources to help members better assist patients and have a productive and caring dialogue with them,” according to the statement. No specific timeline was given for when those resources might be available.
Methotrexate prescriptions
Also of concern are prescriptions for methotrexate, which is prescribed for psoriasis, atopic dermatitis, and other skin diseases. Soon after the Dobbs decision was announced on June 24, pharmacies began to require pharmacists in states that banned abortions to verify that a prescription for methotrexate was not intended for an abortion, since methotrexate is used in combination with misoprostol for termination of an early pregnancy.
The action was taken, spokespersons for several major pharmacies said, to comply with state laws. According to Kara Page, a CVS spokesperson: “Pharmacists are caught in the middle on this issue.” Laws in some states, she told this news organization, “restrict the dispensing of medications for the purpose of inducing an abortion. These laws, some of which include criminal penalties, have forced us to require pharmacists in these states to validate that the intended indication is not to terminate a pregnancy before they can fill a prescription for methotrexate.”
“New laws in various states require additional steps for dispensing certain prescriptions and apply to all pharmacies, including Walgreens,” Fraser Engerman, a spokesperson for Walgreens, told this news organization. “In these states, our pharmacists work closely with prescribers as needed, to fill lawful, clinically appropriate prescriptions. We provide ongoing training and information to help our pharmacists understand the latest requirements in their area, and with these supports, the expectation is they are empowered to fill these prescriptions.”
The iPLEDGE program has numerous requirements before a patient can begin isotretinoin treatment. Patients capable of becoming pregnant must agree to use two effective forms of birth control during the entire treatment period, which typically lasts 4 or 5 months, as well as 1 month before and 1 month after treatment, or commit to total abstinence during that time.
Perspective: A Georgia dermatologist
Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, who sees patients regularly, practices in Georgia, where abortion is now banned at about 6 weeks of pregnancy. Dr. Yeung worries that some dermatologists in Georgia and elsewhere may not even want to take the risk of prescribing isotretinoin, although the results in treating resistant acne are well documented.
That isn’t his only concern. “Some may not want to prescribe it to a patient who reports they are abstinent and instead require them to go on two forms [of contraception].” Or some women who are not sexually active with anyone who can get them pregnant may also be asked to go on contraception, he said. Abstinence is an alternative option in iPLEDGE.
In the past, he said, well before the Dobbs decision, some doctors have argued that iPLEDGE should not include abstinence as an option. That 2020 report was challenged by others who pointed out that removing the abstinence option would pose ethical issues and may disproportionately affect minorities and others.
Before the Dobbs decision, Dr. Yeung noted, dermatologists prescribing isotretinoin focused on pregnancy prevention but knew that if pregnancy accidentally occurred, abortion was available as an option. “The reality after the decision is, it may or may not be available to all our patients.”
Of the 14 states banning most abortions, 10 are clustered within the South and Southeast. A woman living in Arkansas, which bans most abortions, for example, is surrounded by 6 other states that do the same.
Perspective: An Arizona dermatologist
Christina Kranc, MD, is a general dermatologist in Phoenix and Scottsdale. Arizona now bans most abortions. However, this has not changed her practice much when prescribing isotretinoin, she told this news organization, because when selecting appropriate candidates for the medication, she is strict on the contraceptive requirement, and only very rarely agrees to a patient relying on abstinence.
And if a patient capable of becoming pregnant was only having sex with another patient capable of becoming pregnant? Dr. Kranc said she would still require contraception unless it was impossible for pregnancy to occur.
Among the many scenarios a dermatologist might have to consider are a lesbian cisgender woman who is having, or has only had, sexual activity with another cisgender women.
Perspective: A Connecticut dermatologist
The concern is not only about isotretinoin but all teratogenic drugs, according to Jane M. Grant-Kels, MD, vice chair of dermatology and professor of dermatology, pathology, and pediatrics at the University of Connecticut, Farmington. She often prescribes methotrexate, which is also teratogenic.
Her advice for colleagues: “Whether you believe in abortion or not is irrelevant; it’s something you discuss with your patients.” She, too, fears that doctors in states banning abortions will stop prescribing these medications, “and that is very sad.”
For those practicing in states limiting or banning abortions, Dr. Grant-Kels said, “They need to have an even longer discussion with their patients about how serious this is.” Those doctors need to talk about not only two or three types of birth control, but also discuss with the patient about the potential need for travel, should pregnancy occur and abortion be the chosen option.
Although the newer biologics are an option for psoriasis, they are expensive. And, she said, many insurers require a step-therapy approach, and “want you to start with cheaper medications,” such as methotrexate. As a result, “in some states you won’t have access to the targeted therapies unless a patient fails something like methotrexate.”
Dr. Grant-Kels worries in particular about low-income women who may not have the means to travel to get an abortion.
Need for EC education
In a recent survey of 57 pediatric dermatologists who prescribe isotretinoin, only a third said they felt confident in their understanding of emergency contraception.
The authors of the study noted that the most common reasons for pregnancies during isotretinoin therapy reported to the FDA from 2011 to 2017 “included ineffective or inconsistent use” of contraceptives and “unsuccessful abstinence,” and recommended that physicians who prescribe isotretinoin update and increase their understanding of emergency contraception.
Dr. Yeung, Dr. Kranc, Dr. Grant-Kels, and Dr. Frieden reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
More than 3 months after the Dobbs decision by the U.S. Supreme Court overturned Roe v. Wade and revoked the constitutional right to an abortion, Some have beefed up their already stringent instructions and lengthy conversations about avoiding pregnancy while on the medication.
The major fear is that a patient who is taking contraceptive precautions, in accordance with the isotretinoin risk-management program, iPLEDGE, but still becomes pregnant while on isotretinoin may find out about the pregnancy too late to undergo an abortion in her own state and may not be able to travel to another state – or the patient may live in a state where abortions are entirely prohibited and is unable to travel to another state.
Isotretinoin is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane; its former brand name was Accutane.
As of Oct. 7, a total of 14 states have banned most abortions, while 4 others have bans at 6, 15, 18, or 20 weeks. Attempts to restrict abortion on several other states are underway.
“To date, we don’t know of any specific effects of the Dobbs decision on isotretinoin prescribing, but with abortion access banned in many states, we anticipate that this could be a very real issue for individuals who accidentally become pregnant while taking isotretinoin,” said Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and chair of the American Academy of Dermatology Association’s iPLEDGE Workgroup.
The iPLEDGE REMS (Risk Evaluation and Mitigation Strategy) is the Food and Drug Administration–required safety program that is in place to manage the risk of isotretinoin teratogenicity and minimize fetal exposure. The work group meets with the FDA and isotretinoin manufacturers to keep the program safe and operating smoothly. The iPLEDGE workgroup has not yet issued any specific statements on the implications of the Dobbs decision on prescribing isotretinoin.
But work on the issue is ongoing by the American Academy of Dermatology. In a statement issued in September, Mark D. Kaufmann, MD, president of the AAD, said that the academy “is continuing to work with its Patient Guidance for State Regulations Regarding Reproductive Health Task Force to help dermatologists best navigate state laws about how care should be implemented for patients who are or might become pregnant, and have been exposed to teratogenic medications.”
The task force, working with the academy, is “in the process of developing resources to help members better assist patients and have a productive and caring dialogue with them,” according to the statement. No specific timeline was given for when those resources might be available.
Methotrexate prescriptions
Also of concern are prescriptions for methotrexate, which is prescribed for psoriasis, atopic dermatitis, and other skin diseases. Soon after the Dobbs decision was announced on June 24, pharmacies began to require pharmacists in states that banned abortions to verify that a prescription for methotrexate was not intended for an abortion, since methotrexate is used in combination with misoprostol for termination of an early pregnancy.
The action was taken, spokespersons for several major pharmacies said, to comply with state laws. According to Kara Page, a CVS spokesperson: “Pharmacists are caught in the middle on this issue.” Laws in some states, she told this news organization, “restrict the dispensing of medications for the purpose of inducing an abortion. These laws, some of which include criminal penalties, have forced us to require pharmacists in these states to validate that the intended indication is not to terminate a pregnancy before they can fill a prescription for methotrexate.”
“New laws in various states require additional steps for dispensing certain prescriptions and apply to all pharmacies, including Walgreens,” Fraser Engerman, a spokesperson for Walgreens, told this news organization. “In these states, our pharmacists work closely with prescribers as needed, to fill lawful, clinically appropriate prescriptions. We provide ongoing training and information to help our pharmacists understand the latest requirements in their area, and with these supports, the expectation is they are empowered to fill these prescriptions.”
The iPLEDGE program has numerous requirements before a patient can begin isotretinoin treatment. Patients capable of becoming pregnant must agree to use two effective forms of birth control during the entire treatment period, which typically lasts 4 or 5 months, as well as 1 month before and 1 month after treatment, or commit to total abstinence during that time.
Perspective: A Georgia dermatologist
Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, who sees patients regularly, practices in Georgia, where abortion is now banned at about 6 weeks of pregnancy. Dr. Yeung worries that some dermatologists in Georgia and elsewhere may not even want to take the risk of prescribing isotretinoin, although the results in treating resistant acne are well documented.
That isn’t his only concern. “Some may not want to prescribe it to a patient who reports they are abstinent and instead require them to go on two forms [of contraception].” Or some women who are not sexually active with anyone who can get them pregnant may also be asked to go on contraception, he said. Abstinence is an alternative option in iPLEDGE.
In the past, he said, well before the Dobbs decision, some doctors have argued that iPLEDGE should not include abstinence as an option. That 2020 report was challenged by others who pointed out that removing the abstinence option would pose ethical issues and may disproportionately affect minorities and others.
Before the Dobbs decision, Dr. Yeung noted, dermatologists prescribing isotretinoin focused on pregnancy prevention but knew that if pregnancy accidentally occurred, abortion was available as an option. “The reality after the decision is, it may or may not be available to all our patients.”
Of the 14 states banning most abortions, 10 are clustered within the South and Southeast. A woman living in Arkansas, which bans most abortions, for example, is surrounded by 6 other states that do the same.
Perspective: An Arizona dermatologist
Christina Kranc, MD, is a general dermatologist in Phoenix and Scottsdale. Arizona now bans most abortions. However, this has not changed her practice much when prescribing isotretinoin, she told this news organization, because when selecting appropriate candidates for the medication, she is strict on the contraceptive requirement, and only very rarely agrees to a patient relying on abstinence.
And if a patient capable of becoming pregnant was only having sex with another patient capable of becoming pregnant? Dr. Kranc said she would still require contraception unless it was impossible for pregnancy to occur.
Among the many scenarios a dermatologist might have to consider are a lesbian cisgender woman who is having, or has only had, sexual activity with another cisgender women.
Perspective: A Connecticut dermatologist
The concern is not only about isotretinoin but all teratogenic drugs, according to Jane M. Grant-Kels, MD, vice chair of dermatology and professor of dermatology, pathology, and pediatrics at the University of Connecticut, Farmington. She often prescribes methotrexate, which is also teratogenic.
Her advice for colleagues: “Whether you believe in abortion or not is irrelevant; it’s something you discuss with your patients.” She, too, fears that doctors in states banning abortions will stop prescribing these medications, “and that is very sad.”
For those practicing in states limiting or banning abortions, Dr. Grant-Kels said, “They need to have an even longer discussion with their patients about how serious this is.” Those doctors need to talk about not only two or three types of birth control, but also discuss with the patient about the potential need for travel, should pregnancy occur and abortion be the chosen option.
Although the newer biologics are an option for psoriasis, they are expensive. And, she said, many insurers require a step-therapy approach, and “want you to start with cheaper medications,” such as methotrexate. As a result, “in some states you won’t have access to the targeted therapies unless a patient fails something like methotrexate.”
Dr. Grant-Kels worries in particular about low-income women who may not have the means to travel to get an abortion.
Need for EC education
In a recent survey of 57 pediatric dermatologists who prescribe isotretinoin, only a third said they felt confident in their understanding of emergency contraception.
The authors of the study noted that the most common reasons for pregnancies during isotretinoin therapy reported to the FDA from 2011 to 2017 “included ineffective or inconsistent use” of contraceptives and “unsuccessful abstinence,” and recommended that physicians who prescribe isotretinoin update and increase their understanding of emergency contraception.
Dr. Yeung, Dr. Kranc, Dr. Grant-Kels, and Dr. Frieden reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Dermatologists embrace low-dose oral minoxidil as hair loss adjunctive therapy
It’s not a new drug – it’s been available in topical form for hair loss since 1988 and was approved as an antihypertensive in 1979 – but .
The number of scholarly publications examining its use for hair loss has grown dramatically in the last 2 years: There were 2 in 2019, and that jumped to 17 in 2020 and 20 in 2021, with another 16 published so far this year, according to a PubMed search. An August article in The New York Times touting it as a potential cheap magic bullet is likely to drum up even more interest, said dermatologists.
The low-dose formulation is especially exciting for women, as there have been few great oral options for them, clinicians said.
Female hair loss “is devastating,” said Lily Talakoub, MD, adding that topical minoxidil (Rogaine), topical serums, and supplements “really do not provide the considerable growth that women really want to see.” Oral minoxidil is not approved by the U.S. Food and Drug Administration for hair loss, but “it has been shown in studies to cause the hairs to grow,” and has become a “lifeline” for women, said Dr. Talakoub, a dermatologist who is in private practice in McLean, Va.
“For many years we haven’t had anything new to tell patients medically,” said Lynne J. Goldberg, MD, professor of dermatology and pathology at Boston University School of Medicine. “Now, all of the sudden there’s a cheap, widely available efficacious medicine. That’s huge for female-pattern hair loss,” said Dr. Goldberg, who is also the director of the Boston Medical Center’s Hair Clinic.
“I’ve been using oral minoxidil for about 4 years with great success,” said dermatologist Eva Simmons-O’Brien, MD, who is in private practice in Towson, Md. She has used it primarily in women, mainly because she sees more women than men for hair loss.
Dr. Simmons-O’Brien said the excitement about low-dose oral minoxidil follows an increasing recognition in the medical and scientific community that hair loss is more than just a cosmetic issue.
Mechanism not fully understood
When minoxidil was first brought to market as an antihypertensive, clinicians noted hair growth in “balding patients,” which led to the development of the topical form. Even though it has been used for hair growth for decades, its mechanism of action is not fully understood. It is known that minoxidil is a vasodilator; it may also increase DNA synthesis and enhance cell proliferation, according to a review published in 2019.
“The positive effect of minoxidil on hair growth is mainly due to its metabolite, minoxidil sulfate, and the enzyme responsible for this conversion is sulfotransferase, which is located in hair follicles and varies in production among individuals,” write the authors, all affiliated with Mahidol University in Bangkok, Thailand.
Writing in the American Academy of Dermatology’s Dermatology World Insights and Inquiries, Warren R. Heymann, MD, observed that “even after decades of use,” how minoxidil improves alopecia is still not completely understood. He noted that a 2020 review found that minoxidil’s vasodilatory effects “are propagated by upregulation of vascular endothelial growth factor (VEGF), increasing cutaneous blood flow with resultant increase in oxygen and growth factor delivery to the hair follicle.” The medication prolongs the anagen phase and shortens the telogen phase, added Dr. Heymann, head of dermatology at Rowan University, Camden, N.J.
As an antihypertensive, minoxidil is given at 5-40 mg daily. Those doses have produced serious side effects such as sodium and fluid retention, ischemic heart disease, pericardial effusion, and pulmonary hypertension, according to the Thai researchers.
Those side effects have appeared to be rare with low-dose oral minoxidil. However, in JAAD Case Reports, South African researchers reported a case in which low-dose oral minoxidil may have led to cardiac side effects. A healthy 40-year-old woman, who after 3 weeks of treatment with 5% topical minoxidil, tacrolimus ointment 0.1%, clobetasol propionate ointment, 100 mg of doxycycline twice daily, and 0.25 mg of oral minoxidil daily, was hospitalized with full-body edema. An ultrasound showed fluid collections in the pericardium, pleural space, and abdomen. She also had a pleural effusion. The patient was given 40 mg of intravenous furosemide daily for 4 days, and the edema resolved.
“Having excluded other causes of pericardial effusion and anasarca in the previously healthy, young woman, we concluded that LDOM [low-dose oral minoxidil] was responsible for her clinical presentation,” write the authors.
A review of 17 studies published on-line in 2020 in the Journal of the American Academy of Dermatology found low-dose minoxidil to be safe and effective. Androgenetic alopecia was the most commonly studied, with doses of 0.25-1.25 mg proving to be effective and safe. It was also safe and effective for female-pattern hair loss, traction alopecia, chronic telogen effluvium, lichen planopilaris, alopecia areata, and permanent chemotherapy-induced alopecia.
The most common adverse effect was hypertrichosis. Other adverse events included postural hypotension and dizziness, lower-limb edema, and mild blood pressure changes.
In another multicenter, 1,404-patient safety study published in 2021 in JAAD, the authors found that hypertrichosis was the most frequent adverse event, reported by 15% of patients. Systemic adverse events included lightheadedness (1.7% of patients), fluid retention (1.3%), tachycardia (0.9%), headache (0.4%), periorbital edema (0.3%), and insomnia (0.2%). Only 29 patients (1.2%) withdrew because of these side effects.
“It definitely helps, and it’s relatively safe,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University in Washington. “But I wouldn’t want to call it a game-changer,” he said, adding that it works best when used in combination with other therapies. He often uses it with a 5-alpha reductase inhibitor – finasteride (Propecia) or dutasteride (Avodart) – “rather than as a monotherapy,” said Dr. Friedman.
From Australia to around the globe
The first publication on low-dose oral minoxidil for hair loss was in December 2017. The pilot study in female-pattern hair loss was published in the International Journal of Dermatology by Rodney Sinclair, MBBS, MD, a Melbourne, Australia–based dermatologist.
Amy McMichael, MD, professor of dermatology at Wake Forest University, Winston-Salem, N.C., said she first heard Dr. Sinclair present his findings at an alopecia research meeting in Japan shortly before his initial publication.
“After that, I think all of us said, ‘Huh, this is interesting, and let’s try it, because we’re always looking for something more to help our patients,’” Dr. McMichael said, adding that she’s been prescribing low-dose minoxidil to her patients for 5 years.
She and colleagues at Wake Forest, along with Jerry Cooley, MD, a dermatologist in private practice in Charlotte, published a retrospective case series in March, looking at 105 adult patients – 80 women (ages 24-80) and 25 men (ages 19-63) – who were treated for androgenetic alopecia and/or telogen effluvium with oral minoxidil (dose range of 0.625–2.5 mg) once daily for a year, matched to 105 case controls.
Efficacy was based on the clinician’s assessment of clinical response and clinical photographic evaluation using a 3-point scale (worsening, stabilization, and improvement). Half of those treated demonstrated clinical improvement and 43% demonstrated stabilization. There was a significant difference (P < .001) in clinical response between those who received minoxidil and the controls.
Ideal patients?
Given its ease of use and low cost – $4-$12 for a 30-day supply of 2.5 mg tablets, according to GoodRX – low-dose minoxidil is a good fit for many patients, said dermatologists.
The best candidate is “a woman who’s perimenopausal or menopausal who’s got what we would say is moderate to severe loss of hair that’s kind of just starting,” said Dr. Simmons-O’Brien. The medication is not likely to grow hair where there is scarring already, however, she said.
“I tend to use it in people who either don’t want to do the topical minoxidil or have used it and have a lot of potential side effects from it,” like itching and irritation, said Dr. McMichael. She said oral minoxidil can also be helpful as an adjunct in patients with alopecia areata and that it can be used after anti-inflammatory treatments in central centrifugal cicatricial alopecia.
Dr. Goldberg said low-dose minoxidil would not be her first choice for female-pattern hair loss but that it’s “a great alternative” for people who can’t tolerate the topical form. Most of the women she has prescribed it to “have been pretty happy,” she added.
“I would be a little cautious in patients on a number of other medications,” Dr. Goldberg said, noting minoxidil’s potential systemic side effects.
Clinicians said they generally consult with a patient’s internist when they are starting them on oral minoxidil. “I always want to touch base with the primary care physician first,” said Dr. Friedman.
“If they’re on oral antihypertensive medications already, then I would ask them to talk to either their primary care physician or their cardiologist to make sure it’s okay to give this low dose,” said Dr. McMichael.
At the low doses, minoxidil rarely has any blood pressure–lowering effects, dermatologists said.
Women are usually started on 1.25 mg, while men can start at a higher, 2.5-mg dose, said clinicians.
Dr. Goldberg and Dr. Simmons-O’Brien said that recent additional warnings for finasteride about sexual side effects and the potential for suicide have changed the way they approach its use in young men, and that it has highlighted the potential for oral minoxidil as an alternative.
Oral minoxidil is rarely used as a monotherapy. “It takes a village” to address hair loss, said Dr. Simmons-O’Brien, noting that she likes to evaluate nutrition, vitamin D levels, and whether a patient is anemic or has thyroid disease when determining a course of action.
Dermatologists said they use oral minoxidil in combination with spironolactone, topical minoxidil, finasteride, or dutasteride. If patients are already on antihypertensives or at risk for excessive blood pressure–lowering effects of a combination that includes spironolactone, the dermatologists said again they will consult with a patient’s primary care physician first.
For women, the main limiting factor with oral minoxidil may be unwanted hair growth, usually on the face. Most of the clinicians interviewed for this story said they did not use spironolactone to counteract that hypertrichosis.
Dr. McMichael said she cautions African American women or women of African descent – who tend to have more body hair at baseline – that they should be aware of the potential for excess hair growth associated with low-dose minoxidil. She and other dermatologists interviewed for this story said they urge patients who are bothered by the excess hair to shave or wax or use other nonpharmacologic approaches.
The excess hair growth is less bothersome for men, they said.
Not a magic wand
Despite the increased profile and interest, oral minoxidil is not a cure-all, clinicians said.
“It’s important for patients to realize that hair loss can be complicated and there is no one magic wand,” said Dr. Simmons-O’Brien. Clinicians typically “are using several things to help encourage these follicular units to not miniaturize and disappear and create scars,” she said.
Dr. Friedman said he finds that patients have a hard time hearing that to continue to maintain growth, they have to take a medication for the rest of their life. “If you stop, you will have to start again,” he said.
Oral minoxidil, when used in combination with other therapies, will improve hair growth, said Dr. Goldberg. But it will not take someone back a decade, she said. “I try to temper expectations – promise a little and achieve more,” Dr. Goldberg said.
The study was independently supported. Dr. Smith and Dr. Jones report no relevant financial relationships. Dr. Simmons-O’Brien reports that she has received speaking fees from Isdin. Dr. McMichael disclosed relationships with Eli Lilly, Pfizer, Nutrafol, Revian, and UCB Pharma. Dr. Friedman, Dr. Goldberg, and Dr. Talakoub reported no disclosures.
A version of this article first appeared on Medscape.com.
It’s not a new drug – it’s been available in topical form for hair loss since 1988 and was approved as an antihypertensive in 1979 – but .
The number of scholarly publications examining its use for hair loss has grown dramatically in the last 2 years: There were 2 in 2019, and that jumped to 17 in 2020 and 20 in 2021, with another 16 published so far this year, according to a PubMed search. An August article in The New York Times touting it as a potential cheap magic bullet is likely to drum up even more interest, said dermatologists.
The low-dose formulation is especially exciting for women, as there have been few great oral options for them, clinicians said.
Female hair loss “is devastating,” said Lily Talakoub, MD, adding that topical minoxidil (Rogaine), topical serums, and supplements “really do not provide the considerable growth that women really want to see.” Oral minoxidil is not approved by the U.S. Food and Drug Administration for hair loss, but “it has been shown in studies to cause the hairs to grow,” and has become a “lifeline” for women, said Dr. Talakoub, a dermatologist who is in private practice in McLean, Va.
“For many years we haven’t had anything new to tell patients medically,” said Lynne J. Goldberg, MD, professor of dermatology and pathology at Boston University School of Medicine. “Now, all of the sudden there’s a cheap, widely available efficacious medicine. That’s huge for female-pattern hair loss,” said Dr. Goldberg, who is also the director of the Boston Medical Center’s Hair Clinic.
“I’ve been using oral minoxidil for about 4 years with great success,” said dermatologist Eva Simmons-O’Brien, MD, who is in private practice in Towson, Md. She has used it primarily in women, mainly because she sees more women than men for hair loss.
Dr. Simmons-O’Brien said the excitement about low-dose oral minoxidil follows an increasing recognition in the medical and scientific community that hair loss is more than just a cosmetic issue.
Mechanism not fully understood
When minoxidil was first brought to market as an antihypertensive, clinicians noted hair growth in “balding patients,” which led to the development of the topical form. Even though it has been used for hair growth for decades, its mechanism of action is not fully understood. It is known that minoxidil is a vasodilator; it may also increase DNA synthesis and enhance cell proliferation, according to a review published in 2019.
“The positive effect of minoxidil on hair growth is mainly due to its metabolite, minoxidil sulfate, and the enzyme responsible for this conversion is sulfotransferase, which is located in hair follicles and varies in production among individuals,” write the authors, all affiliated with Mahidol University in Bangkok, Thailand.
Writing in the American Academy of Dermatology’s Dermatology World Insights and Inquiries, Warren R. Heymann, MD, observed that “even after decades of use,” how minoxidil improves alopecia is still not completely understood. He noted that a 2020 review found that minoxidil’s vasodilatory effects “are propagated by upregulation of vascular endothelial growth factor (VEGF), increasing cutaneous blood flow with resultant increase in oxygen and growth factor delivery to the hair follicle.” The medication prolongs the anagen phase and shortens the telogen phase, added Dr. Heymann, head of dermatology at Rowan University, Camden, N.J.
As an antihypertensive, minoxidil is given at 5-40 mg daily. Those doses have produced serious side effects such as sodium and fluid retention, ischemic heart disease, pericardial effusion, and pulmonary hypertension, according to the Thai researchers.
Those side effects have appeared to be rare with low-dose oral minoxidil. However, in JAAD Case Reports, South African researchers reported a case in which low-dose oral minoxidil may have led to cardiac side effects. A healthy 40-year-old woman, who after 3 weeks of treatment with 5% topical minoxidil, tacrolimus ointment 0.1%, clobetasol propionate ointment, 100 mg of doxycycline twice daily, and 0.25 mg of oral minoxidil daily, was hospitalized with full-body edema. An ultrasound showed fluid collections in the pericardium, pleural space, and abdomen. She also had a pleural effusion. The patient was given 40 mg of intravenous furosemide daily for 4 days, and the edema resolved.
“Having excluded other causes of pericardial effusion and anasarca in the previously healthy, young woman, we concluded that LDOM [low-dose oral minoxidil] was responsible for her clinical presentation,” write the authors.
A review of 17 studies published on-line in 2020 in the Journal of the American Academy of Dermatology found low-dose minoxidil to be safe and effective. Androgenetic alopecia was the most commonly studied, with doses of 0.25-1.25 mg proving to be effective and safe. It was also safe and effective for female-pattern hair loss, traction alopecia, chronic telogen effluvium, lichen planopilaris, alopecia areata, and permanent chemotherapy-induced alopecia.
The most common adverse effect was hypertrichosis. Other adverse events included postural hypotension and dizziness, lower-limb edema, and mild blood pressure changes.
In another multicenter, 1,404-patient safety study published in 2021 in JAAD, the authors found that hypertrichosis was the most frequent adverse event, reported by 15% of patients. Systemic adverse events included lightheadedness (1.7% of patients), fluid retention (1.3%), tachycardia (0.9%), headache (0.4%), periorbital edema (0.3%), and insomnia (0.2%). Only 29 patients (1.2%) withdrew because of these side effects.
“It definitely helps, and it’s relatively safe,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University in Washington. “But I wouldn’t want to call it a game-changer,” he said, adding that it works best when used in combination with other therapies. He often uses it with a 5-alpha reductase inhibitor – finasteride (Propecia) or dutasteride (Avodart) – “rather than as a monotherapy,” said Dr. Friedman.
From Australia to around the globe
The first publication on low-dose oral minoxidil for hair loss was in December 2017. The pilot study in female-pattern hair loss was published in the International Journal of Dermatology by Rodney Sinclair, MBBS, MD, a Melbourne, Australia–based dermatologist.
Amy McMichael, MD, professor of dermatology at Wake Forest University, Winston-Salem, N.C., said she first heard Dr. Sinclair present his findings at an alopecia research meeting in Japan shortly before his initial publication.
“After that, I think all of us said, ‘Huh, this is interesting, and let’s try it, because we’re always looking for something more to help our patients,’” Dr. McMichael said, adding that she’s been prescribing low-dose minoxidil to her patients for 5 years.
She and colleagues at Wake Forest, along with Jerry Cooley, MD, a dermatologist in private practice in Charlotte, published a retrospective case series in March, looking at 105 adult patients – 80 women (ages 24-80) and 25 men (ages 19-63) – who were treated for androgenetic alopecia and/or telogen effluvium with oral minoxidil (dose range of 0.625–2.5 mg) once daily for a year, matched to 105 case controls.
Efficacy was based on the clinician’s assessment of clinical response and clinical photographic evaluation using a 3-point scale (worsening, stabilization, and improvement). Half of those treated demonstrated clinical improvement and 43% demonstrated stabilization. There was a significant difference (P < .001) in clinical response between those who received minoxidil and the controls.
Ideal patients?
Given its ease of use and low cost – $4-$12 for a 30-day supply of 2.5 mg tablets, according to GoodRX – low-dose minoxidil is a good fit for many patients, said dermatologists.
The best candidate is “a woman who’s perimenopausal or menopausal who’s got what we would say is moderate to severe loss of hair that’s kind of just starting,” said Dr. Simmons-O’Brien. The medication is not likely to grow hair where there is scarring already, however, she said.
“I tend to use it in people who either don’t want to do the topical minoxidil or have used it and have a lot of potential side effects from it,” like itching and irritation, said Dr. McMichael. She said oral minoxidil can also be helpful as an adjunct in patients with alopecia areata and that it can be used after anti-inflammatory treatments in central centrifugal cicatricial alopecia.
Dr. Goldberg said low-dose minoxidil would not be her first choice for female-pattern hair loss but that it’s “a great alternative” for people who can’t tolerate the topical form. Most of the women she has prescribed it to “have been pretty happy,” she added.
“I would be a little cautious in patients on a number of other medications,” Dr. Goldberg said, noting minoxidil’s potential systemic side effects.
Clinicians said they generally consult with a patient’s internist when they are starting them on oral minoxidil. “I always want to touch base with the primary care physician first,” said Dr. Friedman.
“If they’re on oral antihypertensive medications already, then I would ask them to talk to either their primary care physician or their cardiologist to make sure it’s okay to give this low dose,” said Dr. McMichael.
At the low doses, minoxidil rarely has any blood pressure–lowering effects, dermatologists said.
Women are usually started on 1.25 mg, while men can start at a higher, 2.5-mg dose, said clinicians.
Dr. Goldberg and Dr. Simmons-O’Brien said that recent additional warnings for finasteride about sexual side effects and the potential for suicide have changed the way they approach its use in young men, and that it has highlighted the potential for oral minoxidil as an alternative.
Oral minoxidil is rarely used as a monotherapy. “It takes a village” to address hair loss, said Dr. Simmons-O’Brien, noting that she likes to evaluate nutrition, vitamin D levels, and whether a patient is anemic or has thyroid disease when determining a course of action.
Dermatologists said they use oral minoxidil in combination with spironolactone, topical minoxidil, finasteride, or dutasteride. If patients are already on antihypertensives or at risk for excessive blood pressure–lowering effects of a combination that includes spironolactone, the dermatologists said again they will consult with a patient’s primary care physician first.
For women, the main limiting factor with oral minoxidil may be unwanted hair growth, usually on the face. Most of the clinicians interviewed for this story said they did not use spironolactone to counteract that hypertrichosis.
Dr. McMichael said she cautions African American women or women of African descent – who tend to have more body hair at baseline – that they should be aware of the potential for excess hair growth associated with low-dose minoxidil. She and other dermatologists interviewed for this story said they urge patients who are bothered by the excess hair to shave or wax or use other nonpharmacologic approaches.
The excess hair growth is less bothersome for men, they said.
Not a magic wand
Despite the increased profile and interest, oral minoxidil is not a cure-all, clinicians said.
“It’s important for patients to realize that hair loss can be complicated and there is no one magic wand,” said Dr. Simmons-O’Brien. Clinicians typically “are using several things to help encourage these follicular units to not miniaturize and disappear and create scars,” she said.
Dr. Friedman said he finds that patients have a hard time hearing that to continue to maintain growth, they have to take a medication for the rest of their life. “If you stop, you will have to start again,” he said.
Oral minoxidil, when used in combination with other therapies, will improve hair growth, said Dr. Goldberg. But it will not take someone back a decade, she said. “I try to temper expectations – promise a little and achieve more,” Dr. Goldberg said.
The study was independently supported. Dr. Smith and Dr. Jones report no relevant financial relationships. Dr. Simmons-O’Brien reports that she has received speaking fees from Isdin. Dr. McMichael disclosed relationships with Eli Lilly, Pfizer, Nutrafol, Revian, and UCB Pharma. Dr. Friedman, Dr. Goldberg, and Dr. Talakoub reported no disclosures.
A version of this article first appeared on Medscape.com.
It’s not a new drug – it’s been available in topical form for hair loss since 1988 and was approved as an antihypertensive in 1979 – but .
The number of scholarly publications examining its use for hair loss has grown dramatically in the last 2 years: There were 2 in 2019, and that jumped to 17 in 2020 and 20 in 2021, with another 16 published so far this year, according to a PubMed search. An August article in The New York Times touting it as a potential cheap magic bullet is likely to drum up even more interest, said dermatologists.
The low-dose formulation is especially exciting for women, as there have been few great oral options for them, clinicians said.
Female hair loss “is devastating,” said Lily Talakoub, MD, adding that topical minoxidil (Rogaine), topical serums, and supplements “really do not provide the considerable growth that women really want to see.” Oral minoxidil is not approved by the U.S. Food and Drug Administration for hair loss, but “it has been shown in studies to cause the hairs to grow,” and has become a “lifeline” for women, said Dr. Talakoub, a dermatologist who is in private practice in McLean, Va.
“For many years we haven’t had anything new to tell patients medically,” said Lynne J. Goldberg, MD, professor of dermatology and pathology at Boston University School of Medicine. “Now, all of the sudden there’s a cheap, widely available efficacious medicine. That’s huge for female-pattern hair loss,” said Dr. Goldberg, who is also the director of the Boston Medical Center’s Hair Clinic.
“I’ve been using oral minoxidil for about 4 years with great success,” said dermatologist Eva Simmons-O’Brien, MD, who is in private practice in Towson, Md. She has used it primarily in women, mainly because she sees more women than men for hair loss.
Dr. Simmons-O’Brien said the excitement about low-dose oral minoxidil follows an increasing recognition in the medical and scientific community that hair loss is more than just a cosmetic issue.
Mechanism not fully understood
When minoxidil was first brought to market as an antihypertensive, clinicians noted hair growth in “balding patients,” which led to the development of the topical form. Even though it has been used for hair growth for decades, its mechanism of action is not fully understood. It is known that minoxidil is a vasodilator; it may also increase DNA synthesis and enhance cell proliferation, according to a review published in 2019.
“The positive effect of minoxidil on hair growth is mainly due to its metabolite, minoxidil sulfate, and the enzyme responsible for this conversion is sulfotransferase, which is located in hair follicles and varies in production among individuals,” write the authors, all affiliated with Mahidol University in Bangkok, Thailand.
Writing in the American Academy of Dermatology’s Dermatology World Insights and Inquiries, Warren R. Heymann, MD, observed that “even after decades of use,” how minoxidil improves alopecia is still not completely understood. He noted that a 2020 review found that minoxidil’s vasodilatory effects “are propagated by upregulation of vascular endothelial growth factor (VEGF), increasing cutaneous blood flow with resultant increase in oxygen and growth factor delivery to the hair follicle.” The medication prolongs the anagen phase and shortens the telogen phase, added Dr. Heymann, head of dermatology at Rowan University, Camden, N.J.
As an antihypertensive, minoxidil is given at 5-40 mg daily. Those doses have produced serious side effects such as sodium and fluid retention, ischemic heart disease, pericardial effusion, and pulmonary hypertension, according to the Thai researchers.
Those side effects have appeared to be rare with low-dose oral minoxidil. However, in JAAD Case Reports, South African researchers reported a case in which low-dose oral minoxidil may have led to cardiac side effects. A healthy 40-year-old woman, who after 3 weeks of treatment with 5% topical minoxidil, tacrolimus ointment 0.1%, clobetasol propionate ointment, 100 mg of doxycycline twice daily, and 0.25 mg of oral minoxidil daily, was hospitalized with full-body edema. An ultrasound showed fluid collections in the pericardium, pleural space, and abdomen. She also had a pleural effusion. The patient was given 40 mg of intravenous furosemide daily for 4 days, and the edema resolved.
“Having excluded other causes of pericardial effusion and anasarca in the previously healthy, young woman, we concluded that LDOM [low-dose oral minoxidil] was responsible for her clinical presentation,” write the authors.
A review of 17 studies published on-line in 2020 in the Journal of the American Academy of Dermatology found low-dose minoxidil to be safe and effective. Androgenetic alopecia was the most commonly studied, with doses of 0.25-1.25 mg proving to be effective and safe. It was also safe and effective for female-pattern hair loss, traction alopecia, chronic telogen effluvium, lichen planopilaris, alopecia areata, and permanent chemotherapy-induced alopecia.
The most common adverse effect was hypertrichosis. Other adverse events included postural hypotension and dizziness, lower-limb edema, and mild blood pressure changes.
In another multicenter, 1,404-patient safety study published in 2021 in JAAD, the authors found that hypertrichosis was the most frequent adverse event, reported by 15% of patients. Systemic adverse events included lightheadedness (1.7% of patients), fluid retention (1.3%), tachycardia (0.9%), headache (0.4%), periorbital edema (0.3%), and insomnia (0.2%). Only 29 patients (1.2%) withdrew because of these side effects.
“It definitely helps, and it’s relatively safe,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University in Washington. “But I wouldn’t want to call it a game-changer,” he said, adding that it works best when used in combination with other therapies. He often uses it with a 5-alpha reductase inhibitor – finasteride (Propecia) or dutasteride (Avodart) – “rather than as a monotherapy,” said Dr. Friedman.
From Australia to around the globe
The first publication on low-dose oral minoxidil for hair loss was in December 2017. The pilot study in female-pattern hair loss was published in the International Journal of Dermatology by Rodney Sinclair, MBBS, MD, a Melbourne, Australia–based dermatologist.
Amy McMichael, MD, professor of dermatology at Wake Forest University, Winston-Salem, N.C., said she first heard Dr. Sinclair present his findings at an alopecia research meeting in Japan shortly before his initial publication.
“After that, I think all of us said, ‘Huh, this is interesting, and let’s try it, because we’re always looking for something more to help our patients,’” Dr. McMichael said, adding that she’s been prescribing low-dose minoxidil to her patients for 5 years.
She and colleagues at Wake Forest, along with Jerry Cooley, MD, a dermatologist in private practice in Charlotte, published a retrospective case series in March, looking at 105 adult patients – 80 women (ages 24-80) and 25 men (ages 19-63) – who were treated for androgenetic alopecia and/or telogen effluvium with oral minoxidil (dose range of 0.625–2.5 mg) once daily for a year, matched to 105 case controls.
Efficacy was based on the clinician’s assessment of clinical response and clinical photographic evaluation using a 3-point scale (worsening, stabilization, and improvement). Half of those treated demonstrated clinical improvement and 43% demonstrated stabilization. There was a significant difference (P < .001) in clinical response between those who received minoxidil and the controls.
Ideal patients?
Given its ease of use and low cost – $4-$12 for a 30-day supply of 2.5 mg tablets, according to GoodRX – low-dose minoxidil is a good fit for many patients, said dermatologists.
The best candidate is “a woman who’s perimenopausal or menopausal who’s got what we would say is moderate to severe loss of hair that’s kind of just starting,” said Dr. Simmons-O’Brien. The medication is not likely to grow hair where there is scarring already, however, she said.
“I tend to use it in people who either don’t want to do the topical minoxidil or have used it and have a lot of potential side effects from it,” like itching and irritation, said Dr. McMichael. She said oral minoxidil can also be helpful as an adjunct in patients with alopecia areata and that it can be used after anti-inflammatory treatments in central centrifugal cicatricial alopecia.
Dr. Goldberg said low-dose minoxidil would not be her first choice for female-pattern hair loss but that it’s “a great alternative” for people who can’t tolerate the topical form. Most of the women she has prescribed it to “have been pretty happy,” she added.
“I would be a little cautious in patients on a number of other medications,” Dr. Goldberg said, noting minoxidil’s potential systemic side effects.
Clinicians said they generally consult with a patient’s internist when they are starting them on oral minoxidil. “I always want to touch base with the primary care physician first,” said Dr. Friedman.
“If they’re on oral antihypertensive medications already, then I would ask them to talk to either their primary care physician or their cardiologist to make sure it’s okay to give this low dose,” said Dr. McMichael.
At the low doses, minoxidil rarely has any blood pressure–lowering effects, dermatologists said.
Women are usually started on 1.25 mg, while men can start at a higher, 2.5-mg dose, said clinicians.
Dr. Goldberg and Dr. Simmons-O’Brien said that recent additional warnings for finasteride about sexual side effects and the potential for suicide have changed the way they approach its use in young men, and that it has highlighted the potential for oral minoxidil as an alternative.
Oral minoxidil is rarely used as a monotherapy. “It takes a village” to address hair loss, said Dr. Simmons-O’Brien, noting that she likes to evaluate nutrition, vitamin D levels, and whether a patient is anemic or has thyroid disease when determining a course of action.
Dermatologists said they use oral minoxidil in combination with spironolactone, topical minoxidil, finasteride, or dutasteride. If patients are already on antihypertensives or at risk for excessive blood pressure–lowering effects of a combination that includes spironolactone, the dermatologists said again they will consult with a patient’s primary care physician first.
For women, the main limiting factor with oral minoxidil may be unwanted hair growth, usually on the face. Most of the clinicians interviewed for this story said they did not use spironolactone to counteract that hypertrichosis.
Dr. McMichael said she cautions African American women or women of African descent – who tend to have more body hair at baseline – that they should be aware of the potential for excess hair growth associated with low-dose minoxidil. She and other dermatologists interviewed for this story said they urge patients who are bothered by the excess hair to shave or wax or use other nonpharmacologic approaches.
The excess hair growth is less bothersome for men, they said.
Not a magic wand
Despite the increased profile and interest, oral minoxidil is not a cure-all, clinicians said.
“It’s important for patients to realize that hair loss can be complicated and there is no one magic wand,” said Dr. Simmons-O’Brien. Clinicians typically “are using several things to help encourage these follicular units to not miniaturize and disappear and create scars,” she said.
Dr. Friedman said he finds that patients have a hard time hearing that to continue to maintain growth, they have to take a medication for the rest of their life. “If you stop, you will have to start again,” he said.
Oral minoxidil, when used in combination with other therapies, will improve hair growth, said Dr. Goldberg. But it will not take someone back a decade, she said. “I try to temper expectations – promise a little and achieve more,” Dr. Goldberg said.
The study was independently supported. Dr. Smith and Dr. Jones report no relevant financial relationships. Dr. Simmons-O’Brien reports that she has received speaking fees from Isdin. Dr. McMichael disclosed relationships with Eli Lilly, Pfizer, Nutrafol, Revian, and UCB Pharma. Dr. Friedman, Dr. Goldberg, and Dr. Talakoub reported no disclosures.
A version of this article first appeared on Medscape.com.
The marked contrast in pandemic outcomes between Japan and the United States
This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack.
Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.
Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.
Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.
Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.
But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.
Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.
And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.
Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.
Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.
There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.
That’s why I had previously modified the Swiss cheese model to add Paxlovid.
But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.
Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.
No less the previous data through May 2022 showing protection from death across all ages with two boosters
And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.
We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.
Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.
This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack.
Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.
Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.
Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.
Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.
But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.
Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.
And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.
Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.
Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.
There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.
That’s why I had previously modified the Swiss cheese model to add Paxlovid.
But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.
Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.
No less the previous data through May 2022 showing protection from death across all ages with two boosters
And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.
We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.
Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.
This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack.
Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.
Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.
Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.
Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.
But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.
Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.
And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.
Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.
Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.
There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.
That’s why I had previously modified the Swiss cheese model to add Paxlovid.
But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.
Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.
No less the previous data through May 2022 showing protection from death across all ages with two boosters
And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.
We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.
Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.
Keep menstrual cramps away the dietary prevention way
Foods for thought: Menstrual cramp prevention
For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.
About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?
Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.
In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.
The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
Stage 1 of the robot apocalypse is already upon us
The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.
Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.
The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.
In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.
It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”
Oops. Our bad.
Apocalypse, stage 2: Leaping oral superorganisms
The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.
Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.
While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.
Did he say “mobility”? He did, didn’t he?
To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.
“Incubated in human saliva.” There’s a phrase you don’t see every day.
It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”
So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.
Foods for thought: Menstrual cramp prevention
For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.
About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?
Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.
In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.
The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
Stage 1 of the robot apocalypse is already upon us
The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.
Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.
The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.
In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.
It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”
Oops. Our bad.
Apocalypse, stage 2: Leaping oral superorganisms
The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.
Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.
While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.
Did he say “mobility”? He did, didn’t he?
To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.
“Incubated in human saliva.” There’s a phrase you don’t see every day.
It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”
So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.
Foods for thought: Menstrual cramp prevention
For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.
About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?
Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.
In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.
The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
Stage 1 of the robot apocalypse is already upon us
The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.
Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.
The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.
In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.
It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”
Oops. Our bad.
Apocalypse, stage 2: Leaping oral superorganisms
The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.
Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.
While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.
Did he say “mobility”? He did, didn’t he?
To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.
“Incubated in human saliva.” There’s a phrase you don’t see every day.
It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”
So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.
Randomized, Double-Blind Placebo-Controlled Trial to Assess the Effect of Probiotics on Irritable Bowel Syndrome in Veterans With Gulf War Illness
About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).1 Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.2 Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.3
The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.4 Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.5 Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.6 In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.7 A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.
A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.10 Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.
If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.11 Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.12 Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.15 Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.16,17
Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.18-20
Methods
Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.21 Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.
Protocol
After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.
Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.
Each probiotic packet contains 900 billion probiotic bacteria per sachet.11 This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.
Measures
Veterans completed the bowel disease questionnaire to record baseline bowel habits.22 All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.23,24
IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.25 The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).26
Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).27 Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.28 BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.
Symptom data were compared after 8 weeks of treatment. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, extra-intestinal symptoms, and PTSD score. The study was approved by the Salt Lake City Veterans Affairs Medical Center and the University of Utah Institutional Review Board and registered in ClinicalTrials.gov (NCT03078530).
Statistical Methods
Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ2 test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.
Results
We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).
Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).
Discussion
GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.3 A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.29 These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.
The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.30 A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.31 Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.32 Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.
Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.33 The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.20 A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.34 Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.
The effect of probiotics on QOL has not been investigated by many studies.37 In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.35,41 The probiotic used in our study contained other species along with these 2 microorganisms.
The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.35 However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.42 In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.43 Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.
An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.44
In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.6 Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.45
Limitations
The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.46 These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.
Conclusions
This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.
The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.
Acknowledgments
AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.
1. O’Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025.
2. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987.
3. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.066100
4. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001.
5. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: Evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142.
6. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8.
7. Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med. 1991;325(20):1423-1428. doi:10.1056/NEJM199111143252006 8. Clancy RL, Gleeson M, Cox A, et al. Reversal in fatigued athletes of a defect in interferon gamma secretion after administration of Lactobacillus acidophilus. Br J Sports Med. 2006;40(4):351-354. doi:10.1136/bjsm.2005.024364
9. Sullivan A, Nord CE, Evengard B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J. 2009;8:4. doi:10.1186/1475-2891-8-4
10. Pittayanon R, Lau JT, Yuan Y, et al. Gut microbiota in patients with irritable bowel syndrome—a systematic review. Gastroenterology. 2019;157(1):97-108. doi:10.1053/j.gastro.2019.03.049
11. Rao RK, Samak G. Protection and restitution of gut barrier by probiotics: nutritional and clinical implications. Curr Nutr Food Sci. 2013;9(2):99-107. doi:10.2174/1573401311309020004
12. O´Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025
13. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987
14. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.06610015. O´Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551. doi:10.1053/j.gastro.2004.11.050
16. Alhasson F, Das S, Seth R, et al. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One. 2017;12(3):e0172914. doi:10.1371/journal.pone.0172914.17. Janulewicz PA, Seth RK, Carlson JM, et al. The gut-microbiome in Gulf War veterans: a preliminary report. Int J Environ Res Public Health. 2019;16(19). doi:10.3390/ijerph16193751
18. Dang X, Xu M, Liu D, Zhou D, Yang W. Assessing the efficacy and safety of fecal microbiota transplantation and probiotic VSL#3 for active ulcerative colitis: a systematic review and meta-analysis. PLoS One. 2020;15(3):e0228846. doi:10.1371/journal.pone.0228846
19. Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-1561; quiz 1546, 1562. doi:10.1038/ajg.2014.202
20. Rohatgi S, Ahuja V, Makharia GK, et al. VSL#3 induces and maintains short-term clinical response in patients with active microscopic colitis: a two-phase randomised clinical trial. BMJ Open Gastroenterol. 2015;2(1):e000018. doi:10.1136/bmjgast-2014-000018
21. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130(5):1480-1491. doi:10.1053/j.gastro.2005.11.061
22. Talley NJ, Phillips SF, Melton J, 3rd, Wiltgen C, Zinsmeister AR. A patient questionnaire to identify bowel disease. Ann Intern Med. 1989;111(8):671-674. doi:10.7326/0003-4819-111-8-671
23. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA. 1998;280(18):1585-1589. doi:10.1001/jama.280.18.1585
24. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11(2):395-402. doi:10.1046/j.1365-2036.1997.142318000.x
25. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43(2):400-411. doi:10.1023/a:1018831127942
26. Attanasio V, Andrasik F, Blanchard EB, Arena JG. Psychometric properties of the SUNYA revision of the Psychosomatic Symptom Checklist. J Behav Med. 1984;7(2):247-257. doi:10.1007/BF00845390
27. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Accessed August 25, 2022. https://www.researchgate.net/publication/291448760_The_PTSD_Checklist_PCL_Reliability_validity_and_diagnostic_utility
28. Derogatis L. Brief Symptom Inventory-18 (BSI-18): Administration, Scoring, and Procedure Manual. Ed 3 ed. National Computer Systems; 2000.
29. Stamps BW, Lyon WJ, Irvin AP, Kelley-Loughnane N, Goodson MS. A pilot study of the effect of deployment on the gut microbiome and traveler´s diarrhea susceptibility. Front Cell Infect Microbiol. 2020;10:589297. doi:10.3389/fcimb.2020.589297
30. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17(7):895-904. doi:10.1046/j.1365-2036.2003.01543.x
31. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005;17(5):687-696. doi:10.1111/j.1365-2982.2005.00695.x32. Michail S, Kenche H. Gut microbiota is not modified by randomized, double-blind, placebo-controlled trial of vsl#3 in diarrhea-predominant irritable bowel syndrome. Probiotics Antimicrob Proteins. 2011;3(1):1-7. doi:10.1007/s12602-010-9059-y
33. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59(3):325-332. doi:10.1136/gut.2008.167270
34. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001
35. Dale HF, Rasmussen SH, Asiller OO, Lied GA. Probiotics in irritable bowel syndrome: an up-to-date systematic review. Nutrients. 2019;11(9). doi:10.3390/nu11092048
36. Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis. World J Gastroenterol. 2015;21(10):3072-84. doi:10.3748/wjg.v21.i10.3072
37. Hungin APS, Mitchell CR, Whorwell P, et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms—an updated evidence-based international consensus. Aliment Pharmacol Ther. 2018;47(8):1054-1070. doi:10.1111/apt.14539
38. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142
39. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8
40. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2-26; quiz S27. doi: 10.1038/ajg.2014.187
41. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-76. doi:10.1136/gutjnl-2012-302167
42. Ki Cha B, Mun Jung S, Hwan Choi C, et al. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012;46(3):220-7. doi:10.1097/MCG.0b013e31823712b1
43. Connell M, Shin A, James-Stevenson T, Xu H, Imperiale TF, Herron J. Systematic review and meta-analysis: Efficacy of patented probiotic, VSL#3, in irritable bowel syndrome. Neurogastroenterol Motil. 2018;30(12):e13427. doi:10.1111/nmo.13427
44. Lyra A, Hillila M, Huttunen T, et al. Irritable bowel syndrome symptom severity improves equally with probiotic and placebo. World J Gastroenterol. 2016;22(48):10631-10642. doi:10.3748/wjg.v22.i48.10631
45. Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut. 2013;62(5):787-796. doi:10.1136/gutjnl-2012-302504
46. Tuteja AK. Deployment-associated functional gastrointestinal disorders: do we know the etiology? Dig Dis Sci. 2011;56(11):3109-3111. doi:10.1007/s10620-011-1856-y
About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).1 Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.2 Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.3
The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.4 Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.5 Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.6 In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.7 A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.
A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.10 Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.
If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.11 Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.12 Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.15 Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.16,17
Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.18-20
Methods
Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.21 Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.
Protocol
After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.
Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.
Each probiotic packet contains 900 billion probiotic bacteria per sachet.11 This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.
Measures
Veterans completed the bowel disease questionnaire to record baseline bowel habits.22 All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.23,24
IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.25 The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).26
Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).27 Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.28 BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.
Symptom data were compared after 8 weeks of treatment. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, extra-intestinal symptoms, and PTSD score. The study was approved by the Salt Lake City Veterans Affairs Medical Center and the University of Utah Institutional Review Board and registered in ClinicalTrials.gov (NCT03078530).
Statistical Methods
Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ2 test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.
Results
We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).
Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).
Discussion
GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.3 A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.29 These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.
The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.30 A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.31 Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.32 Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.
Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.33 The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.20 A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.34 Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.
The effect of probiotics on QOL has not been investigated by many studies.37 In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.35,41 The probiotic used in our study contained other species along with these 2 microorganisms.
The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.35 However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.42 In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.43 Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.
An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.44
In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.6 Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.45
Limitations
The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.46 These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.
Conclusions
This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.
The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.
Acknowledgments
AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.
About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).1 Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.2 Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.3
The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.4 Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.5 Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.6 In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.7 A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.
A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.10 Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.
If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.11 Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.12 Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.15 Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.16,17
Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.18-20
Methods
Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.21 Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.
Protocol
After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.
Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.
Each probiotic packet contains 900 billion probiotic bacteria per sachet.11 This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.
Measures
Veterans completed the bowel disease questionnaire to record baseline bowel habits.22 All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.23,24
IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.25 The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).26
Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).27 Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.28 BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.
Symptom data were compared after 8 weeks of treatment. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, extra-intestinal symptoms, and PTSD score. The study was approved by the Salt Lake City Veterans Affairs Medical Center and the University of Utah Institutional Review Board and registered in ClinicalTrials.gov (NCT03078530).
Statistical Methods
Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ2 test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.
Results
We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).
Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).
Discussion
GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.3 A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.29 These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.
The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.30 A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.31 Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.32 Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.
Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.33 The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.20 A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.34 Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.
The effect of probiotics on QOL has not been investigated by many studies.37 In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.35,41 The probiotic used in our study contained other species along with these 2 microorganisms.
The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.35 However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.42 In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.43 Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.
An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.44
In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.6 Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.45
Limitations
The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.46 These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.
Conclusions
This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.
The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.
Acknowledgments
AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.
1. O’Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025.
2. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987.
3. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.066100
4. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001.
5. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: Evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142.
6. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8.
7. Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med. 1991;325(20):1423-1428. doi:10.1056/NEJM199111143252006 8. Clancy RL, Gleeson M, Cox A, et al. Reversal in fatigued athletes of a defect in interferon gamma secretion after administration of Lactobacillus acidophilus. Br J Sports Med. 2006;40(4):351-354. doi:10.1136/bjsm.2005.024364
9. Sullivan A, Nord CE, Evengard B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J. 2009;8:4. doi:10.1186/1475-2891-8-4
10. Pittayanon R, Lau JT, Yuan Y, et al. Gut microbiota in patients with irritable bowel syndrome—a systematic review. Gastroenterology. 2019;157(1):97-108. doi:10.1053/j.gastro.2019.03.049
11. Rao RK, Samak G. Protection and restitution of gut barrier by probiotics: nutritional and clinical implications. Curr Nutr Food Sci. 2013;9(2):99-107. doi:10.2174/1573401311309020004
12. O´Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025
13. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987
14. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.06610015. O´Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551. doi:10.1053/j.gastro.2004.11.050
16. Alhasson F, Das S, Seth R, et al. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One. 2017;12(3):e0172914. doi:10.1371/journal.pone.0172914.17. Janulewicz PA, Seth RK, Carlson JM, et al. The gut-microbiome in Gulf War veterans: a preliminary report. Int J Environ Res Public Health. 2019;16(19). doi:10.3390/ijerph16193751
18. Dang X, Xu M, Liu D, Zhou D, Yang W. Assessing the efficacy and safety of fecal microbiota transplantation and probiotic VSL#3 for active ulcerative colitis: a systematic review and meta-analysis. PLoS One. 2020;15(3):e0228846. doi:10.1371/journal.pone.0228846
19. Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-1561; quiz 1546, 1562. doi:10.1038/ajg.2014.202
20. Rohatgi S, Ahuja V, Makharia GK, et al. VSL#3 induces and maintains short-term clinical response in patients with active microscopic colitis: a two-phase randomised clinical trial. BMJ Open Gastroenterol. 2015;2(1):e000018. doi:10.1136/bmjgast-2014-000018
21. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130(5):1480-1491. doi:10.1053/j.gastro.2005.11.061
22. Talley NJ, Phillips SF, Melton J, 3rd, Wiltgen C, Zinsmeister AR. A patient questionnaire to identify bowel disease. Ann Intern Med. 1989;111(8):671-674. doi:10.7326/0003-4819-111-8-671
23. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA. 1998;280(18):1585-1589. doi:10.1001/jama.280.18.1585
24. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11(2):395-402. doi:10.1046/j.1365-2036.1997.142318000.x
25. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43(2):400-411. doi:10.1023/a:1018831127942
26. Attanasio V, Andrasik F, Blanchard EB, Arena JG. Psychometric properties of the SUNYA revision of the Psychosomatic Symptom Checklist. J Behav Med. 1984;7(2):247-257. doi:10.1007/BF00845390
27. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Accessed August 25, 2022. https://www.researchgate.net/publication/291448760_The_PTSD_Checklist_PCL_Reliability_validity_and_diagnostic_utility
28. Derogatis L. Brief Symptom Inventory-18 (BSI-18): Administration, Scoring, and Procedure Manual. Ed 3 ed. National Computer Systems; 2000.
29. Stamps BW, Lyon WJ, Irvin AP, Kelley-Loughnane N, Goodson MS. A pilot study of the effect of deployment on the gut microbiome and traveler´s diarrhea susceptibility. Front Cell Infect Microbiol. 2020;10:589297. doi:10.3389/fcimb.2020.589297
30. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17(7):895-904. doi:10.1046/j.1365-2036.2003.01543.x
31. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005;17(5):687-696. doi:10.1111/j.1365-2982.2005.00695.x32. Michail S, Kenche H. Gut microbiota is not modified by randomized, double-blind, placebo-controlled trial of vsl#3 in diarrhea-predominant irritable bowel syndrome. Probiotics Antimicrob Proteins. 2011;3(1):1-7. doi:10.1007/s12602-010-9059-y
33. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59(3):325-332. doi:10.1136/gut.2008.167270
34. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001
35. Dale HF, Rasmussen SH, Asiller OO, Lied GA. Probiotics in irritable bowel syndrome: an up-to-date systematic review. Nutrients. 2019;11(9). doi:10.3390/nu11092048
36. Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis. World J Gastroenterol. 2015;21(10):3072-84. doi:10.3748/wjg.v21.i10.3072
37. Hungin APS, Mitchell CR, Whorwell P, et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms—an updated evidence-based international consensus. Aliment Pharmacol Ther. 2018;47(8):1054-1070. doi:10.1111/apt.14539
38. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142
39. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8
40. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2-26; quiz S27. doi: 10.1038/ajg.2014.187
41. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-76. doi:10.1136/gutjnl-2012-302167
42. Ki Cha B, Mun Jung S, Hwan Choi C, et al. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012;46(3):220-7. doi:10.1097/MCG.0b013e31823712b1
43. Connell M, Shin A, James-Stevenson T, Xu H, Imperiale TF, Herron J. Systematic review and meta-analysis: Efficacy of patented probiotic, VSL#3, in irritable bowel syndrome. Neurogastroenterol Motil. 2018;30(12):e13427. doi:10.1111/nmo.13427
44. Lyra A, Hillila M, Huttunen T, et al. Irritable bowel syndrome symptom severity improves equally with probiotic and placebo. World J Gastroenterol. 2016;22(48):10631-10642. doi:10.3748/wjg.v22.i48.10631
45. Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut. 2013;62(5):787-796. doi:10.1136/gutjnl-2012-302504
46. Tuteja AK. Deployment-associated functional gastrointestinal disorders: do we know the etiology? Dig Dis Sci. 2011;56(11):3109-3111. doi:10.1007/s10620-011-1856-y
1. O’Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025.
2. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987.
3. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.066100
4. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001.
5. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: Evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142.
6. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8.
7. Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med. 1991;325(20):1423-1428. doi:10.1056/NEJM199111143252006 8. Clancy RL, Gleeson M, Cox A, et al. Reversal in fatigued athletes of a defect in interferon gamma secretion after administration of Lactobacillus acidophilus. Br J Sports Med. 2006;40(4):351-354. doi:10.1136/bjsm.2005.024364
9. Sullivan A, Nord CE, Evengard B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J. 2009;8:4. doi:10.1186/1475-2891-8-4
10. Pittayanon R, Lau JT, Yuan Y, et al. Gut microbiota in patients with irritable bowel syndrome—a systematic review. Gastroenterology. 2019;157(1):97-108. doi:10.1053/j.gastro.2019.03.049
11. Rao RK, Samak G. Protection and restitution of gut barrier by probiotics: nutritional and clinical implications. Curr Nutr Food Sci. 2013;9(2):99-107. doi:10.2174/1573401311309020004
12. O´Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012;152(3):189-205. doi:10.1016/j.ijfoodmicro.2011.05.025
13. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55(2):191-196. doi:10.1136/gut.2005.070987
14. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182-190. doi:10.1136/gut.2005.06610015. O´Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551. doi:10.1053/j.gastro.2004.11.050
16. Alhasson F, Das S, Seth R, et al. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One. 2017;12(3):e0172914. doi:10.1371/journal.pone.0172914.17. Janulewicz PA, Seth RK, Carlson JM, et al. The gut-microbiome in Gulf War veterans: a preliminary report. Int J Environ Res Public Health. 2019;16(19). doi:10.3390/ijerph16193751
18. Dang X, Xu M, Liu D, Zhou D, Yang W. Assessing the efficacy and safety of fecal microbiota transplantation and probiotic VSL#3 for active ulcerative colitis: a systematic review and meta-analysis. PLoS One. 2020;15(3):e0228846. doi:10.1371/journal.pone.0228846
19. Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-1561; quiz 1546, 1562. doi:10.1038/ajg.2014.202
20. Rohatgi S, Ahuja V, Makharia GK, et al. VSL#3 induces and maintains short-term clinical response in patients with active microscopic colitis: a two-phase randomised clinical trial. BMJ Open Gastroenterol. 2015;2(1):e000018. doi:10.1136/bmjgast-2014-000018
21. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130(5):1480-1491. doi:10.1053/j.gastro.2005.11.061
22. Talley NJ, Phillips SF, Melton J, 3rd, Wiltgen C, Zinsmeister AR. A patient questionnaire to identify bowel disease. Ann Intern Med. 1989;111(8):671-674. doi:10.7326/0003-4819-111-8-671
23. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA. 1998;280(18):1585-1589. doi:10.1001/jama.280.18.1585
24. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11(2):395-402. doi:10.1046/j.1365-2036.1997.142318000.x
25. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43(2):400-411. doi:10.1023/a:1018831127942
26. Attanasio V, Andrasik F, Blanchard EB, Arena JG. Psychometric properties of the SUNYA revision of the Psychosomatic Symptom Checklist. J Behav Med. 1984;7(2):247-257. doi:10.1007/BF00845390
27. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Accessed August 25, 2022. https://www.researchgate.net/publication/291448760_The_PTSD_Checklist_PCL_Reliability_validity_and_diagnostic_utility
28. Derogatis L. Brief Symptom Inventory-18 (BSI-18): Administration, Scoring, and Procedure Manual. Ed 3 ed. National Computer Systems; 2000.
29. Stamps BW, Lyon WJ, Irvin AP, Kelley-Loughnane N, Goodson MS. A pilot study of the effect of deployment on the gut microbiome and traveler´s diarrhea susceptibility. Front Cell Infect Microbiol. 2020;10:589297. doi:10.3389/fcimb.2020.589297
30. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17(7):895-904. doi:10.1046/j.1365-2036.2003.01543.x
31. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005;17(5):687-696. doi:10.1111/j.1365-2982.2005.00695.x32. Michail S, Kenche H. Gut microbiota is not modified by randomized, double-blind, placebo-controlled trial of vsl#3 in diarrhea-predominant irritable bowel syndrome. Probiotics Antimicrob Proteins. 2011;3(1):1-7. doi:10.1007/s12602-010-9059-y
33. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59(3):325-332. doi:10.1136/gut.2008.167270
34. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(10):1044-1060. doi:10.1111/apt.15001
35. Dale HF, Rasmussen SH, Asiller OO, Lied GA. Probiotics in irritable bowel syndrome: an up-to-date systematic review. Nutrients. 2019;11(9). doi:10.3390/nu11092048
36. Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis. World J Gastroenterol. 2015;21(10):3072-84. doi:10.3748/wjg.v21.i10.3072
37. Hungin APS, Mitchell CR, Whorwell P, et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms—an updated evidence-based international consensus. Aliment Pharmacol Ther. 2018;47(8):1054-1070. doi:10.1111/apt.14539
38. Niu HL, Xiao JY. The efficacy and safety of probiotics in patients with irritable bowel syndrome: evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116-127. doi:10.1016/j.ijsu.2020.01.142
39. Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci. 2015;60(1):186-194. doi:10.1007/s10620-014-3299-8
40. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2-26; quiz S27. doi: 10.1038/ajg.2014.187
41. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-76. doi:10.1136/gutjnl-2012-302167
42. Ki Cha B, Mun Jung S, Hwan Choi C, et al. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012;46(3):220-7. doi:10.1097/MCG.0b013e31823712b1
43. Connell M, Shin A, James-Stevenson T, Xu H, Imperiale TF, Herron J. Systematic review and meta-analysis: Efficacy of patented probiotic, VSL#3, in irritable bowel syndrome. Neurogastroenterol Motil. 2018;30(12):e13427. doi:10.1111/nmo.13427
44. Lyra A, Hillila M, Huttunen T, et al. Irritable bowel syndrome symptom severity improves equally with probiotic and placebo. World J Gastroenterol. 2016;22(48):10631-10642. doi:10.3748/wjg.v22.i48.10631
45. Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut. 2013;62(5):787-796. doi:10.1136/gutjnl-2012-302504
46. Tuteja AK. Deployment-associated functional gastrointestinal disorders: do we know the etiology? Dig Dis Sci. 2011;56(11):3109-3111. doi:10.1007/s10620-011-1856-y
Support for Policy Changes for Therapy Related to Homefront Missions
Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.
Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.1,2
As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.
Discussion
Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.
The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).3 These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.4-7
Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.
As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.
Therapists with experience primarily treating patients with PTSD related to combat or MST will need to be sensitive to the unique experiences of the National Guard and Reserve service members. For example, this component of soldiers served on COVID-19–related missions that provided food service support to nursing homes residents who were locked down from family members. As a result, they developed bonds with residents who later died. This may have been the first time that these soldiers witnessed death. If such a soldier is assessed and does not have PTSD but is nonetheless distressed, then the soldier may need alternate therapies, such as grief counseling. This need may be more pronounced for those soldiers who lost loved ones to COVID-19 while they served on these missions.
New Jersey Army National Guard soldiers provided food service support at the Woodland Behavioral and Nursing Center in Andover, New Jersey. These soldiers witnessed the unfortunate conditions in this facility, which included stacked bodies in a makeshift morgue during the height of the pandemic; however, they did not have the ability to make changes. The facility is under investigation for abuse and neglect of its residents.13
New Jersey National Guard soldiers supporting that facility and similar ones may have experienced moral injury, defined as “…perpetrating, failing to prevent, or bearing witness to acts that transgress deeply held moral beliefs and expectations.”14 Importantly, when these soldiers present for therapy and express moral injury, their therapists need to be open to spiritual discourse. However, vet centers do not have chaplains on staff, so therapists must refer patients to chaplaincy services.
Among therapists with existing cultural competency for treating members of the military, some nuances exist for National Guard and Reserve service members. National Guard and Reserve component personnel already may feel that their problems are less important than those experienced by active-duty service members. Now that these soldiers have the eligibility to receive therapy, therapists may have to make extra efforts to both reassure this population that they are welcomed and to validate their need for services.
Special outreach efforts to those who served on historical National Guard and active-duty Reserve missions are a way to show good faith in serving these soldiers because they may have untreated PTSD or other undiagnosed mental health disorders related to earlier deployments, such as hurricane recovery missions. A study of disaster survivors found that the prevalence rate of severe and very severe psychological impact after a natural disaster was about 34%.15 Another epidemiologic study found that the prevalence rate of PTSD was 10% to 20% among disaster rescue workers.16 Specific data about the psychological problems of National Guard and Reserve components serving in disaster recovery are unavailable but is an area for future research.
Therapists who have treated active-duty service members and veterans who worked in mortuary services in a combat zone are used to hearing graphic details of horrifying scenes, but homefront experiences are different. Soldiers on homefront mortuary-based missions frequently reported being unable to forget the faces or the smell of dead bodies as they were stacked up and overwhelming the systems. Experienced vet center therapists should be prepared for the challenges in treating this new cohort of patients.
Conclusions
Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.
1. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1550(2): readjustment counseling service. January 26, 2021. Accessed September 1, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=9168
2. US Department of Veterans Affairs. Vet centers (readjustment counseling: vet center eligibility. Updated January 3, 2022. Accessed September 1, 2022. https://www.vetcenter.va.gov/eligibility.asp
3. US Department of Defense, US Department of Veterans Affairs. VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress reaction, version 3.0, 2017. Accessed September 1, 2022. https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf
4. US Department of Veterans Affairs, National Center for PTSD. Prolonged exposure (PE) therapy. Updated August 10, 2022. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/prolonged_exposure.asp
5. US Department of Veterans Affairs, National Center for PTSD. Cognitive processing therapy (CPT) for PTSD: how to help your loved one during treatment. Accessed September 1, 2022. https://www.ptsd.va.gov/publications/print/CPT_familyhandout.pdf
6. US Department of Veterans Affairs, National Center for PTSD. A provider’s guide to brief cognitive behavioral therapy. Accessed September 1, 2022. https://www.mirecc.va.gov/visn16/docs/Therapists_Guide_to_Brief_CBTManual.pdf
7. US Department of Veterans Affairs, National Center for PTSD. Eye movement desensitization and reprocessing (EMDR) for PTSD. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/emdr.asp
8. Wachen JS, Dondanville KA, Evans WR, Morris K, Cole A. Adjusting the timeframe of evidence-based therapies for PTSD-massed treatments. Curr Treat Options Psych. 2019;6(2):107-118. doi:10.1007/s40501-019-00169-9
9. Dell L, Sbisa AM, Forbes A, et al. Effect of massed v. standard prolonged exposure therapy on PTSD in military personnel and veterans: a non-inferiority randomised controlled trial [published online ahead of print, 2022 Apr 20]. Psychol Med. 2022;1-8. doi:10.1017/S0033291722000927
10. Held P, Kovacevic M, Petrey K, et al. Treating posttraumatic stress disorder at home in a single week using 1-week virtual massed cognitive processing therapy. J Trauma Stress. 2022;35(4):1215-1225. doi:10.1002/jts.22831
11. Yamokoski C, Flores H, Facemire V, Maieritsch K, Perez S, Fedynich A. Feasibility of an intensive outpatient treatment program for posttraumatic stress disorder within the veterans health care administration [published online ahead of print, 2022 Mar 7]. Psychol Serv. 2022;10.1037/ser0000628. doi:10.1037/ser0000628
12. Galovski TE, Werner KB, Weaver TL, et al. Massed cognitive processing therapy for posttraumatic stress disorder in women survivors of intimate partner violence. Psychol Trauma. 2022;14(5):769-779. doi:10.1037/tra0001100
13. Fallon S. NJ to send monitors into troubled nursing home that stacked bodies in makeshift morgue. Updated March 10, 2022. Accessed September 1, 2022. https://www.northjersey.com/story/news/health/2022/03/09/sussex-county-nj-nursing-home-monitors-covid-morgue/9447243002/
14. Litz BT, Stein N, Delaney E, et al. Moral injury and moral repair in war veterans: a preliminary model and intervention strategy. Clin Psychol Rev. 2009;29(8):695-706. doi:10.1016/j.cpr.2009.07.003009
15. Norris FH, Friedman MJ, Watson PJ, Byrne CM, Diaz E, Kaniasty K. 60,000 disaster victims speak: Part I. An empirical review of the empirical literature, 1981-2001. Psychiatry. 2002;65(3):207-239. doi:10.1521/psyc.65.3.207.20173
16. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters. Epidemiol Rev. 2005;27:78-91. doi:10.1093/epirev/mxi003
Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.
Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.1,2
As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.
Discussion
Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.
The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).3 These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.4-7
Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.
As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.
Therapists with experience primarily treating patients with PTSD related to combat or MST will need to be sensitive to the unique experiences of the National Guard and Reserve service members. For example, this component of soldiers served on COVID-19–related missions that provided food service support to nursing homes residents who were locked down from family members. As a result, they developed bonds with residents who later died. This may have been the first time that these soldiers witnessed death. If such a soldier is assessed and does not have PTSD but is nonetheless distressed, then the soldier may need alternate therapies, such as grief counseling. This need may be more pronounced for those soldiers who lost loved ones to COVID-19 while they served on these missions.
New Jersey Army National Guard soldiers provided food service support at the Woodland Behavioral and Nursing Center in Andover, New Jersey. These soldiers witnessed the unfortunate conditions in this facility, which included stacked bodies in a makeshift morgue during the height of the pandemic; however, they did not have the ability to make changes. The facility is under investigation for abuse and neglect of its residents.13
New Jersey National Guard soldiers supporting that facility and similar ones may have experienced moral injury, defined as “…perpetrating, failing to prevent, or bearing witness to acts that transgress deeply held moral beliefs and expectations.”14 Importantly, when these soldiers present for therapy and express moral injury, their therapists need to be open to spiritual discourse. However, vet centers do not have chaplains on staff, so therapists must refer patients to chaplaincy services.
Among therapists with existing cultural competency for treating members of the military, some nuances exist for National Guard and Reserve service members. National Guard and Reserve component personnel already may feel that their problems are less important than those experienced by active-duty service members. Now that these soldiers have the eligibility to receive therapy, therapists may have to make extra efforts to both reassure this population that they are welcomed and to validate their need for services.
Special outreach efforts to those who served on historical National Guard and active-duty Reserve missions are a way to show good faith in serving these soldiers because they may have untreated PTSD or other undiagnosed mental health disorders related to earlier deployments, such as hurricane recovery missions. A study of disaster survivors found that the prevalence rate of severe and very severe psychological impact after a natural disaster was about 34%.15 Another epidemiologic study found that the prevalence rate of PTSD was 10% to 20% among disaster rescue workers.16 Specific data about the psychological problems of National Guard and Reserve components serving in disaster recovery are unavailable but is an area for future research.
Therapists who have treated active-duty service members and veterans who worked in mortuary services in a combat zone are used to hearing graphic details of horrifying scenes, but homefront experiences are different. Soldiers on homefront mortuary-based missions frequently reported being unable to forget the faces or the smell of dead bodies as they were stacked up and overwhelming the systems. Experienced vet center therapists should be prepared for the challenges in treating this new cohort of patients.
Conclusions
Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.
Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.
Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.1,2
As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.
Discussion
Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.
The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).3 These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.4-7
Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.
As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.
Therapists with experience primarily treating patients with PTSD related to combat or MST will need to be sensitive to the unique experiences of the National Guard and Reserve service members. For example, this component of soldiers served on COVID-19–related missions that provided food service support to nursing homes residents who were locked down from family members. As a result, they developed bonds with residents who later died. This may have been the first time that these soldiers witnessed death. If such a soldier is assessed and does not have PTSD but is nonetheless distressed, then the soldier may need alternate therapies, such as grief counseling. This need may be more pronounced for those soldiers who lost loved ones to COVID-19 while they served on these missions.
New Jersey Army National Guard soldiers provided food service support at the Woodland Behavioral and Nursing Center in Andover, New Jersey. These soldiers witnessed the unfortunate conditions in this facility, which included stacked bodies in a makeshift morgue during the height of the pandemic; however, they did not have the ability to make changes. The facility is under investigation for abuse and neglect of its residents.13
New Jersey National Guard soldiers supporting that facility and similar ones may have experienced moral injury, defined as “…perpetrating, failing to prevent, or bearing witness to acts that transgress deeply held moral beliefs and expectations.”14 Importantly, when these soldiers present for therapy and express moral injury, their therapists need to be open to spiritual discourse. However, vet centers do not have chaplains on staff, so therapists must refer patients to chaplaincy services.
Among therapists with existing cultural competency for treating members of the military, some nuances exist for National Guard and Reserve service members. National Guard and Reserve component personnel already may feel that their problems are less important than those experienced by active-duty service members. Now that these soldiers have the eligibility to receive therapy, therapists may have to make extra efforts to both reassure this population that they are welcomed and to validate their need for services.
Special outreach efforts to those who served on historical National Guard and active-duty Reserve missions are a way to show good faith in serving these soldiers because they may have untreated PTSD or other undiagnosed mental health disorders related to earlier deployments, such as hurricane recovery missions. A study of disaster survivors found that the prevalence rate of severe and very severe psychological impact after a natural disaster was about 34%.15 Another epidemiologic study found that the prevalence rate of PTSD was 10% to 20% among disaster rescue workers.16 Specific data about the psychological problems of National Guard and Reserve components serving in disaster recovery are unavailable but is an area for future research.
Therapists who have treated active-duty service members and veterans who worked in mortuary services in a combat zone are used to hearing graphic details of horrifying scenes, but homefront experiences are different. Soldiers on homefront mortuary-based missions frequently reported being unable to forget the faces or the smell of dead bodies as they were stacked up and overwhelming the systems. Experienced vet center therapists should be prepared for the challenges in treating this new cohort of patients.
Conclusions
Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.
1. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1550(2): readjustment counseling service. January 26, 2021. Accessed September 1, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=9168
2. US Department of Veterans Affairs. Vet centers (readjustment counseling: vet center eligibility. Updated January 3, 2022. Accessed September 1, 2022. https://www.vetcenter.va.gov/eligibility.asp
3. US Department of Defense, US Department of Veterans Affairs. VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress reaction, version 3.0, 2017. Accessed September 1, 2022. https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf
4. US Department of Veterans Affairs, National Center for PTSD. Prolonged exposure (PE) therapy. Updated August 10, 2022. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/prolonged_exposure.asp
5. US Department of Veterans Affairs, National Center for PTSD. Cognitive processing therapy (CPT) for PTSD: how to help your loved one during treatment. Accessed September 1, 2022. https://www.ptsd.va.gov/publications/print/CPT_familyhandout.pdf
6. US Department of Veterans Affairs, National Center for PTSD. A provider’s guide to brief cognitive behavioral therapy. Accessed September 1, 2022. https://www.mirecc.va.gov/visn16/docs/Therapists_Guide_to_Brief_CBTManual.pdf
7. US Department of Veterans Affairs, National Center for PTSD. Eye movement desensitization and reprocessing (EMDR) for PTSD. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/emdr.asp
8. Wachen JS, Dondanville KA, Evans WR, Morris K, Cole A. Adjusting the timeframe of evidence-based therapies for PTSD-massed treatments. Curr Treat Options Psych. 2019;6(2):107-118. doi:10.1007/s40501-019-00169-9
9. Dell L, Sbisa AM, Forbes A, et al. Effect of massed v. standard prolonged exposure therapy on PTSD in military personnel and veterans: a non-inferiority randomised controlled trial [published online ahead of print, 2022 Apr 20]. Psychol Med. 2022;1-8. doi:10.1017/S0033291722000927
10. Held P, Kovacevic M, Petrey K, et al. Treating posttraumatic stress disorder at home in a single week using 1-week virtual massed cognitive processing therapy. J Trauma Stress. 2022;35(4):1215-1225. doi:10.1002/jts.22831
11. Yamokoski C, Flores H, Facemire V, Maieritsch K, Perez S, Fedynich A. Feasibility of an intensive outpatient treatment program for posttraumatic stress disorder within the veterans health care administration [published online ahead of print, 2022 Mar 7]. Psychol Serv. 2022;10.1037/ser0000628. doi:10.1037/ser0000628
12. Galovski TE, Werner KB, Weaver TL, et al. Massed cognitive processing therapy for posttraumatic stress disorder in women survivors of intimate partner violence. Psychol Trauma. 2022;14(5):769-779. doi:10.1037/tra0001100
13. Fallon S. NJ to send monitors into troubled nursing home that stacked bodies in makeshift morgue. Updated March 10, 2022. Accessed September 1, 2022. https://www.northjersey.com/story/news/health/2022/03/09/sussex-county-nj-nursing-home-monitors-covid-morgue/9447243002/
14. Litz BT, Stein N, Delaney E, et al. Moral injury and moral repair in war veterans: a preliminary model and intervention strategy. Clin Psychol Rev. 2009;29(8):695-706. doi:10.1016/j.cpr.2009.07.003009
15. Norris FH, Friedman MJ, Watson PJ, Byrne CM, Diaz E, Kaniasty K. 60,000 disaster victims speak: Part I. An empirical review of the empirical literature, 1981-2001. Psychiatry. 2002;65(3):207-239. doi:10.1521/psyc.65.3.207.20173
16. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters. Epidemiol Rev. 2005;27:78-91. doi:10.1093/epirev/mxi003
1. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1550(2): readjustment counseling service. January 26, 2021. Accessed September 1, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=9168
2. US Department of Veterans Affairs. Vet centers (readjustment counseling: vet center eligibility. Updated January 3, 2022. Accessed September 1, 2022. https://www.vetcenter.va.gov/eligibility.asp
3. US Department of Defense, US Department of Veterans Affairs. VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress reaction, version 3.0, 2017. Accessed September 1, 2022. https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf
4. US Department of Veterans Affairs, National Center for PTSD. Prolonged exposure (PE) therapy. Updated August 10, 2022. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/prolonged_exposure.asp
5. US Department of Veterans Affairs, National Center for PTSD. Cognitive processing therapy (CPT) for PTSD: how to help your loved one during treatment. Accessed September 1, 2022. https://www.ptsd.va.gov/publications/print/CPT_familyhandout.pdf
6. US Department of Veterans Affairs, National Center for PTSD. A provider’s guide to brief cognitive behavioral therapy. Accessed September 1, 2022. https://www.mirecc.va.gov/visn16/docs/Therapists_Guide_to_Brief_CBTManual.pdf
7. US Department of Veterans Affairs, National Center for PTSD. Eye movement desensitization and reprocessing (EMDR) for PTSD. Accessed September 1, 2022. https://www.ptsd.va.gov/understand_tx/emdr.asp
8. Wachen JS, Dondanville KA, Evans WR, Morris K, Cole A. Adjusting the timeframe of evidence-based therapies for PTSD-massed treatments. Curr Treat Options Psych. 2019;6(2):107-118. doi:10.1007/s40501-019-00169-9
9. Dell L, Sbisa AM, Forbes A, et al. Effect of massed v. standard prolonged exposure therapy on PTSD in military personnel and veterans: a non-inferiority randomised controlled trial [published online ahead of print, 2022 Apr 20]. Psychol Med. 2022;1-8. doi:10.1017/S0033291722000927
10. Held P, Kovacevic M, Petrey K, et al. Treating posttraumatic stress disorder at home in a single week using 1-week virtual massed cognitive processing therapy. J Trauma Stress. 2022;35(4):1215-1225. doi:10.1002/jts.22831
11. Yamokoski C, Flores H, Facemire V, Maieritsch K, Perez S, Fedynich A. Feasibility of an intensive outpatient treatment program for posttraumatic stress disorder within the veterans health care administration [published online ahead of print, 2022 Mar 7]. Psychol Serv. 2022;10.1037/ser0000628. doi:10.1037/ser0000628
12. Galovski TE, Werner KB, Weaver TL, et al. Massed cognitive processing therapy for posttraumatic stress disorder in women survivors of intimate partner violence. Psychol Trauma. 2022;14(5):769-779. doi:10.1037/tra0001100
13. Fallon S. NJ to send monitors into troubled nursing home that stacked bodies in makeshift morgue. Updated March 10, 2022. Accessed September 1, 2022. https://www.northjersey.com/story/news/health/2022/03/09/sussex-county-nj-nursing-home-monitors-covid-morgue/9447243002/
14. Litz BT, Stein N, Delaney E, et al. Moral injury and moral repair in war veterans: a preliminary model and intervention strategy. Clin Psychol Rev. 2009;29(8):695-706. doi:10.1016/j.cpr.2009.07.003009
15. Norris FH, Friedman MJ, Watson PJ, Byrne CM, Diaz E, Kaniasty K. 60,000 disaster victims speak: Part I. An empirical review of the empirical literature, 1981-2001. Psychiatry. 2002;65(3):207-239. doi:10.1521/psyc.65.3.207.20173
16. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters. Epidemiol Rev. 2005;27:78-91. doi:10.1093/epirev/mxi003
A Veteran Presenting for Low Testosterone and Lower Urinary Tract Symptoms
►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?
►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.1
►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.
Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.
Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?
►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.2 However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.3 In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.
Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.4 Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.5 In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.
►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?
►Dr. Ananthakrishnan: In a healthy patient, surgery often results in a several-fold increase in the secretion of cortisol to balance the unique stressors surgery places on the body.6 This patient is at increased risk for complete or partial adrenal insufficiency in the setting of both his pituitary macroadenoma as well as his previous left nephrectomy, which could have affected his left adrenal gland as well. Thus, this patient may not be able to mount the appropriate cortisol response needed to counter the stresses of surgery. His cortisol level is abnormally low for a morning value, with a relatively normal ACTH reference range of 6 to 50 pg/mL. He may have some degree of adrenal insufficiency, and thus will benefit from perioperative steroids.
►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.
Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?
►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.7 In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.
►Dr. Bhatnagar: During the first 4 postoperative days the patient produced approximately 1 L of urine per day with a stable creatinine level. It is over this same time that the hydrocortisone was discontinued given improving hemodynamics. However, throughout postoperative day 5, the patient’s creatinine level acutely rose to a peak of 5.8 mg/dL. In addition, his urine output dramatically dropped to < 5 mL per hour, with blood clots noted in his Foley catheter. Dr. Rifkin, what is your differential for causing this acute change in both his creatinine level and urine output this far out from his procedure, and what might you do to help further evaluate?
►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).8 However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.
►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.
Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?
►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.9
There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.10 This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.
►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.
Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.
1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. doi:10.1210/jc.2009-2354
2. Kay FU, Canvasser NE, Xi Y, et al. Diagnostic performance and interreader agreement of a standardized MR imaging approach in the prediction of small renal mass histology. Radiology. 2018;287(2):543-553. doi:10.1148/radiol.2018171557
3. Sahni VA, Silverman SG. Biopsy of renal masses: when and why. Cancer Imaging. 2009;9(1):44-55. doi:10.1102/1470-7330.2009.0005
4. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010;363(7):609-619. doi:10.1056/NEJMoa1000552
5. Kunath F, Schmidt S, Krabbe L-M, et al. Partial nephrectomy versus radical nephrectomy for clinical localised renal masses. Cochrane Database Syst Rev. 2017;5(5):CD012045. doi:10.1002/14651858.CD012045.pub2
6. Kehlet H, Binder C. Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid-treated patients. Br J Anaesth. 1973;45(10):1043-1048. doi:10.1093/bja/45.10.1043
7. Chapman D, Moore R, Klarenbach S, Braam B. Residual renal function after partial or radical nephrectomy for renal cell carcinoma. Can Urol Assoc J. 2010;4(5):337-343. doi:10.5489/cuaj.909
8. Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician. 2012;86(7):631-639.
9. Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab. 2011;15(suppl 3):S188-S196. doi:10.4103/2230-8210.84862
10. Glezer A, Bronstein MD. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch Endocrinol Metab. 2015;59(3):259-264. doi:10.1590/2359-3997000000047
►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?
►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.1
►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.
Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.
Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?
►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.2 However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.3 In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.
Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.4 Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.5 In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.
►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?
►Dr. Ananthakrishnan: In a healthy patient, surgery often results in a several-fold increase in the secretion of cortisol to balance the unique stressors surgery places on the body.6 This patient is at increased risk for complete or partial adrenal insufficiency in the setting of both his pituitary macroadenoma as well as his previous left nephrectomy, which could have affected his left adrenal gland as well. Thus, this patient may not be able to mount the appropriate cortisol response needed to counter the stresses of surgery. His cortisol level is abnormally low for a morning value, with a relatively normal ACTH reference range of 6 to 50 pg/mL. He may have some degree of adrenal insufficiency, and thus will benefit from perioperative steroids.
►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.
Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?
►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.7 In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.
►Dr. Bhatnagar: During the first 4 postoperative days the patient produced approximately 1 L of urine per day with a stable creatinine level. It is over this same time that the hydrocortisone was discontinued given improving hemodynamics. However, throughout postoperative day 5, the patient’s creatinine level acutely rose to a peak of 5.8 mg/dL. In addition, his urine output dramatically dropped to < 5 mL per hour, with blood clots noted in his Foley catheter. Dr. Rifkin, what is your differential for causing this acute change in both his creatinine level and urine output this far out from his procedure, and what might you do to help further evaluate?
►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).8 However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.
►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.
Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?
►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.9
There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.10 This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.
►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.
Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.
►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?
►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.1
►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.
Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.
Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?
►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.2 However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.3 In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.
Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.4 Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.5 In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.
►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?
►Dr. Ananthakrishnan: In a healthy patient, surgery often results in a several-fold increase in the secretion of cortisol to balance the unique stressors surgery places on the body.6 This patient is at increased risk for complete or partial adrenal insufficiency in the setting of both his pituitary macroadenoma as well as his previous left nephrectomy, which could have affected his left adrenal gland as well. Thus, this patient may not be able to mount the appropriate cortisol response needed to counter the stresses of surgery. His cortisol level is abnormally low for a morning value, with a relatively normal ACTH reference range of 6 to 50 pg/mL. He may have some degree of adrenal insufficiency, and thus will benefit from perioperative steroids.
►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.
Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?
►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.7 In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.
►Dr. Bhatnagar: During the first 4 postoperative days the patient produced approximately 1 L of urine per day with a stable creatinine level. It is over this same time that the hydrocortisone was discontinued given improving hemodynamics. However, throughout postoperative day 5, the patient’s creatinine level acutely rose to a peak of 5.8 mg/dL. In addition, his urine output dramatically dropped to < 5 mL per hour, with blood clots noted in his Foley catheter. Dr. Rifkin, what is your differential for causing this acute change in both his creatinine level and urine output this far out from his procedure, and what might you do to help further evaluate?
►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).8 However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.
►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.
Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?
►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.9
There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.10 This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.
►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.
Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.
1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. doi:10.1210/jc.2009-2354
2. Kay FU, Canvasser NE, Xi Y, et al. Diagnostic performance and interreader agreement of a standardized MR imaging approach in the prediction of small renal mass histology. Radiology. 2018;287(2):543-553. doi:10.1148/radiol.2018171557
3. Sahni VA, Silverman SG. Biopsy of renal masses: when and why. Cancer Imaging. 2009;9(1):44-55. doi:10.1102/1470-7330.2009.0005
4. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010;363(7):609-619. doi:10.1056/NEJMoa1000552
5. Kunath F, Schmidt S, Krabbe L-M, et al. Partial nephrectomy versus radical nephrectomy for clinical localised renal masses. Cochrane Database Syst Rev. 2017;5(5):CD012045. doi:10.1002/14651858.CD012045.pub2
6. Kehlet H, Binder C. Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid-treated patients. Br J Anaesth. 1973;45(10):1043-1048. doi:10.1093/bja/45.10.1043
7. Chapman D, Moore R, Klarenbach S, Braam B. Residual renal function after partial or radical nephrectomy for renal cell carcinoma. Can Urol Assoc J. 2010;4(5):337-343. doi:10.5489/cuaj.909
8. Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician. 2012;86(7):631-639.
9. Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab. 2011;15(suppl 3):S188-S196. doi:10.4103/2230-8210.84862
10. Glezer A, Bronstein MD. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch Endocrinol Metab. 2015;59(3):259-264. doi:10.1590/2359-3997000000047
1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. doi:10.1210/jc.2009-2354
2. Kay FU, Canvasser NE, Xi Y, et al. Diagnostic performance and interreader agreement of a standardized MR imaging approach in the prediction of small renal mass histology. Radiology. 2018;287(2):543-553. doi:10.1148/radiol.2018171557
3. Sahni VA, Silverman SG. Biopsy of renal masses: when and why. Cancer Imaging. 2009;9(1):44-55. doi:10.1102/1470-7330.2009.0005
4. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010;363(7):609-619. doi:10.1056/NEJMoa1000552
5. Kunath F, Schmidt S, Krabbe L-M, et al. Partial nephrectomy versus radical nephrectomy for clinical localised renal masses. Cochrane Database Syst Rev. 2017;5(5):CD012045. doi:10.1002/14651858.CD012045.pub2
6. Kehlet H, Binder C. Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid-treated patients. Br J Anaesth. 1973;45(10):1043-1048. doi:10.1093/bja/45.10.1043
7. Chapman D, Moore R, Klarenbach S, Braam B. Residual renal function after partial or radical nephrectomy for renal cell carcinoma. Can Urol Assoc J. 2010;4(5):337-343. doi:10.5489/cuaj.909
8. Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician. 2012;86(7):631-639.
9. Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab. 2011;15(suppl 3):S188-S196. doi:10.4103/2230-8210.84862
10. Glezer A, Bronstein MD. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch Endocrinol Metab. 2015;59(3):259-264. doi:10.1590/2359-3997000000047
Psychedelics and the Military: What a Long, Strange Trip It’s Been
In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.1 While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.2 When I read of these ambitious projects, I recalled 2 prescient memories from my youth.
The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”
The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”
Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.3
Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.4
Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.5 Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.5 These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.
LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.
The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.6 Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.7
This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.8 Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.10 Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.10
These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.9 It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.
1. US Department of Defense, Defense Advanced Research Projects Agency. Structure-guided drug design could yield fast-acting remedies for complex neuropsychiatric conditions. Accessed September 12, 2022. https://www.darpa.mil/news-events/2019-09-11#
2. Londono E. After six-decade hiatus, experimental psychedelic therapy returns to the VA. https://www.nytimes.com/2022/06/24/us/politics/psychedelic-therapy-veterans.html
3. Disbennett B. ‘This is the happy warrior, this is he:’ an analysis of CIA and military testing of LSD on non-consenting U.S. service-members and recovery through the VA disability system. Tennessee J Race, Gender, Social Justice. 2015;3(2):1-32. doi:10.2139/ssrn.2416478
4. Smith H. James Ketchum, who conducted mind-altering experiments on soldiers dies at 87. Accessed September 12, 2022. https://www.washingtonpost.com/local/obituaries/james-ketchum-who-conducted-mind-altering-experiments-on-soldiers-dies-at-87/2019/06/04/7b5ad322-86cc-11e9-a491-25df61c78dc4_story.html
5. Ross CA. LSD experiments by the United States Army. Hist Psychiatry. 2017;28(4):427-442. doi:10.1177/0957154X17717678
6. Albott CS, Lim KO, Forbes MK, et al. Efficacy, safety, and durability of repeated ketamine infusions of comorbid posttraumatic stress disorder and treatment resistant depression. Clin Psychiatry. 2018;79(3): 17m11634. doi:10.4088/JCP.17m11634
7. Shawler IC, Jordan CH, Jackson CA. Veteran and military mental health issues. Stat Pearls. Updated May 23, 2022. Accessed September 12, 2022. https://www.ncbi.nlm.nih.gov/books/NBK572092/#_NBK572092_pubdet_
8. Santayana G. The Life of Reason. 1905. Accessed September 12, 2022. https://www.gutenberg.org/files/15000/15000-h/15000-h.htm
9. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1200.05(2). Requirements for the protection of human subjects in research. Amended January 8, 2021. Accessed September 12, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=8171
10. US Department of Defense, Military Health System. Research protections. Accessed September 12, 2022. https://www.health.mil/About-MHS/OASDHA/Defense-Health-Agency/Research-and-Engineering/Research-Protections
In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.1 While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.2 When I read of these ambitious projects, I recalled 2 prescient memories from my youth.
The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”
The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”
Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.3
Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.4
Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.5 Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.5 These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.
LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.
The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.6 Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.7
This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.8 Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.10 Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.10
These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.9 It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.
In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.1 While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.2 When I read of these ambitious projects, I recalled 2 prescient memories from my youth.
The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”
The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”
Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.3
Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.4
Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.5 Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.5 These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.
LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.
The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.6 Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.7
This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.8 Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.10 Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.10
These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.9 It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.
1. US Department of Defense, Defense Advanced Research Projects Agency. Structure-guided drug design could yield fast-acting remedies for complex neuropsychiatric conditions. Accessed September 12, 2022. https://www.darpa.mil/news-events/2019-09-11#
2. Londono E. After six-decade hiatus, experimental psychedelic therapy returns to the VA. https://www.nytimes.com/2022/06/24/us/politics/psychedelic-therapy-veterans.html
3. Disbennett B. ‘This is the happy warrior, this is he:’ an analysis of CIA and military testing of LSD on non-consenting U.S. service-members and recovery through the VA disability system. Tennessee J Race, Gender, Social Justice. 2015;3(2):1-32. doi:10.2139/ssrn.2416478
4. Smith H. James Ketchum, who conducted mind-altering experiments on soldiers dies at 87. Accessed September 12, 2022. https://www.washingtonpost.com/local/obituaries/james-ketchum-who-conducted-mind-altering-experiments-on-soldiers-dies-at-87/2019/06/04/7b5ad322-86cc-11e9-a491-25df61c78dc4_story.html
5. Ross CA. LSD experiments by the United States Army. Hist Psychiatry. 2017;28(4):427-442. doi:10.1177/0957154X17717678
6. Albott CS, Lim KO, Forbes MK, et al. Efficacy, safety, and durability of repeated ketamine infusions of comorbid posttraumatic stress disorder and treatment resistant depression. Clin Psychiatry. 2018;79(3): 17m11634. doi:10.4088/JCP.17m11634
7. Shawler IC, Jordan CH, Jackson CA. Veteran and military mental health issues. Stat Pearls. Updated May 23, 2022. Accessed September 12, 2022. https://www.ncbi.nlm.nih.gov/books/NBK572092/#_NBK572092_pubdet_
8. Santayana G. The Life of Reason. 1905. Accessed September 12, 2022. https://www.gutenberg.org/files/15000/15000-h/15000-h.htm
9. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1200.05(2). Requirements for the protection of human subjects in research. Amended January 8, 2021. Accessed September 12, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=8171
10. US Department of Defense, Military Health System. Research protections. Accessed September 12, 2022. https://www.health.mil/About-MHS/OASDHA/Defense-Health-Agency/Research-and-Engineering/Research-Protections
1. US Department of Defense, Defense Advanced Research Projects Agency. Structure-guided drug design could yield fast-acting remedies for complex neuropsychiatric conditions. Accessed September 12, 2022. https://www.darpa.mil/news-events/2019-09-11#
2. Londono E. After six-decade hiatus, experimental psychedelic therapy returns to the VA. https://www.nytimes.com/2022/06/24/us/politics/psychedelic-therapy-veterans.html
3. Disbennett B. ‘This is the happy warrior, this is he:’ an analysis of CIA and military testing of LSD on non-consenting U.S. service-members and recovery through the VA disability system. Tennessee J Race, Gender, Social Justice. 2015;3(2):1-32. doi:10.2139/ssrn.2416478
4. Smith H. James Ketchum, who conducted mind-altering experiments on soldiers dies at 87. Accessed September 12, 2022. https://www.washingtonpost.com/local/obituaries/james-ketchum-who-conducted-mind-altering-experiments-on-soldiers-dies-at-87/2019/06/04/7b5ad322-86cc-11e9-a491-25df61c78dc4_story.html
5. Ross CA. LSD experiments by the United States Army. Hist Psychiatry. 2017;28(4):427-442. doi:10.1177/0957154X17717678
6. Albott CS, Lim KO, Forbes MK, et al. Efficacy, safety, and durability of repeated ketamine infusions of comorbid posttraumatic stress disorder and treatment resistant depression. Clin Psychiatry. 2018;79(3): 17m11634. doi:10.4088/JCP.17m11634
7. Shawler IC, Jordan CH, Jackson CA. Veteran and military mental health issues. Stat Pearls. Updated May 23, 2022. Accessed September 12, 2022. https://www.ncbi.nlm.nih.gov/books/NBK572092/#_NBK572092_pubdet_
8. Santayana G. The Life of Reason. 1905. Accessed September 12, 2022. https://www.gutenberg.org/files/15000/15000-h/15000-h.htm
9. US Department of Veterans Affairs, Veterans Health Administration. VHA Directive 1200.05(2). Requirements for the protection of human subjects in research. Amended January 8, 2021. Accessed September 12, 2022. https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=8171
10. US Department of Defense, Military Health System. Research protections. Accessed September 12, 2022. https://www.health.mil/About-MHS/OASDHA/Defense-Health-Agency/Research-and-Engineering/Research-Protections
The truth about the ‘happy hormone’: Why we shouldn’t mess with dopamine
Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.
A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
Levodopa: An indifferent precursor
When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”
Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.
The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
Reserpine and rabbit ears
While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.
Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.
Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.
It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.
Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.
Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
Skeptics are silenced
In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”
That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.
By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
Still misunderstood
The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.
After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.
In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.
Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.
In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.
We should be careful how we handle such a delicate and still little-known system.
A version of this article first appeared on Medscape.com.
Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.
A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
Levodopa: An indifferent precursor
When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”
Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.
The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
Reserpine and rabbit ears
While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.
Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.
Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.
It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.
Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.
Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
Skeptics are silenced
In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”
That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.
By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
Still misunderstood
The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.
After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.
In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.
Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.
In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.
We should be careful how we handle such a delicate and still little-known system.
A version of this article first appeared on Medscape.com.
Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.
A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
Levodopa: An indifferent precursor
When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”
Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.
The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
Reserpine and rabbit ears
While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.
Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.
Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.
It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.
Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.
Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
Skeptics are silenced
In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”
That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.
By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
Still misunderstood
The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.
After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.
In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.
Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.
In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.
We should be careful how we handle such a delicate and still little-known system.
A version of this article first appeared on Medscape.com.
How do patients with chronic urticaria fare during pregnancy?
In addition, the rates of preterm births and medical problems of newborns in patients with CU are similar to those of the normal population and not linked to treatment used during pregnancy.
Those are the key findings from an analysis of new data from PREG-CU, an international, multicenter study of the Urticaria Centers of Reference and Excellence (UCARE) network. Results from the first PREG-CU analysis published in 2021 found that CU improved in about half of patients with CU during pregnancy. “However, two in five patients reported acute exacerbations of CU especially at the beginning and end of pregnancy,” investigators led by Emek Kocatürk, MD, of the department of dermatology and UCARE at Koç University School of Medicine, Istanbul, wrote in the new study, recently published in the Journal of the European Academy of Dermatology and Venereology.
“In addition, 1 in 10 pregnant CU patients required urticaria emergency care and 1 of 6 had angioedema during pregnancy,” they said. Risk factors for worsening CU during pregnancy, they added, were “mild disease and no angioedema before pregnancy, not taking treatment before pregnancy, chronic inducible urticaria, CU worsening during a previous pregnancy, stress as a driver of exacerbations, and treatment during pregnancy.”
Analysis involved 288 pregnant women
To optimize treatment of CU during pregnancy and to better understand how treatment affects pregnancy outcomes, the researchers analyzed 288 pregnancies in 288 women with CU from 13 countries and 21 centers worldwide. Their mean age at pregnancy was 32.1 years, and their mean duration of CU was 84.9 months. Prior to pregnancy, 35.7% of patients rated the severity of their CU symptoms as mild, 34.2% rated it as moderate, and 29.7% rated it as severe.
The researchers found that during pregnancy, 60% of patients used urticaria medication, including standard-dose second-generation H1-antihistamines (35.1%), first-generation H1-antihistamines (7.6%), high-dose second-generation H1-antihistamines (5.6%), and omalizumab (5.6%). The preterm birth rate was 10.2%, which was similar between patients who did and did not receive treatment during pregnancy (11.6% vs. 8.7%, respectively; P = .59).
On multivariate logistic regression, two predictors for preterm birth emerged: giving birth to twins (a 13.3-fold increased risk; P = .016) and emergency referrals for CU (a 4.3-fold increased risk; P =.016). The cesarean delivery rate was 51.3%, and more than 90% of newborns were healthy at birth. There was no link between any patient or disease characteristics or treatments and medical problems at birth.
In other findings, 78.8% of women with CU breastfed their babies. Of the 58 patients who did not breastfeed, 20.7% indicated severe urticaria/angioedema and/or taking medications as the main reason for not breastfeeding.
“Most CU patients use treatment during pregnancy and such treatments, especially second generation H1 antihistamines, seem to be safe during pregnancy regardless of the trimester,” the researchers concluded. “Outcomes of pregnancy in patients with CU were similar compared to the general population and not linked to treatment used during pregnancy. Notably, emergency referral for CU was an independent risk factor for preterm birth,” and the high cesarean delivery rate was “probably linked to comorbidities associated with the disease,” they added. “Overall, these findings suggest that patients should continue their treatments using an individualized dose to provide optimal symptom control.”
International guidelines
The authors noted that international guidelines for the management of urticaria published in 2022 suggest that modern second-generation H1-antihistamines should be used for pregnant patients, preferably loratadine with a possible extrapolation to desloratadine, cetirizine, or levocetirizine.
“Similarly, in this population, we found that cetirizine and loratadine were the most commonly used antihistamines, followed by levocetirizine and fexofenadine,” Dr. Kocatürk and colleagues wrote.
“Guidelines also suggest that the use of first-generation H1-antihistamines should be avoided given their sedative effects; but if these are to be given, it would be wise to know that use of first-generation H1-antihistamines immediately before parturition could cause respiratory depression and other adverse effects in the neonate,” they added, noting that chlorpheniramine and diphenhydramine are the first-generation H1-antihistamines with the greatest evidence of safety in pregnancy.
They acknowledged certain limitations of the analysis, including its retrospective design and the fact that there were no data on low birth weight, small for gestational age, or miscarriage rates. In addition, disease activity or severity during pregnancy and after birth were not monitored.
Asked to comment on these results, Raj Chovatiya, MD, PhD, who directs the center for eczema and itch in the department of dermatology at Northwestern University, Chicago, noted that despite a higher prevalence of CU among females compared with males, very little is known about how the condition is managed during pregnancy. “This retrospective study shows that most patients continue to utilize CU treatment during pregnancy (primarily second-generation antihistamines), with similar birth outcomes as the general population,” he said. “Interestingly, cesarean rates were higher among mothers with CU, and emergency CU referral was a risk factor for preterm birth. While additional prospective studies are needed, these results suggest that CU patients should be carefully managed, particularly during pregnancy, when treatment should be optimized.”
Dr. Kocatürk reported having received personal fees from Novartis, Ibrahim Etem-Menarini, and Sanofi, outside the submitted work. Many coauthors reported having numerous financial disclosures. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.
In addition, the rates of preterm births and medical problems of newborns in patients with CU are similar to those of the normal population and not linked to treatment used during pregnancy.
Those are the key findings from an analysis of new data from PREG-CU, an international, multicenter study of the Urticaria Centers of Reference and Excellence (UCARE) network. Results from the first PREG-CU analysis published in 2021 found that CU improved in about half of patients with CU during pregnancy. “However, two in five patients reported acute exacerbations of CU especially at the beginning and end of pregnancy,” investigators led by Emek Kocatürk, MD, of the department of dermatology and UCARE at Koç University School of Medicine, Istanbul, wrote in the new study, recently published in the Journal of the European Academy of Dermatology and Venereology.
“In addition, 1 in 10 pregnant CU patients required urticaria emergency care and 1 of 6 had angioedema during pregnancy,” they said. Risk factors for worsening CU during pregnancy, they added, were “mild disease and no angioedema before pregnancy, not taking treatment before pregnancy, chronic inducible urticaria, CU worsening during a previous pregnancy, stress as a driver of exacerbations, and treatment during pregnancy.”
Analysis involved 288 pregnant women
To optimize treatment of CU during pregnancy and to better understand how treatment affects pregnancy outcomes, the researchers analyzed 288 pregnancies in 288 women with CU from 13 countries and 21 centers worldwide. Their mean age at pregnancy was 32.1 years, and their mean duration of CU was 84.9 months. Prior to pregnancy, 35.7% of patients rated the severity of their CU symptoms as mild, 34.2% rated it as moderate, and 29.7% rated it as severe.
The researchers found that during pregnancy, 60% of patients used urticaria medication, including standard-dose second-generation H1-antihistamines (35.1%), first-generation H1-antihistamines (7.6%), high-dose second-generation H1-antihistamines (5.6%), and omalizumab (5.6%). The preterm birth rate was 10.2%, which was similar between patients who did and did not receive treatment during pregnancy (11.6% vs. 8.7%, respectively; P = .59).
On multivariate logistic regression, two predictors for preterm birth emerged: giving birth to twins (a 13.3-fold increased risk; P = .016) and emergency referrals for CU (a 4.3-fold increased risk; P =.016). The cesarean delivery rate was 51.3%, and more than 90% of newborns were healthy at birth. There was no link between any patient or disease characteristics or treatments and medical problems at birth.
In other findings, 78.8% of women with CU breastfed their babies. Of the 58 patients who did not breastfeed, 20.7% indicated severe urticaria/angioedema and/or taking medications as the main reason for not breastfeeding.
“Most CU patients use treatment during pregnancy and such treatments, especially second generation H1 antihistamines, seem to be safe during pregnancy regardless of the trimester,” the researchers concluded. “Outcomes of pregnancy in patients with CU were similar compared to the general population and not linked to treatment used during pregnancy. Notably, emergency referral for CU was an independent risk factor for preterm birth,” and the high cesarean delivery rate was “probably linked to comorbidities associated with the disease,” they added. “Overall, these findings suggest that patients should continue their treatments using an individualized dose to provide optimal symptom control.”
International guidelines
The authors noted that international guidelines for the management of urticaria published in 2022 suggest that modern second-generation H1-antihistamines should be used for pregnant patients, preferably loratadine with a possible extrapolation to desloratadine, cetirizine, or levocetirizine.
“Similarly, in this population, we found that cetirizine and loratadine were the most commonly used antihistamines, followed by levocetirizine and fexofenadine,” Dr. Kocatürk and colleagues wrote.
“Guidelines also suggest that the use of first-generation H1-antihistamines should be avoided given their sedative effects; but if these are to be given, it would be wise to know that use of first-generation H1-antihistamines immediately before parturition could cause respiratory depression and other adverse effects in the neonate,” they added, noting that chlorpheniramine and diphenhydramine are the first-generation H1-antihistamines with the greatest evidence of safety in pregnancy.
They acknowledged certain limitations of the analysis, including its retrospective design and the fact that there were no data on low birth weight, small for gestational age, or miscarriage rates. In addition, disease activity or severity during pregnancy and after birth were not monitored.
Asked to comment on these results, Raj Chovatiya, MD, PhD, who directs the center for eczema and itch in the department of dermatology at Northwestern University, Chicago, noted that despite a higher prevalence of CU among females compared with males, very little is known about how the condition is managed during pregnancy. “This retrospective study shows that most patients continue to utilize CU treatment during pregnancy (primarily second-generation antihistamines), with similar birth outcomes as the general population,” he said. “Interestingly, cesarean rates were higher among mothers with CU, and emergency CU referral was a risk factor for preterm birth. While additional prospective studies are needed, these results suggest that CU patients should be carefully managed, particularly during pregnancy, when treatment should be optimized.”
Dr. Kocatürk reported having received personal fees from Novartis, Ibrahim Etem-Menarini, and Sanofi, outside the submitted work. Many coauthors reported having numerous financial disclosures. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.
In addition, the rates of preterm births and medical problems of newborns in patients with CU are similar to those of the normal population and not linked to treatment used during pregnancy.
Those are the key findings from an analysis of new data from PREG-CU, an international, multicenter study of the Urticaria Centers of Reference and Excellence (UCARE) network. Results from the first PREG-CU analysis published in 2021 found that CU improved in about half of patients with CU during pregnancy. “However, two in five patients reported acute exacerbations of CU especially at the beginning and end of pregnancy,” investigators led by Emek Kocatürk, MD, of the department of dermatology and UCARE at Koç University School of Medicine, Istanbul, wrote in the new study, recently published in the Journal of the European Academy of Dermatology and Venereology.
“In addition, 1 in 10 pregnant CU patients required urticaria emergency care and 1 of 6 had angioedema during pregnancy,” they said. Risk factors for worsening CU during pregnancy, they added, were “mild disease and no angioedema before pregnancy, not taking treatment before pregnancy, chronic inducible urticaria, CU worsening during a previous pregnancy, stress as a driver of exacerbations, and treatment during pregnancy.”
Analysis involved 288 pregnant women
To optimize treatment of CU during pregnancy and to better understand how treatment affects pregnancy outcomes, the researchers analyzed 288 pregnancies in 288 women with CU from 13 countries and 21 centers worldwide. Their mean age at pregnancy was 32.1 years, and their mean duration of CU was 84.9 months. Prior to pregnancy, 35.7% of patients rated the severity of their CU symptoms as mild, 34.2% rated it as moderate, and 29.7% rated it as severe.
The researchers found that during pregnancy, 60% of patients used urticaria medication, including standard-dose second-generation H1-antihistamines (35.1%), first-generation H1-antihistamines (7.6%), high-dose second-generation H1-antihistamines (5.6%), and omalizumab (5.6%). The preterm birth rate was 10.2%, which was similar between patients who did and did not receive treatment during pregnancy (11.6% vs. 8.7%, respectively; P = .59).
On multivariate logistic regression, two predictors for preterm birth emerged: giving birth to twins (a 13.3-fold increased risk; P = .016) and emergency referrals for CU (a 4.3-fold increased risk; P =.016). The cesarean delivery rate was 51.3%, and more than 90% of newborns were healthy at birth. There was no link between any patient or disease characteristics or treatments and medical problems at birth.
In other findings, 78.8% of women with CU breastfed their babies. Of the 58 patients who did not breastfeed, 20.7% indicated severe urticaria/angioedema and/or taking medications as the main reason for not breastfeeding.
“Most CU patients use treatment during pregnancy and such treatments, especially second generation H1 antihistamines, seem to be safe during pregnancy regardless of the trimester,” the researchers concluded. “Outcomes of pregnancy in patients with CU were similar compared to the general population and not linked to treatment used during pregnancy. Notably, emergency referral for CU was an independent risk factor for preterm birth,” and the high cesarean delivery rate was “probably linked to comorbidities associated with the disease,” they added. “Overall, these findings suggest that patients should continue their treatments using an individualized dose to provide optimal symptom control.”
International guidelines
The authors noted that international guidelines for the management of urticaria published in 2022 suggest that modern second-generation H1-antihistamines should be used for pregnant patients, preferably loratadine with a possible extrapolation to desloratadine, cetirizine, or levocetirizine.
“Similarly, in this population, we found that cetirizine and loratadine were the most commonly used antihistamines, followed by levocetirizine and fexofenadine,” Dr. Kocatürk and colleagues wrote.
“Guidelines also suggest that the use of first-generation H1-antihistamines should be avoided given their sedative effects; but if these are to be given, it would be wise to know that use of first-generation H1-antihistamines immediately before parturition could cause respiratory depression and other adverse effects in the neonate,” they added, noting that chlorpheniramine and diphenhydramine are the first-generation H1-antihistamines with the greatest evidence of safety in pregnancy.
They acknowledged certain limitations of the analysis, including its retrospective design and the fact that there were no data on low birth weight, small for gestational age, or miscarriage rates. In addition, disease activity or severity during pregnancy and after birth were not monitored.
Asked to comment on these results, Raj Chovatiya, MD, PhD, who directs the center for eczema and itch in the department of dermatology at Northwestern University, Chicago, noted that despite a higher prevalence of CU among females compared with males, very little is known about how the condition is managed during pregnancy. “This retrospective study shows that most patients continue to utilize CU treatment during pregnancy (primarily second-generation antihistamines), with similar birth outcomes as the general population,” he said. “Interestingly, cesarean rates were higher among mothers with CU, and emergency CU referral was a risk factor for preterm birth. While additional prospective studies are needed, these results suggest that CU patients should be carefully managed, particularly during pregnancy, when treatment should be optimized.”
Dr. Kocatürk reported having received personal fees from Novartis, Ibrahim Etem-Menarini, and Sanofi, outside the submitted work. Many coauthors reported having numerous financial disclosures. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.
FROM JEADV
