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April 22, 2024

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Experimental model elucidates willful starvation in anorexia nervosa

by Jacqueline Mitchell, Beth Israel Deaconess Medical Center

A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) suggests that female mice that are prone to anxiety may prefer and actively seek out a starvation-like state in response to repeated exposure to stress. The findings, published in the journal Neuron , may provide a useful experimental model for investigating the neural mechanisms underlying anorexia nervosa—particularly its onset.

"While anorexia nervosa has been documented for over 300 years, its underlying causes remain unknown," said first author Hakan Kucukdereli, Ph.D., of the division of Endocrinology, Diabetes and Metabolism in the Department of Medicine at BIDMC.

"Current animal models fail to capture a key hallmark of the disorder—willful starvation. Thus, there has been the pressing need for a pre-clinical mouse model that captures the intentional seeking of a starvation state."

In healthy individuals, the state of hunger (or caloric deficit) is a mildly uncomfortable state that drives food-seeking behavior. In the lab, Kucukdereli, senior author Mark L. Andermann, and colleagues knew that precise stimulation of a few thousand neurons known as AgRP neurons will cause even a well-fed mouse to seek out another meal.

They also knew that actual food restriction—which activates these AgRP neurons—and the artificial starvation state caused by stimulating these neurons can tamp down anxiety, thereby promoting food-seeking. (Imagine a hungry mouse in your kitchen that needs to be bold enough to hunt for food, even when your cat is around.)

Based on prior associations between stress , anxiety, and anorexia nervosa, Andermann and colleagues hypothesized that exposure to high levels of stress may actually trigger individuals to willfully seek starvation as a means of reducing anxiety. The scientists trained 15 male and 17 female mice to run through a virtual reality corridor where they could choose to stop in one room associated with stimulation of their AgRP neurons or a second room associated with no stimulation.

In the absences of stress, male mice avoided AgRP stimulation; however, only a minority of female mice exhibited a strong aversion to it. Subsequent to repeated stress, however, many of these same mice behaved very differently. When the researchers exposed the mice to a five-minute period of unpredictable tail shocks, the males became, on average, less averse to AgRP stimulation. Meanwhile, female mice—on average—preferred AgRP stimulation following stress.

"Strikingly, a subset of females, but not males, began to vigorously seek this starvation-like state following stress," said Andermann, who is also a professor of Medicine and Neurobiology at Harvard Medical School. "Surprisingly, individuals' baseline levels of anxiety-like behavior measured weeks before the experiment could predict which females will develop a preference for this starvation-like state."

Using machine learning to analyze the animals' facial expressions, the researchers found that, after exposure to stress, female mice with strong preference for AgRP stimulation also showed facial expressions that directly correlated with their behavior, potentially reflecting relief associated with a reduction in anxiety.

"Future research can link these moment-to-moment changes in facial expressions with ongoing activity of many neurons in brain regions that track physiological states or that process negative emotions ," Kucukdereli said. "Our approach lays the groundwork for future work that will identify the neural circuits that underlie the voluntary maintenance of long-term starvation in individuals with anorexia nervosa."

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Key searches, groundbreaking study shows substantial differences in brain structure in people with anorexia.

New findings from the largest study to date by an international group of neuroscience experts show significant reductions in grey matter in people with anorexia nervosa.

Eating disorders are often misunderstood as lifestyle choices gone awry or oversimplified as the unfortunate result of societal pressures. These misconceptions obscure the fact that eating disorders are serious and potentially fatal mental illnesses that can be treated effectively with early intervention. Mortality rates for people with eating disorders are high compared to other mental illnesses, particularly for those with anorexia nervosa, a condition characterized by a severe restriction of food intake and an abnormally low body weight. People with anorexia can literally starve themselves, causing severe and potentially fatal medical complications. The second leading cause of death for people with anorexia is suicide.

Now, a groundbreaking new study by a global team of researchers led by the Keck School of Medicine of USC’s Mark and Mary Stevens Neuroimaging and Informatics Institute ( Stevens INI )  has revealed that individuals with anorexia demonstrate notable reductions in three critical measures of the brain: cortical thickness, subcortical volumes, and cortical surface area. These reductions are between two and four times larger than the abnormalities in brain size and shape of individuals with other mental illnesses. Reductions in brain size are particularly concerning, as they may imply the destruction of brain cells or the connections between them.

Equipped with these results, the research team is calling attention to the pressing need for prompt treatment to help people with anorexia avoid long-term, structural brain changes, which could lead to a variety of additional medical issues. Anorexia can be successfully treated with healthy weight gain and cognitive behavioral therapy. Ongoing work by the same group shows that successful treatment can have a positive impact on brain structure.

“By comparing nearly 2,000 pre-existing brain scans for people with anorexia, people in recovery and healthy controls, we found that for people in recovery from anorexia, reductions in brain structure were less severe,” says Paul M. Thompson, PhD , associate director of the Stevens INI. “This implies that early treatment and support can help the brain to repair itself.”

In addition to researchers from the Stevens INI, the research team includes neuroscientists from the Technical University in Dresden, Germany; the Icahn School of Medicine at Mount Sinai, New York; University of Bath, UK; and King’s College London. The researchers came together under the ENIGMA Eating Disorders working group ( ENIGMA-ED ), a part of the  ENIGMA Consortium , co-founded and led by Thompson. ENIGMA is an international effort to bring together researchers in imaging genomics, neurology, and psychiatry, to understand the link between brain structure, function and mental health.

Through advances in neuroimaging, researchers are gaining a better understanding of the link between serious mental health disorders and brain abnormalities. By demonstrating the effects of anorexia on brain structure, ENIGMA-ED has underscored the severity of the condition and the need for early intervention, while paving the way for the development of more effective treatments.

“The international scale of this work is extraordinary. Because scientists from twenty-two centers worldwide pooled their brain scans together, we were able to create the most detailed picture to date of how anorexia affects the brain, “says Thompson, professor of ophthalmology, neurology, psychiatry and the behavioral sciences, radiology, pediatrics and engineering. “The brain changes in anorexia were more severe than in any other psychiatric condition we have studied. Effects of treatments and interventions can now be evaluated, using these new brain maps as a reference.”

“This study exemplifies why the work at the Stevens INI is so essential,” says INI Director and longtime colleague of Thompson, Arthur W. Toga , PhD. “The goal of the ENIGMA Consortium is to bring researchers together from around the world so that we can combine existing data samples and really improve our power to examine the brain and detect the subtle brain alterations associated with a given illness. At the Stevens INI we apply this goal to all our large-scale studies. We are committed to participating in large studies with diverse research cohorts and sharing data to advance the entire scientific community.”

About ENIGMA ED

ENIGMA-ED is dedicated to improving our understanding of structural brain changes in patients with anorexia nervosa and bulimia nervosa and how those changes normalize during or after recovery. This group aims to conduct a meta-analysis of existing MRI data with adolescents and adults who have or had an eating disorder in the past. ENIGMA-ED welcomes new cohorts. For more information on how to join and contribute anorexia nervosa data, contact Dr. Stefan Ehrlich ( [email protected] ). To join and contribute bulimia nervosa data, contact Dr. Laura Berner ( [email protected] ).

Several researchers at the Stevens INI have also partnered with Stuart Murray , director of the Eating Disorders Program at the Keck School of Medicine of USC to study binge eating disorder in young children . See their most recent findings here and here .

Access the full study  ‘Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals with Anorexia Nervosa – A Coordinated Analysis by the ENIGMA Eating Disorders Working Group’  published in the Journal Biological Psychiatry . Other USC co-authors contributing to the study include Neda Jahanshad, PhD, associate professor of neurology and biomedical engineering, and Sophia Thomopoulos, BS, consortium manager for the ENIGMA study.

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Journal of Eating Disorders

Call for papers: mindful journeys: a careful exploration of psychedelics in eating disorder treatment.

Phillipa Hay , Editor-in-Chief

Western Sydney University, Australia

Professor Phillipa Hay is a leading mental health researcher, educator, and practicing Psychiatrist. Her research has been translational, guided policy and practice, and award winning, e.g., in 2015 she received the Lifetime Leadership Award from the ANZ Academy for Eating Disorders, and in 2020 she was awarded the Royal Australian and New Zealand College of Psychiatrists (RANZCP) Senior Research Award. She laid the foundations for mental health programs in two new medical schools James Cook and Western Sydney. She has a DPhil in Psychiatry from the University of Oxford and MD (Medicine) from University of Otago, is a Fellow of the RANZCP, and Fellow of the Academy for Eating Disorders (AED).

Stephen Touyz , Editor-in-Chief

University of Sydney, Australia

Stephen Touyz is an Emeritus Professor at the University of Sydney and Director of the Inside Out Institute, a joint partnership between the Sydney Local Health District and the University of Sydney. He is Editor in Chief of the Journal of Eating Disorders which he co-founded a decade ago. He is a past president of the Eating Disorders Research Society. He is a member of the Commonwealth Government of Australia’s Technical Advisory Group for Eating Disorders and a member of the steering committee of the National Eating Disorders Collaboration. He was presented with a leadership award in research by the Academy of Eating Disorders in 2012, the first ever Lifetime Achievement Award by the Australian and New Zealand Academy of Eating Disorders in 2014 and the Ian M Campbell Prize in Clinical Psychology from the Australian Psychological Society in 2014. He has edited/co-edited 6 books and published over 480 scholarly papers/book chapters.

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• Published: 24 July 2023

Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study

• Stephanie Knatz Peck   ORCID: orcid.org/0000-0001-9421-9158 1 ,
• Samantha Shao 1 ,
• Tessa Gruen 1 , 2 ,
• Kevin Yang   ORCID: orcid.org/0000-0002-1451-258X 1 ,
• Alexandra Babakanian 1 ,
• Julie Trim 1 ,
• Daphna M. Finn   ORCID: orcid.org/0000-0003-2572-7778 1 &
• Walter H. Kaye   ORCID: orcid.org/0000-0002-4478-4906 1  

Nature Medicine volume  29 ,  pages 1947–1953 ( 2023 ) Cite this article

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This article has been updated

Anorexia nervosa (AN) is a deadly illness with no proven treatments to reverse core symptoms and no medications approved by the US Food and Drug Administration. Novel treatments are urgently needed to improve clinical outcomes. In this open-label feasibility study, 10 adult female participants (mean body mass index 19.7 kg m − 2 ; s.d. 3.7) who met Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) criteria for AN or pAN (partial remission) were recruited to a study conducted at an academic clinical research institute. Participants received a single 25-mg dose of synthetic psilocybin in conjunction with psychological support. The primary aim was to assess safety, tolerability and feasibility at post-treatment by incidences and occurrences of adverse events (AEs) and clinically significant changes in electrocardiogram (ECG), laboratory tests, vital signs and suicidality. No clinically significant changes were observed in ECG, vital signs or suicidality. Two participants developed asymptomatic hypoglycemia at post-treatment, which resolved within 24 h. No other clinically significant changes were observed in laboratory values. All AEs were mild and transient in nature. Participants’ qualitative perceptions suggest that the treatment was acceptable for most participants. Results suggest that psilocybin therapy is safe, tolerable and acceptable for female AN, which is a promising finding given physiological dangers and problems with treatment engagement. ClinicalTrials.gov identifier NCT04661514 .

Anorexia nervosa (AN) is a costly and deadly mental illness, which is notoriously difficult to treat 1 . It is associated with substantial morbidity and mortality, including an elevated suicide rate and an 18-fold increase in mortality 2 , 3 . Despite its seriousness, there are no proven treatments for adult AN that reverse core symptoms and no approved pharmacological interventions 1 . As a result, estimates suggest that less than half of patients achieve recovery; relapse rates approach 50%; and approximately 20% of those with AN will develop a chronic course 3 . There have been minimal advancements in novel treatment strategies and stagnant outcomes over the past several decades, resulting in a ‘crisis in care’ 4 , 5 . Novel and innovative treatments methods are urgently needed to improve treatment engagement and outcomes. One such avenue may be psilocybin therapy.

Psilocybin is a psychedelic molecule whose mechanism of action is thought to be mediated by serotonin 2A (5-HT 2A ) 6 and is the main psychoactive compound in the Psilocybe genus of mushrooms 7 . Considerable evidence suggests that individuals with AN have altered brain serotonin (5-HT) function, altered function of the 5-HT 2A receptor and altered endogenous brain 5-HT secretion 8 , 9 , supporting the speculation that the 5-HT 2A effects of psilocybin might effect change in AN symptoms. Unlike other serotonergic medications requiring repeated administrations, a single dose of psilocybin may lead to rapid and enduring synaptic adaptations that have the potential to improve AN symptoms 10 . However, the role of 5-HT dysfunction in AN and related affective states associated with restriction remains poorly understood with mixed findings 11 , 12 .

Mechanisms of action are not well elucidated, but psilocybin is thought to directly modulate the serotonergic system and indirectly modulate dopaminergic and glutamatergic systems and gene expression 10 . Psilocybin effects have been documented at the pharmacological, neural and psychological levels, all of which may contribute to improvements in mental illness 13 . Findings suggest that psilocybin may increase emotional and brain network plasticity, which may be responsible for sustained improvements in mental health status 14 . Psilocybin therapy typically involves the administration of psilocybin in conjunction with psychological support delivered by one to two trained therapists 15 . When administered in a safe and therapeutic setting in conjunction with psychological support, participants can report transformative experiences characterized by profound changes in values, beliefs and perspectives, which can lead to positive changes in subjective well-being, increased openness and greater cognitive flexibility 16 , 17 , 18 . Available evidence suggests that psilocybin therapy may hold promise for other treatment-resistant mental illnesses with studies demonstrating robust and rapid effects, but no modern studies have reported data on potential effects for AN 19 .

AN is characterized by excessive and undue preoccupation, fear and distress surrounding food, weight, shape and eating. This typically leads to rigid and repetitive behavioral patterns of control, such as restriction 20 . Improvements in anxiety 21 and cognitive flexibility 18 , 22 , which have been shown to occur with psilocybin therapy, may assist with disrupting cardinal symptoms of AN mediated by these mechanisms, including eating disorder (ED)-related preoccupations, rigid thinking styles and entrenched behavioral patterns 23 , 24 . AN is often ego-syntonic in nature 25 , and AN behaviors are perceived as effective means to achieve internalized weight/shape ideals and avoid dysphoric mood states that result from eating 9 . Thus, individuals with AN may resist intervention or fail to acknowledge the seriousness of the illness, resulting in low treatment acceptability and substantial treatment dropout 26 . Psilocybin therapy, which has been shown to improve openness 27 and occasion transformative experiences 17 , may facilitate a re-organization of values, shifting the relative importance of shape and weight and/or induce greater permeability to new attitudes and behaviors by directly targeting these features. Previous observational and naturalistic studies exploring the value of psilocybin and other psychedelic drugs in people with EDs have reported on emerging themes, such as increased affective and intellectual awareness, reduction in ED symptoms, positive mood changes, emotional processing and increases in self-acceptance 28 , 29 , 30 .

To date, no modern publications have reported data regarding the safety, tolerability and efficacy of psilocybin therapy for AN within the context of a clinical intervention; however, at the time of this publication, two additional registered clinical trials are currently underway ( NCT04505189 and NCT04052568 ), and other ED expert groups have provided rationales for further evaluation of psychedelic treatments for AN 31 , 32 .

To our knowledge, the present study is the first modern trial to report data on the safety, tolerability and exploratory efficacy of a single 25-mg dose of psilocybin in conjunction with psychological support.

Patient information

Enrollment started in April 2021 and finished in December 2021. In total, 158 individuals expressed interest in participating. Most were self-referred and became familiar with the study via ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT04661514 ) or through community providers familiar with the study through community outreach efforts (see Table 1 for sample demographics, Fig. 1 for study design and timeline, and Fig. 2 for participant flowchart).

This figure outlines the participation process from prescreening through end of study (EOS) for participants.

This figure summarizes the number of participants captured and retained through the screening process. COMP360, psilocybin.

Source data

Primary outcomes: safety and tolerability.

To evaluate safety, we examined changes in vital signs, electrocardiograms (ECGs), clinical laboratory tests and suicidality from baseline (day −1) to day 1 (Table 2 ) and 1-week follow-up; we also examined reports of adverse events (AEs). The acute effects of psilocybin were well tolerated by all participants, and no serious AEs were observed (Table 2 ). No clinically significant changes were observed in vital signs or ECG. In relation to clinical laboratory values, two participants, both of whom were required to eat breakfast at the clinic before administration, developed hypoglycemia in follow-up clinical laboratory assessments, which resolved within 24 h. Participants were asymptomatic, and no intervention was required. No other clinically significant changes were observed in laboratory values. Suicidality was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) 33 at each timepoint. There were no increases in suicidal ideation (SI), and no suicidal behaviors were present in the post-dosing follow-up visits. One participant with a history of major depressive disorder (MDD) and SI reported an increase in SI at 3-month follow-up, which did not appear related to study participation. AEs (Table 2 ) were mild and transient in nature, with headache, nausea and fatigue being the most common.

Secondary outcomes: changes in psychopathology

Average changes on Eating Disorder Examination (EDE) subscales are shown in Table 3 . Results from t -tests indicated that weight concerns decreased significantly from baseline (day −1) to 1-month ( P  = 0.036, Cohenʼs d  = 0.78) and 3-month ( P  = 0.04, d  = 0.78) follow-up, with a medium to large effect. Shape concerns significantly decreased at 1-month follow-up ( P  = 0.036, d  = 0.78) but were no longer significant at 3-month follow-up ( P  = 0.081, d  = 0.62). Changes on the eating concern and dietary restraint subscales were not significant, but changes in eating concerns approached significance at 3-month follow-up ( P  = 0.051, d  = 0.71). Effects of treatment were, however, highly variable among participants, as is illustrated from the case series data (Extended Data Fig. 1 ). Four participants (40% of sample) demonstrated global EDE scores that decreased to within 1 s.d. of community norms (mean 0.93, s.d. 0.80) 34 at 3-month follow-up (Extended Data Fig. 2 ), which we interpret to be clinically significant. No correlations were observed between any assessed participant characteristics and outcomes. Three of four responders met criteria for AN (versus pAN), and one had a diagnosis of anorexia nervosa binge–purge (AN-BP).

Body mass index

On average, changes in body mass index (BMI) were not statistically significant (see Extended Data Tables 2 and 3 for mean BMI scores over time and BMI changes over time for each participant). Of the four participants who demonstrated clinically significant reductions in eating disorder pathology as measured by the EDE, changes in BMI were variable, and there was no correlation between outcomes and weight status. Five participants demonstrated an increase in BMI at 3-month follow-up (range, 0.4–1.2 kg m − 2 ).

Other secondary measures of psychopathology

Results for other secondary measures were also highly variable among participants. On average, participants demonstrated significant reductions at the primary endpoint of 1-month follow-up across the following domains: trait body image anxiety (Physical Appearance State and Trait Anxiety Scale (PASTAS)) ( P  = 0.04, d  = 0.76), trait anxiety (Spielberger State-Trait Anxiety Inventory (STAI-T)) ( P  = 0.036, d  = 0.78) and preoccupations and rituals surrounding food, eating and shape (Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS)) ( P  = 0.043, d  = 0.75) (Extended Data Tables 2 and 4 ).

Exploratory outcomes: changes in psychopathology

Patient experience and acceptability.

Qualitative responses highlighting participants’ reports of impactfulness are summarized in Table 4 . Overall, the psilocybin experience was regarded as meaningful by participants. Ninety percent endorsed feeling more positive about life endeavors; 80% endorsed the experience as one of the top five most meaningful of life; and 70% reported experiencing a shift in personal identity and overall quality of life. Notably, 90% of participants reported that one dosing session was not enough. Phenomenological and qualitative information related to participants’ experience will be presented in a forthcoming manuscript.

Response to psilocybin

Average self-reported intensity of the experience using the 11 subscales of the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire is reported in Extended Data Fig. 3 . No participants required anxiolytic rescue medication during the dosing session.

Exploratory measures of psychopathology

We also explored changes in depression scores (Quick Inventory of Depressive Symptomatology (QIDS)), functional impairment related to ED psychopathology (Clinical Impairment Assessment (CIA)) and readiness and motivation to change (Readiness Motivation Questionnaire (RMQ)) at 1-month follow-up. Results are presented in Extended Data Table 5 . Results from t -tests indicated that functional impairment related to disordered eating as measured by the CIA decreased significantly from baseline (day −1) to 1 month ( P  = 0.041, d  = 0.75). Other changes measured were not statistically significant.

To our knowledge, this is the first data report on the effects of psilocybin therapy in AN in a clinical research trial. This open-label pilot study examined the safety and tolerability of administering psilocybin therapy to participants with AN and pAN. We chose to include participants in partial remission because we were most interested in exploring potential changes in core ED psychopathology (versus weight), which can lead to treatment resistance and which can persist after weight restoration 35 . Additionally, pAN has been shown to be common, severe, persistent and undertreated 3 , 35 .

Psilocybin therapy, which includes psychological support by trained therapists, was found to be safe and well tolerated for the 10 participants who received treatment in this study. Most participants endorsed the treatment as highly meaningful and the experience as a positive life impact, and yet effects on ED psychopathology were highly variable, with a subset of participants demonstrating a robust response for a single-dose treatment. Results of this study are preliminary and inconclusive given its size and design. In this section, we discuss study findings related to primary outcomes, patient acceptability and qualitative perceptions as well as ED-specific psychopathology.

No participants in our study experienced any serious AEs, and all treatment-emergent AEs resolved within 24 h and without intervention (with the exception of one report of orthostatic heart rate that was reported at 3-month follow-up for one participant). Hypoglycemia occurred in two participants on the dosing day and resolved in 24 h. We hypothesize that this was related to a prolonged period of fasting on the dosing day (a common effect of psilocybin) versus any direct relationship to the drug, given the state of malnutrition and low carbohydrate stores associated with AN. Food was available on request to participants during the dosing day, but participants were not required to eat during the therapeutic experience. To our knowledge, there are no reports of psilocybin-induced hypogylcemia. However, individuals with AN often have reduced plasma glucose levels 36 . The incidence of hypoglycemia is clinically important and may indicate that attention to blood glucose levels before and after intervention may be warranted in participants with compromised nutritional status given the dangers associated with hypoglycemia in AN, including sudden death 36 . Both incidents of hypoglycemia occurred in participants who were given a standardized breakfast upon arrival. AN has a high prevalence of serious medical complications and physiological disturbances, which account for much illness-related death. The lack of negative incidences regarding safety in our study is promising for future research with the AN population; however, larger studies with a more diverse participant group continue to be needed to determine safety 37 .

Most participants self-reported positive changes 3 months after the psilocybin dosing. That the treatment was regarded as beneficial by most participants and that there were no dropouts are promising signs of engagement. Dropout rates in currently available treatments tend to be high 38 . Positive patient perceptions are also notable because they may suggest improved quality of life, which is clinically important for those with a potentially severe and enduring illness 38 . These self-reported data suggest that most participants perceived some benefit that may have been ED-non-specific in nature or not well captured by our assessment measures. Although our treatment included AN-specific therapeutic elements, adjunctive therapy was brief. Additional therapeutic methods, or extended therapeutic time, may be a useful consideration to facilitate further behavioral change and increased specificity, as has been employed in other psilocybin studies 39 , 40 . Our effect sizes and response rates were less robust than those reported for primary outcomes in psilocybin studies for other psychiatric disorders 41 , 42 , 43 . This may also be related to a heterogenous sample, a single-dose trial (compared to a two-dose design used in other studies), a lack of sensitivity in assessment measures or unique/specific features of AN that are not as readily addressed by psilocybin therapy or that require dosing adjustments. AN is a difficult-to-treat disorder with a complex physiology and physical recovery needs that differentiate it from other mental illnesses. Notably, 90% of participants reported that one dosing session was not enough, suggesting that an additional psilocybin experience(s) may be beneficial 44 .

Our exploratory analysis showed some significant reductions in ED-related psychopathology when the sample was aggregated; however, the results were highly variable among participants. Forty percent (4/10) of participants demonstrated clinically significant reductions 34 in ED psychopathology (EDE) at 3-month follow-up, with scores decreasing from clinical ranges to within 1 s.d. of community normative values 34 . Within the responder group, ED psychopathology decreased precipitously and dropped below clinical levels within the month after the psilocybin dosing session. Three of the responders were not enrolled in any concurrent mental health services during the study period but had mental health treatment histories, and one was in longstanding, outpatient therapy that did not change during study enrollment. Symptoms continued to improve between 1-month and 3-month follow-up. Given the size and design of this study, these effects are preliminary and inconclusive. However, it is notable that we found such a robust response in a subset of participants in a single-dose trial of psilocybin delivered over a brief time period, because currently available treatments for adult AN result in only modest improvements in symptoms and often focus on weight and nutritional rehabilitation without adequately addressing underlying psychopathology 38 . Participants also experienced significant reductions in anxiety; however, mean changes in depression scores were not significant. Changes in general psychopathology may partially explain the effects on ED symptoms 44 .

We did not observe a significant effect on BMI over time, and results were highly variable among participants. BMI did not follow the same change trajectory as ED psychopathology for participants who showed reductions on core psychopathology. Of the four treatment responders, two showed positive BMI trends, one remained stable at a normal BMI and one showed a two-point decrease over time. It is also possible that a longer follow-up period is necessary to observe meaningful changes in BMI, which has been suggested by ED experts 45 , 46 . Notably, there are well-documented phenomena associated with AN that impede upon weight rehabilitation, including hypermetabolism and unusually high caloric requirements 37 . When queried about the lack of weight change, one treatment responder stated, ‘The irony is that now that I want to recover I can eat intuitively, but that is not enough to support physical recovery’. These findings may suggest that targeted nutritional rehabilitation emblematic of traditional treatment may be a necessary adjunctive treatment even when significant improvements in ED psychopathology are conferred.

Limitations of this study include its small sample size, the lack of a control comparison and the open-label design. Owing to the exploratory nature of this study, we did not conduct a power analysis or correct for multiple comparisons. As a result, these findings are not conclusive and should be interpreted with caution. Additionally, all of the participants were self-referred, which may have resulted in a selection bias. Similarly, suggestibility and expectations of positive outcomes related to positive popular media coverage surrounding psychedelics, and attending treatment at a well-reputed ED service (particularly for those who were nonlocal), may have resulted in a suggestibility that influenced positive outcomes. Our sample included a diverse range of severity; however, many participants had mild to moderate AN. More research is needed to evaluate psilocybin therapy for severe presentations. The study also lacked gender, racial and cultural diversity.

Strengths of this study included administration of a precise dose of pure synthesized psilocybin and the evaluation of a highly novel treatment modality for a treatment-resistant population. Larger, adequately powered, well-controlled trials with comparator treatments are needed to evaluate the efficacy of psilocybin therapy in a diverse sample of patients with AN. Future studies should further investigate mechanisms of action and moderators of treatment to discern how psilocybin may lead to changes in AN and whether psilocybin therapy is more suitable and effective for a specific subset of AN. Additionally, future studies are needed for optimization to identify adequate dosage, identify the optimal number of psilocybin administrations and investigate the need for possible adjunctive treatments that could optimize treatment outcomes.

In conclusion, results from this open-label, single-arm study suggest that psilocybin therapy is safe and tolerable in participants with AN; however, adequately powered, randomized controlled trials are needed to draw any conclusions.

Study design and participants

This open-label pilot study evaluated the safety, tolerability and preliminary efficacy of psilocybin therapy for participants with AN. Participants were 10 female adults who met current Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) criteria for AN (anorexia nervosa restricting (AN-R) and AN-BP subtypes) within a current episode or in partial remission. All participants received a 25-mg dose of investigational drug COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation, optimized for stability and purity, developed by COMPASS Pathfinder Ltd. administered in conjunction with psychological support. The inclusion criteria were a current diagnosis of AN or pAN and an age range of 18–40 years. No financial compensation was provided for participation. Medical exclusion criteria included BMI < 16 kg m − 2 , medical instability, positive pregnancy test, cardiovascular conditions within the last year and any other clinically significant illnesses or disturbances of physical systems. Psychiatric exclusions included a current or previously diagnosed psychotic disorder, substantial suicide risk, substance use disorder (within the last year), history of mania and positive screening for borderline personality disorder (McLean Screening Instrument). Demographics are reported in Table 1 .

Study information was posted on ClinicalTrials.gov and advertised through the Eating Disorder Treatment & Research Center at the University of California, San Diego (UCSD). The trial was approved by the US Food and Drug Administration, the Regulatory Approval Committee of California and the UCSD Institutional Review Board (site-specific approvals). All participants provided written informed consent to the study team personnel at the start of the in-person screening visit. It is well known that AN is more prevalent and more often diagnosed in females 47 , 48 . Thus, it is challenging to recruit males. The vast majority of those who expressed interest in this study were female (<1% male), and all participants were identified females by self-report.

The study investigational drug was COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation, optimized for stability and purity, developed by COMPASS Pathfinder Ltd. (five capsules of 5 mg of psilocybin) 49 . A DEA Form 223 license was obtained by the principal investigator (PI) for storage and dispensing authorization. Screening included review of informed consent and written signature and medical screening, including an ECG, blood tests, assessment of vitals and review of past medical records. This also included a psychiatric interview, and assessment, including the Mini-International Neuropsychiatric Interview 7.0.2 (MINI) 50 , to ascertain a diagnosis of AN and rule out a current or past psychotic disorder, bipolar disorder and history of mania was completed. Other psychiatric screening assessments included imminent suicidality within the past year (C-SSRS) 33 , the McClean Screening Instrument for Borderline Personality Disorder 51 and an interview informed by DSM-5 criteria to rule out substance use disorders within the past year. Ten eligible participants were included in the study, including three participants from outside of the southern California region who received partial study funding for relocation expenses. Participants did not enroll/change mental health treatment during study screening and enrollment. One participant received concurrent treatment at a partial hospitalization program commencing at the onset of screening. Five participants continued to participate in ongoing weekly outpatient therapy services that did not change during study enrollment.

The study team reviewed the results of the screening to determine eligibility. Eligible participants who were on serotonergic medications were titrated off these medications over the screening period. During this ‘washout period’, they met with the study PI, who monitored titration and assessed response, and a clinical psychologist, who conducted a suicide assessment (C-SSRS) weekly throughout the screening period. Baseline assessments were conducted the day before the psilocybin session (day −1) (see Fig. 1 for study schemata, visit timeline and repeated assessments).

In the 2 weeks leading up to the psilocybin session, participants met with the lead study psychologist for two preparation sessions (Extended Data Table 1 , ‘Overview of the therapeutic model’). All sessions were conducted at the UCSD Altman Clinical and Translational Research Institute (ACTRI). On the day of the dosing session, participants arrived at the clinic at 7:00. Upon arrival to the clinic, the study team assessed participant orthostatic vitals, and the participant completed a urine drug screen. We introduced a standardized breakfast at the sixth participant as a measure to control for hypoglycemia. After determining a negative screen and consuming food (for participants 6–10), the study team then administered 25 mg of psilocybin (five capsules × 5 mg). Two psychologists were present in the room throughout the day to provide support and assess for safety, and participants were required to remain in their rooms at the ACTRI for 8 h commencing from the time the psilocybin was ingested. Before departure and once a participant reported diminished effect of the drug and a return to baseline experience, the study team administered the 5D-ASC rating scale 52 , and the study PI determined the participant’s suitability to be discharged (Fig. 2 ).

Participants returned to the clinic the morning after the dosing visit (day 1), during which they completed post-treatment repeated assessments and met the study psychologists for a safety assessment and a 60–90-min integration session (see the ‘Inventory of Supporting Information’ document, ‘Overview of the therapeutic model’, for information on integration sessions). Participants then returned to the clinic for continued assessment at 1-week, 1-month and 3-month follow-up. Participants also received two integration sessions at day 1 and day 7. The 3-month follow-up visit was conducted via telehealth for seven participants owing to change in location.

Assessments

The main objective of this study was to evaluate the safety and tolerability of psilocybin therapy for AN. To this end, the primary outcome measures were reports of AEs, changes in vital signs, ECGs, clinically significant changes in clinical laboratory tests and suicidality. These features were assessed in all 10 participants the day before the dosing session (day −1), after the dosing session (day 1) and at 1-week follow-up to evaluate any changes. We also assessed pre-specified secondary measures of response to the treatment and preliminary treatment efficacy by exploring changes in ED symptoms and behaviors and related psychopathology ( n  = 10 participants). The primary measure for exploring effects of the treatment on ED symptoms and behaviors was the EDE 53 . We explored sample mean changes in ED symptoms and behaviors, including weight concerns, shape concerns, eating concerns and dietary restraint at 1 month and 3 months after the dosing session.

We were primarily interested in changes in the EDE because it is designed to assess the full range of specific psychopathology related to EDs and is considered the gold standard measurement 53 for ED pathology with good reliability and validity. We also administered the EDE-QS 54 , which is a self-report questionnaire form of the EDE (delivered at 1-week follow-up), and the Eating Disorders Inventory (EDI) 55 . Additionally, we assessed changes in features that can characterize AN, including BMI, body image (PASTAS) 56 , Body Image State Scales (BISS) 56 , 57 , state and trait anxiety (STAI-T) 58 and preoccupation and rituals related to eating, food, weight and shape (YBC-EDS) 59 ( n  = 10 participants).

Pre-specified exploratory outcomes included assessing for changes in ED-related functional impairment (CIA) 60 , depressive symptoms (Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR)) 61 , 62 , readiness toward actionable change (Readiness and Motivation Questionnaire) 62 , psychedelic intensity ratings (5D-ASC) 52 and patient acceptability. The primary endpoint for all psychological measures was 1-month follow-up. We also repeated measures at 3-month follow-up. At 3-month follow-up, patient acceptability was evaluated by asking participants qualitative yes/no questions about the effect of their experience on life and well-being, some of which were developed by Griffiths et al. 63 .

Statistical analysis

Owing to the exploratory nature of this study, we did not perform a power analysis. Ten participants were studied to provide an initial impression of safety, tolerability, acceptability and efficacy of this treatment in an effort to inform future trials. In this report, we summarize the results of 10 participants by presenting incidences of AEs and incidences of significant changes in our safety measures (ECG, clinical laboratory tests, suicidality and vitals) at day 1 and 1-week follow-up. To explore initial efficacy, we evaluated mean sample changes in secondary outcome measures at 1-month follow-up using paired t -tests (α = 0.05, two-sided). All data were collected using Qualtrics (version dates April 2021, May 2021 and November 2021). Data were analyzed using SAS analytic software version 9.4 We also present individual participant changes in the EDE and BMI (primary diagnostic qualifiers) 64 at 1-month and 3-month follow-up using a case series design. Owing to the small sample size for this initial pilot study, we have also included effect sizes using Cohen’s d values. Multiple a priori comparisons were explored for this study; however, owing to its exploratory nature, we chose not to use a correction accounting for multiple comparisons.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

The datasets generated and/or analyzed during the current study are available in the Dryad Data repository and available upon reasonable request. Data include individual de-identified participant data and de-identified individual responses to self-report assessments, semi-structured interviews and physiological and biological data. Links to dataset are as follows: https://datadryad.org/stash/share/-l-cJuzYIJo3_ftcjtpYZgcZzIttyqQJf0AOTZRWbkM and https://doi.org/10.5061/dryad.47d7wm3hq .

A summary of the research protocol is available on ClinicalTrials.gov (identifier: NCT04661514 ) and is available upon reasonable request. Source data are provided with this paper.

Change history

27 july 2023.

In the version of this article initially published, the ClinicalTrials.gov ID was not included in the Abstract and is now amended in the HTML and PDF versions of the article.

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Acknowledgements

A special thank you to Compass Pathways and their team for funding this study (W.H.K.) and to Phastar for performing statistical analyses.

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Stephanie Knatz Peck, Samantha Shao, Tessa Gruen, Kevin Yang, Alexandra Babakanian, Julie Trim, Daphna M. Finn & Walter H. Kaye

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Contributions

S.K.P. acted as a sub-investigator of the study. She contributed to the intellectual conceptualization of the study, wrote and applied for initial regulatory approvals and protocol, contributed to the development of the psychological support model, provided psychological support for participants, conducted assessments and was the primary author of the manuscript. S.S. acted as research coordinator. She conducted all primary assessments and screening, oversaw clinical research coordination, organized and managed the database of results and edited the manuscript. T.G. acted as research coordinator. She conducted primary assessments and screening, oversaw clinical research coordination, organized and managed the database of results and edited the manuscript. K.Y. oversaw medical assessments for all participants and edited the manuscript. A.B. assisted with clinical coordination and conducted initial participant screenings and assessments. J.T. contributed to the intellectual conceptualization of the psychological support model, acted as primary therapist on the study and edited the manuscript. D.M.F. assisted with medical screening and psychiatric oversight for participants and edited the manuscript. W.H.K. was principal investigator on the study, contributed to intellectual conceptualization, provided executive oversight of the study at large, selected and screened all participants, provided psychiatric and medical oversight and contributed to the writing and editing of the manuscript.

Corresponding authors

Correspondence to Stephanie Knatz Peck or Walter H. Kaye .

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Competing interests.

S.K.P. is a senior clinical consultant for Compass Pathways, the funder of the study, and receives compensation for this role. Additionally, she is a sub-investigator for an upcoming Compass-sponsored randomized trial evaluating psilocybin for anorexia nervosa and is a lead therapist for this trial and other Compass-sponsored trials. W.H.K. has served as a consultant and advisor for Compass Pathways, the funder of this study, and has received compensation for these roles. W.H.K. has also received financial support for this study and for an upcoming randomized controlled trial evaluating psilocybin for anorexia nervosa, which is sponsored by Compass Pathways. Additionally, he serves as site principal investigator for the upcoming referenced trial. S.S., T.G., K.Y., A.B., J.T. and D.F.M. report no competing interests.

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Extended data

Extended data fig. 1 eating disorder psychopathology over time, by participant..

Scores represented are global scores calculated from the Eating Disorder Examination for all participants.

Extended Data Fig. 2 Number of participants with EDE scores within community norm values.

* REMISSION CLASSIFIED BASED ON GLOBAL EDE. SCORES WITHIN 1 SD OF COMMUNITY NORM OF 0.93. Remission characterized by EDE scores within 1 standard deviation of community normative values (m 0.93, SD 0.805) Participants who were in remission at Day -1 qualified for study based on weight criterion, h/o illness, and diagnosis ascertained by MINI 7.0.2.

Extended Data Fig. 3 5-Dimensional Altered States of Consciousness (5D-ASC) Self-Report Ratings.

Scores represent mean scores on each of eleven subscales for the 5D-ASC. Scores are out of a total of 100.

Supplementary information

Reporting summary, source data fig. 2.

Unidentified prescreen and screen information.

Source Data Extended Data Fig. 1

Global EDE scores at timepoints: day −1, day 28 and day 84.

Source Data Extended Data Fig. 2

Global EDE scores at timepoints: day −1, day 28 and day 84 (community normative values (mean/s.d.) noted on spreadsheet).

Source Data Extended Data Fig. 3

Participant subscale scores for 5D-ASC questionnaire.

Source Data Extended Data Table 2

Baseline (day −1) and day 28 (1 month) participant scores for EDE-QS, EDI, YBC-EDS and BMI assessments.

Source Data Extended Data Table 4

Baseline (day −1) and day 28 (1 month) participant scores for PASTAS-trait, PASTAS-state, STAI-state, STAI-trait and BISS.

Source Data Extended Data Table 5

Baseline (day −1) and day 28 (1 month) participant scores for CIA, QIDS and RMQ Action.

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Peck, S.K., Shao, S., Gruen, T. et al. Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study. Nat Med 29 , 1947–1953 (2023). https://doi.org/10.1038/s41591-023-02455-9

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New Research Aims to Elucidate Neurobiology of Anorexia Nervosa

Studies in animal models help scientists identify systems that may induce vulnerability to eating disorders, and aid in pinpointing brain consequences of behaviors that underpin anorexia nervosa.

For nearly a dozen years, psychiatry researchers at Johns Hopkins have been studying behavioral and neurological changes related to anorexia using the activity-based anorexia, or ABA, model in young female rats. Some lessons learned in these animals are being applied to clinical research in search of better understanding and management of the condition for patients.

There is a dearth of information about the neurobiology of anorexia, which can make treatment challenging, says  Kimberly Smith , assistant professor of psychiatry and behavioral sciences: “Using the ABA model, we can begin to shed light on that underlying neurobiology and can answer questions such as: Does anorexia change neural circuitry? Does it change physiology? What’s going on in the brain or in the body that may maintain the disorder? Through such inquiries, we may begin to identify treatment targets.”

The ABA model gives rats free access to a running wheel and restricted time for food intake. Studies over the years have indicated that rats exposed to the program can rapidly acquire alterations in taste and restricted food preferences, increased anxiety and lower circulating levels of some antioxidants, among other changes, says  Timothy Moran , director of Johns Hopkins’ Behavioral Neurosciences Laboratory.

The work “has helped identify brain systems that might induce a vulnerability to eating disorders, Moran says, “and it has identified brain consequences of engaging in the kind of behaviors that underlie anorexia nervosa.”

One study directed by psychiatry researcher  Kellie Tamashiro  and Angela Guarda, director of the Johns Hopkins Eating Disorders Program, is looking at levels of an appetite-stimulating peptide called agouti-related peptide, also known as AgRP, in patients with anorexia. Previous work by Tamashiro’s lab demonstrated that rats who passively reacted to stress induced by the ABA model had less AgRP and were more vulnerable to weight loss. The current study compares circulating levels of AgRP in the blood of patients with anorexia at the time of hospital admission and again after their weight has been restored. The researchers will look at hypothalamic regions of the brain controlling hunger using MRI to identify if the hormone is associated with greater disease severity.

“This could be the first clear identification of something that might not be simply a response to anorexia nervosa, but may be a predisposing factor,” says Moran, a coinvestigator.

Building on that work, Smith, another coinvestigator, has started her own study funded by the National Institute of Mental Health to compare eating-related anxiety in people with and without anorexia, and if that changes following treatment. The work includes using functional MRI to identify any underlying brain differences when participants are shown pictures of high calorie-density foods such as a donut or low calorie-density foods such as strawberries, and asked how comfortable they would be eating those items. Results in the first few patients indicate that anxiety is lessened after meal-based behavioral treatment, when patients are restored to a healthy weight.

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Psychiatry researchers are studying the neurobiology of anorexia in animal models to identify systems that may induce vulnerability to eating disorders. They also are looking at changes anorexia causes to the brain. Click to Tweet

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In Canada, the COVID-19 pandemic started in month 63 (March 1, 2020). The shading indicates the 95% CIs, blue circles, cases (A) and hospitalizations (B) per month before the first wave of the pandemic; blue line, prepandemic trend line of cases (A) and hospitalizations (B); orange diamonds, cases (A) and hospitalizations (B) per month during the first wave of the pandemic; orange line, trend line of cases (A) and hospitalizations (B) during the first wave of the pandemic.

eFigure 1. Interrupted Time Series of New Anorexia Nervosa/Atypical Anorexia Nervosa Cases per Month (With 95% Confidence Interval) by Study Site, January 2015 to November 2020

eFigure 2. Interrupted Time Series of Hospitalizations for New Anorexia Nervosa/Atypical Anorexia Nervosa per Month (With 95% Confidence Interval) by Study Site, January 2015 to November 2020

• Critical Escalation of de Novo Pediatric Anorexia Nervosa JAMA Network Open Invited Commentary December 7, 2021 Youngjung Kim, MD, PhD

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Agostino H , Burstein B , Moubayed D, et al. Trends in the Incidence of New-Onset Anorexia Nervosa and Atypical Anorexia Nervosa Among Youth During the COVID-19 Pandemic in Canada. JAMA Netw Open. 2021;4(12):e2137395. doi:10.1001/jamanetworkopen.2021.37395

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Trends in the Incidence of New-Onset Anorexia Nervosa and Atypical Anorexia Nervosa Among Youth During the COVID-19 Pandemic in Canada

• 1 Division of Adolescent Medicine, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada
• 2 Division of Pediatric Emergency Medicine, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada
• 3 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
• 4 Section of Adolescent Medicine, Department of Pediatrics, Sainte Justine Hospital, Université de Montréal, Montreal, Quebec, Canada
• 5 Division of Adolescent Medicine, Department of Pediatrics, McMaster’s Children’s Hospital, McMaster University, Hamilton, Ontario, Canada
• 6 Section of Adolescent Medicine, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
• 7 Faculty of Social Work, Departments of Pediatrics and Psychiatry, University of Calgary, Calgary, Alberta, Canada
• 8 Division of Adolescent Medicine, Department of Pediatrics, Janeway Children’s Hospital, Memorial University, St John’s, Newfoundland, Canada
• 9 Department of Psychiatry, University of British Columbia, and Provincial Specialized Eating Disorders Program for Children and Adolescents, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
• Invited Commentary Critical Escalation of de Novo Pediatric Anorexia Nervosa Youngjung Kim, MD, PhD JAMA Network Open

Question   Is the COVID-19 pandemic associated with a change in the incidence and hospitalization rates for new-onset anorexia nervosa or atypical anorexia nervosa among youth?

Findings   In this cross-sectional study of 1883 children and adolescents with newly diagnosed anorexia nervosa or atypical anorexia nervosa, the incidence of the disease increased from 24.5 to 40.6 cases per month and hospitalizations among these patients increased from 7.5 to 20.0 per month. During the first wave of the pandemic, the onset of illness was more rapid and disease severity was greater at presentation than before the pandemic.

Meaning   Findings of this study suggest a need for expansion of eating disorder services as well as research to better understand the drivers and prognosis for this pediatric population.

Importance   The COVID-19 pandemic has had considerable mental health consequences for children and adolescents, including the exacerbation of previously diagnosed eating disorders. Whether the pandemic is a factor associated with the concomitant increase in new-onset anorexia nervosa or atypical anorexia nervosa remains unknown.

Objective   To assess the incidence and severity of newly diagnosed anorexia nervosa or atypical anorexia nervosa in a national sample of youth before and during the first wave of the COVID-19 pandemic.

Design, Setting, and Participants   This repeated cross-sectional study analyzed new eating disorder assessments that were conducted at 6 pediatric tertiary-care hospitals in Canada between January 1, 2015, and November 30, 2020. Patients aged 9 to 18 years with a new anorexia nervosa or atypical anorexia nervosa diagnosis at the index assessment were included.

Exposures   COVID-19–associated public health confinement measures during the first wave of the pandemic (March 1 to November 30, 2020).

Main Outcomes and Measures   Primary outcomes were the incidence and hospitalization rates within 7 days of de novo anorexia nervosa or atypical anorexia nervosa diagnosis. Event rate trends during the first wave were compared with trends in the 5-year prepandemic period (January 1, 2015, to February 28, 2020) using an interrupted time series with linear regression models. Demographic and clinical variables were compared using a χ 2 test for categorical data and t tests for continuous data.

Results   Overall, 1883 children and adolescents with newly diagnosed anorexia nervosa or atypical anorexia nervosa (median [IQR] age, 15.9 [13.8-16.9] years; 1713 female patients [91.0%]) were included. Prepandemic anorexia nervosa or atypical anorexia nervosa diagnoses were stable over time (mean [SD], 24.5 [1.6] cases per month; β coefficient, 0.043; P  = .33). New diagnoses increased during the first wave of the pandemic to a mean (SD) of 40.6 (20.1) cases per month with a steep upward trend (β coefficient, 5.97; P  < .001). Similarly, hospitalizations for newly diagnosed patients increased from a mean (SD) of 7.5 (2.8) to 20.0 (9.8) cases per month, with a significant increase in linear trend (β coefficient, −0.008 vs 3.23; P  < .001). These trends were more pronounced in Canadian provinces with higher rates of COVID-19 infections. Markers of disease severity were worse among patients who were diagnosed during the first wave rather than before the pandemic, including more rapid progression (mean [SD], 7.0 [4.2] months vs 9.8 [7.4] months; P  < .001), greater mean (SD) weight loss (19.2% [9.4%] vs 17.5% [9.6%]; P  = .01), and more profound bradycardia (mean [SD] heart rate, 57 [15.8] beats per minute vs 63 [15.9] beats per minute; P  < .001).

Conclusions and Relevance   This cross-sectional study found a higher number of new diagnoses of and hospitalizations for anorexia nervosa or atypical anorexia nervosa in children and adolescents during the first wave of the COVID-19 pandemic in Canada. Research is needed to better understand the drivers and prognosis for these patients and to prepare for their mental health needs in the event of future pandemics or prolonged social isolation.

The COVID-19 pandemic has had adverse implications for both the physical and mental health of children and adolescents worldwide. 1 - 7 The World Health Organization declared COVID-19 a pandemic on March 11, 2020. Shortly after this declaration, public health mitigation strategies were mandated throughout Canada. By mid-March, Canadian provinces and territories had abruptly implemented, to varying degrees, school closures, prohibitions on gatherings, closures of nonessential businesses, and cancellation of sports and extracurricular activities. Public health authorities also cautioned against unnecessary visits to health care facilities to reduce viral transmission and to maintain capacity to accommodate surges in COVID-19 cases. 1 Pediatric hospitals worldwide experienced decreased emergency department (ED) visits and hospital admissions throughout 2020. 2 - 4 Despite the substantial reduction in the number of children and adolescents brought into hospitals for medical attention during the pandemic, numerous studies have reported increased pediatric mental health visits. 5 - 7

The association between stressful events and exacerbations in eating disorder symptoms has been documented. 8 Studies of adult patients with preexisting eating disorders reported worsening symptoms during the first wave of the COVID-19–associated confinement, including greater caloric restriction, increased self-induced vomiting, worsening body dysmorphia, and heightened exercise drive. 9 - 11 Two single-center studies from Australia also found an increase in hospitalizations during the first wave of the pandemic among adolescents with previously diagnosed anorexia nervosa. 12 , 13 Similarly, a recent single-center study in the US reported a doubling of hospitalizations for restrictive eating disorders during the COVID-19 pandemic. 14 To date, the association between the pandemic and its confinement measures and the genesis of new-onset anorexia nervosa or atypical anorexia nervosa has not been studied. In this study, we sought to assess the incidence and severity of newly diagnosed anorexia nervosa or atypical anorexia nervosa in a national sample of children and adolescents before and during the first wave of the COVID-19 pandemic.

This cross-sectional study was approved by the Research Ethics Board at each of the 6 participating institutions in Canada (Alberta Children’s Hospital, Calgary, Alberta; British Columbia Children’s Hospital, Vancouver, British Columbia; Janeway Children’s Hospital, St John’s, Newfoundland; McMaster Children’s Hospital, Hamilton, Ontario; Montreal Children’s Hospital, Montreal, Quebec; and Sainte Justine Hospital, Montreal, Quebec). Approval to waive direct patient consent was obtained from the Research Ethics Board at these sites for reasons of feasibility. We followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. 15

We conducted a repeated cross-sectional analysis of all new eating disorder assessments between January 1, 2015, and November 30, 2020, at 6 of the 10 Canadian pediatric hospitals with tertiary-level eating disorder programs, which span 5 Canadian provinces from the western to the eastern coasts. Each of these 10 eating disorder programs were invited to participate in the study. At all of the participating study sites, the adolescent medicine service is involved with the assessment of consultations for youth younger than 18 years with symptoms that are suggestive of eating disorders. The referral sources for each program include community physicians, hospital subspecialists, and EDs that assess patients with acute presentations. Those who are diagnosed with an eating disorder and severely malnourished at the time of presentation are hospitalized for medical stabilization and nutritional rehabilitation. Admission criteria for patients with an eating disorder that are common to all study sites include full food refusal and/or evidence of substantial cardiovascular compromise (resting heart rate <50 beats per minute [bpm] and/or systolic blood pressure <90 mm Hg), as outlined by guidelines from the Society for Adolescent Health and Medicine. 16 All 6 sites continued to conduct new eating disorder assessments throughout the study period (March 1 to November 30, 2020).

Patients were included in this study if they were aged 9 to 18 years and received a new diagnosis of anorexia nervosa or atypical anorexia nervosa, according to recognized definitions of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) ( DSM-5 ). Because the DSM-5 does not identify a specific weight threshold for atypical anorexia nervosa, patients with a percentage of median body mass index (BMI) that was greater than 85% at the time of assessment were classified as having atypical anorexia nervosa, as described elsewhere. 17 Patients were excluded if they met the criteria for a DSM-5 eating disorder other than anorexia nervosa or atypical anorexia nervosa (eg, avoidant restrictive food intake disorder, bulimia nervosa, and binge eating disorder) or if their diagnosis remained unclear after the initial assessment. Patients who were diagnosed with an eating disorder before the index assessment were also excluded from analysis. Metrics on race and ethnicity were not collected because these are not routinely included at Canadian databanks or medical records.

The primary outcome measures were the incidence and hospitalization rates within 7 days of de novo anorexia nervosa or atypical anorexia nervosa diagnosis. Secondary outcomes included eating disorder–specific variables of interest that were obtained from patient medical records: self-reported duration of restrictive behaviors before assessment, vital signs at time of assessment, percentage of median BMI, percentage of body weight loss, and amount and rate of weight loss. Baseline demographic data were also collected, including age, sex assigned at birth, BMI at assessment, and index visit diagnosis. The World Health Organization growth curves for age and sex were used to calculate median BMI. Premorbid weight and amount and rate of weight loss were calculated according to the growth records at the time of the assessment. When not available, premorbid weight was based on self-reported information.

The main exposure was COVID-19–associated public health confinement measures. For the purpose of this analysis, the beginning of the pandemic period was defined as March 1, 2020, which corresponded with the earliest public health recommendations that slightly preceded the official provincial state-of-emergency declarations and lockdown measures across Canada (from March 13 to 27, 2020). 18 The prepandemic period was defined as January 1, 2015, to February 28, 2020.

Incidence and hospitalization rates for all de novo anorexia nervosa or atypical anorexia nervosa diagnoses during the first wave of the pandemic were compared with rates in the 5-year prepandemic period. Monthly counts were plotted for the number of new cases and for the number of patients requiring medical hospitalization within 7 days of their index presentation or diagnosis.

We performed an interrupted time series analysis with linear regression modeling to estimate time trends (and 95% CIs) in national monthly event rates before and during the first wave of the pandemic as well as to identify the change in time trends associated with COVID-19 (March 2020) and the immediate implication of COVID-19 for the event rate (equivalent to the mean difference between pre- and post-COVID-19 event rates, controlling for time trends). In addition to pooled national-level analyses, site-specific charts were plotted and analyzed for each of the 6 study sites. Autocorrelation was assessed between months using Durbin-Watson tests and was further validated for the interrupted time series with the Newey-West adjustment for SE, which also demonstrated no correlation.

No data were missing for the primary or secondary analyses. Baseline demographic and clinical data for eating disorder–specific variables were presented in descriptive tables and were compared before and during the first wave of the pandemic using either a χ 2 test for categorical data or an unpaired t test for continuous data. A 2-tailed P  < .05 was considered statistically significant. All analyses were performed using SAS, version 9.4 (SAS Institute).

A total of 1883 children and adolescents (median [IQR] age, 15.9 [13.8-16.9] years; 1713 female [91.0%] and 170 male [9.0%] youth) who were newly diagnosed with anorexia nervosa or atypical anorexia nervosa across the 6 study sites were included in the analysis. The number of patients included from each site and their baseline characteristics before and during the first wave of the COVID-19 pandemic are shown in Table 1 . Most patients were diagnosed with atypical anorexia nervosa both before (783 of 1538 [50.8%]) and during (175 of 345 [50.7%]) the first wave.

The time trends of total newly diagnosed cases and hospitalizations per month in the pooled national sample are shown in the Figure . For the 5-year period preceding the pandemic, the time trend was stable over time (β coefficient, 0.043; P  = .33), and the mean (SD) number of newly diagnosed cases during this period was 24.5 (1.6) cases per month ( Table 2 ). During the first wave, newly diagnosed cases demonstrated a steep upward trend (β coefficient, 5.97; P  < .001), and the mean (SD) cases during this period increased to 40.6 (20.1) cases per month ( P  < .001). Hospitalizations for new patients similarly increased sharply along with the pandemic (β coefficient, −0.008 vs 3.23; P  < .001), with the mean (SD) cases increasing from 7.5 (2.8) cases per month to 20.0 (9.8) cases per month ( P  < .001).

To assess for site-specific trends, new anorexia nervosa or atypical anorexia nervosa cases (eFigure 1 in the Supplement ) and hospitalizations (eFigure 2 in the Supplement ) were also analyzed by study site. Hospitals located in the Central Canadian provinces of Ontario and Quebec demonstrated the greatest increases in mean (SD) number of monthly cases (5.1 [2.3] to 10.4 [5.7] for McMaster Children’s Hospital; 4.5 [2.3] to 8.7 [5.9] for Montreal Children’s Hospital; and 5.8 [2.2] to 11.7 [6.7] for Sainte Justine Hospital) and monthly hospitalizations (2.2 [1.5] to 6.6 [4.1] for McMaster Children’s Hospital; 0.8 [1.0] to 3.6 [2.6] for Montreal Children’s Hospital; and 1.6 [1.3] to 5.0 [3.6] for Sainte Justine Hospital) during the first wave of the pandemic ( Table 2 ). Upward linear trends at these sites most resembled the pooled national sample. Linear trends in hospitalizations at 2 additional sites (Alberta Children’s Hospital and Janeway Children’s Hospital) approached significance compared with prepandemic trends. Only 1 study site experienced no change in linear trend for new cases or hospitalizations compared with the prepandemic period (British Columbia Children’s Hospital).

To better understand the concomitant increase in hospitalizations, markers of anorexia nervosa severity were compared before and during the first wave of the pandemic for patients with newly diagnosed anorexia nervosa or atypical anorexia nervosa at all sites that reported an increase in newly diagnosed cases ( Table 3 ). At these sites, all in Central Canada, patients with a new diagnosis during the pandemic had a shorter mean (SD) duration of restrictive symptoms (7.0 [4.2] months vs 9.8 [7.4] months; P  < .001), with a higher mean (SD) percentage of body weight lost (19.2% [9.4%] vs 17.5% [9.6%]; P  = .01) at a faster mean (SD) rate (2.1 [2.0] kg/mo vs 1.6 [1.7] kg/mo; P  < .001). Moreover, these patients presented with more profound bradycardia at diagnosis (mean [SD] heart rate, 57 [15.8] bpm vs 63 [15.9] bpm; P  < .001), with a greater proportion of patients meeting clinical criteria for admission compared with patients who were diagnosed before the pandemic (45.8% [121 of 264] vs 32.6% [317 of 972]; P  < .001).

To our knowledge, this study was the first to evaluate the association between the COVID-19 pandemic and new-onset anorexia nervosa or atypical anorexia nervosa in any patient population. In a broad national sample of youth who underwent an assessment in a tertiary care setting during the first wave of the pandemic, monthly cases of new-onset anorexia nervosa or atypical anorexia nervosa increased by more than 60% (24.5 to 40.6), and monthly hospitalizations nearly tripled (7.5 to 20.0) compared with prepandemic rates. Linear trends for both new cases and hospitalizations increased sharply, concomitant with pandemic confinement measures that began in March 2020. At sites with the greatest number of new cases, patients who received a diagnosis during the pandemic presented with more rapidly evolving and more severe markers of disease, which likely explains the observed increase in hospitalizations.

The largest increase in both new diagnoses and hospitalizations of anorexia nervosa or atypical anorexia nervosa was reported in Central Canada provinces (Quebec and Ontario). In these provinces, cases of COVID-19 and related mortality per capita were the highest during the first wave of the pandemic, 18 and therefore the most restrictive confinement measures were adopted. 19 In contrast, Western Canada reported relatively small growth in COVID-19 cases, and few cases were reported in Atlantic Canada. 19 These findings suggested that provinces with high cases of COVID-19 infections and stricter confinement measures experienced a higher burden of newly diagnosed anorexia nervosa and atypical anorexia nervosa.

Provincial variations in the management of health services (eg, closures of primary care practices) may also be a factor in the differences between sites in the number of eating disorder assessments that were performed during the first wave of the pandemic. Some studies reported increases in acute mental health presentations at the ED 6 , 7 ; however, it is unclear how these observations can be interpreted in the context of the pandemic. During the first wave, pediatric hospitals experienced dramatic decreases in ED visits and hospitalizations. 3 , 4 Mental health presentations increased as a proportion of these visits, 20 but not necessarily in absolute number. Moreover, in many provinces in Canada, public health authorities also mandated the closure of primary care clinics, limiting access to other mental health community resources. Therefore, analyses of ED visits and hospitalizations from the ED for anorexia nervosa or atypical anorexia nervosa may overestimate the true incidence. A strength of the present study was the inclusion of eating disorder assessments from a broad catchment of referral sources (outpatient clinics, inpatient wards, and EDs) at all study sites. As such, this study likely more accurately estimated the true burden of new-onset anorexia nervosa or atypical anorexia nervosa during the first wave than analyses of ED visits and hospitalizations alone.

The increase in new anorexia nervosa or atypical anorexia nervosa diagnoses during the first wave of the COVID-19 pandemic is likely multifactorial. Patients who were previously diagnosed reported experiencing worsening symptoms because of the pandemic. 9 - 11 A recent single-center study at an adolescent eating disorder program found that, across all eating disorders, 40% of newly diagnosed patients cited the pandemic as a trigger for their eating disorder. 21 Interviews conducted with adults with an eating disorder revealed an exacerbation of symptoms that was associated with increased anxiety, social isolation, and reduced contact with their treatment teams. 9 , 22 Moreover, adults also reported worsening eating disorder symptoms in conjunction with a lack of distractions and constant exposure to stressful messages on social media. 23 It is possible that these same stressors play a role in new-onset anorexia nervosa or atypical anorexia nervosa among children and adolescents.

COVID-19–associated restrictions varied in intensity and duration across Canada, but all provinces initially closed schools and nonessential businesses and canceled extracurricular activities. These changes had substantial consequences for eating, physical activity, and social patterns of adolescents, each of which may be a risk factor for developing anorexia nervosa cognitions. 23 Lack of a clear routine may be associated with a higher risk for eating disorder–related behaviors because it removes structures that normalize eating. Confinement orders limit access to regular physical activity, which, in combination with disrupted eating patterns, may have a role in the heightened concern about body shape and weight. 24 In addition, school closures likely expand social media use as a means of communication with peers. Media use has been associated with an increased risk for disordered eating, in particular through exposure to thin ideals and diet-related content. 25 Furthermore, social media trends referring to weight gain during confinement and a focus on home cooking and exercise routines may have further elevated the eating disorder risk among youth.

Many adolescents with an eating disorder also have comorbid psychopathology, including depression, anxiety, and obsessive-compulsive disorder. 26 Evidence suggests that the COVID-19 pandemic has had detrimental consequences for the mental health of both youths and their parents. 5 - 7 , 27 Rates of depression and suicidal ideation were higher in adults in COVID-19–associated lockdowns compared with those who were not under these restrictions. 28 In children and adolescents, the disruption of routines and disconnection from peers were associated with the increase in mental health burden and emergence of depression and anxiety. 20 , 29 A worsening of overall mental health status may explain the increased rate of newly diagnosed anorexia nervosa or atypical anorexia nervosa found in the present study.

Protective factors against eating disorders in youth were also disrupted by the COVID-19 pandemic. Social support has been identified as a protective factor during stressful periods and as key to managing and reducing disordered eating. 30 During the first wave of the pandemic, most countries used social distancing measures as a primary public health mitigation strategy. Many children and adolescents, who rely on peer group validation and connectedness, lost a primary source of social support that made them more vulnerable to stressful circumstances. In addition, access to primary care and routine screening was reduced or limited to virtual care. A consensus panel recently issued its recommendations for in-person medical evaluation for eating disorders when needed to ensure the appropriate assessment of medical instability. 31 Reduced in-person medical assessments would likely make early detection of disordered eating more challenging and impede the early deployment of therapeutic interventions to slow or stop the progression of illness.

This study has some limitations. We were unable to make concrete causal inferences because factors other than the COVID-19 pandemic may have been associated with the increase of new-onset anorexia nervosa or atypical anorexia nervosa during the study period. Data collection occurred in 6 of the 10 pediatric tertiary eating disorder programs in Canada, spanning both coasts and including sites from the 4 most populous provinces (representing nearly 90% of the Canadian populace). However, not every province was represented, and all study sites are located in urban centers; thus, the findings may not be generalizable to all practice settings. All 6 study sites continued to see new eating disorder assessments during the first wave of the pandemic, and no site limited the number of hospitalizations. However, because of growing patient volumes, all sites shifted to prioritize the evaluation of youth with more severe presentations (eg, large amount of weight loss, substantial change in vital signs, or need for hospitalization); therefore, the possibility of selection bias cannot be excluded. Conversely, fewer youth with anorexia nervosa or atypical anorexia nervosa may have been identified and referred for assessment because of school closures, and many children and adolescents and their families may have chosen to avoid hospital centers for fear of exposure to COVID-19 infection. These factors suggest that the findings may be an underestimation of the true burden of newly diagnosed anorexia nervosa or atypical anorexia nervosa. This study only included patients who met the DSM-5 criteria for anorexia nervosa or atypical anorexia nervosa at the initial assessment and therefore does not capture the total incidence and hospitalization rates across all eating disorder diagnoses. Other centers may have reached clinical significance if all eating disorder diagnoses were included. The degree of social confinement and school closures varied temporally between provinces, with Central Canada adopting longer and stricter confinement measures during the study period. The second wave of the pandemic (September 1 to December 31, 2020), which affected provinces more uniformly, was unlikely to be captured in these results and may have had a greater impact in provinces outside of Central Canada.

In this cross-sectional study, we found an increase in the incidence and hospitalization rates of newly diagnosed anorexia nervosa or atypical anorexia nervosa in a national sample of youth during the first wave of the COVID-19 pandemic in Canada. Patients who were diagnosed in this period were more likely to present with rapidly evolving and more severe markers of disease. These findings highlight the need for expanded eating disorder and mental health programs during and after the COVID-19 pandemic. Research is still needed to better understand the drivers and prognosis for these patients and how best to prepare for their mental health needs in the event of future pandemics or prolonged social isolation.

Accepted for Publication: October 11, 2021.

Published: December 7, 2021. doi:10.1001/jamanetworkopen.2021.37395

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2021 Agostino H et al. JAMA Network Open .

Corresponding Author: Holly Agostino, MD, CM, Division of Adolescent Medicine, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, 1040 Atwater, Montreal, QC H3Z 1X3, Canada ( [email protected] ).

Author Contributions: Drs Agostino and Burstein had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Agostino, Burstein, Vyver, Dimitropoulos, Dominic.

Acquisition, analysis, or interpretation of data: Agostino, Burstein, Moubayed, Taddeo, Grady, Vyver, Dominic, Coelho.

Drafting of the manuscript: Agostino, Burstein, Grady, Vyver.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Agostino, Burstein.

Administrative, technical, or material support: Agostino, Moubayed, Taddeo, Grady, Vyver, Coelho.

Supervision: Dimitropoulos, Coelho.

Conflict of Interest Disclosures: Dr Vyver reported receiving funding from the Canadian Paediatric Surveillance Program/Public Health Agency of Canada for a surveillance study of anorexia nervosa during COVID19 outside the submitted work. No other disclosures were reported.

Funding/Support: This study received no funding. Dr Burstein was funded by a career award from the Quebec Health Research Fund. Dr Coelho was funded by an investigator award from the Michael Smith Foundation for Health Research Health Professional.

Role of the Funder/Sponsor: The Quebec Health Research Fund and the Michael Smith Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Xun Zhang, PhD, Research Institute of McGill University Health Centre, for assisting with statistical analyses. We also thank Deepika Bajaj, BA, Pei-Yoong Lam, MBBS, and Fiza Syal, BC Children’s Hospital; Gisele Marcoux, MSc, and Manya Singh, MEd, University of Calgary; Ashley Tritt, MD, Sainte Justine Hospital; and Cheryl Webb, MSW, RSW, McMaster Children’s Hospital, for assisting with data collection. These individuals received no additional compensation, outside of their usual salary, for their contributions.

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Yale Team Uncovers Promising New Therapeutic for Anorexia Nervosa

Anorexia nervosa (AN) is the deadliest psychiatric illness  aside from opioid use disorder, with scarce effective treatment options. A new study by Yale researchers reveals a potential new therapeutic for the disorder, as well as for cancer-induced anorexia and other mood disorders.

While scientists still don’t understand the molecular mechanisms that underlie anorexia, a team led by principal investigator Yingqun Huang, MD, PhD , professor of obstetrics, gynecology & reproductive sciences at Yale School of Medicine, found that a small synthetic molecule called Bobcat339 significantly weakened AN, as well as associated anxiety and depressive-like behaviors, in a mouse model, causing few side effects.

The team hopes the findings, published in Proceedings of the National Academy of Sciences , is a step toward developing new and safe therapeutics.

“This small molecule, Bobcat339, can mitigate AN in a mouse model,” says Huang. “So, we propose that it may also be effective in treating human AN and perhaps cancer-induced anorexia and associated mood disorders.”

A Surprise in the Lab Points Researchers Toward Anorexia

The discovery of Bobcat339, says Huang, was “a serendipitous thing.” She had been studying a protein called TET3, a member of the TET protein family (TET1/2/3), in the context of type 2 diabetes and found in 2020 that its expression was increased in the livers of patients with diabetes. Through delivering genetic material known as small interfering RNAs (siRNAs) that targeted TET3 specifically to the livers of mice, her team discovered that they could attenuate type 2 diabetes in animal models.

In humans, [anorexia nervosa] usually manifests during puberty, but mood problems often persist through adulthood. A similar thing happened with our mouse model. Yingqun Huang, MD, PhD

Then, Huang learned that Bobcat339 is a TET protein inhibitor. Intrigued, she hoped it might be a good molecule for treating type 2 diabetes. To her surprise, after ingesting Bobcat339 through their drinking water, the mice did not get better. “The mice began eating like crazy—hyperphagia,” says Huang. “At first, this was so disappointing.”

But the path that Bobcat339 took through the mice’s bodies led to a crucial finding. After Huang’s team fed the mice the molecule, they discovered that it also traveled to the brain, where it regulated TET3 by interacting with AgRP neurons. This group of neurons, located in the hypothalamus, plays a significant role in regulating feeding, energy expenditure, and other complex behavior including anxiety, depression, and compulsive behaviors.

“These neurons are very important not only for regulating food intake, but also mood,” says paper co-author Tamas Horvath, DVM, PhD, chair and Jean and David W. Wallace Professor of Comparative Medicine and professor of neuroscience and of obstetrics, gynecology & reproductive science.

This led to another publication , in which Huang and Horvath teams used CRISPR knockdown of TET3 specifically in AgRP neurons in mice and discovered this induced hyperphagia as well as anti-anxiety and anti-depressive effects. This sparked the teams’ interest in using Bobcat339 to knockdown TET3 and treat an entirely different condition altogether—AN.

Anorexia Damages the Body and Mind

AN is characterized by reduced food intake, low body weight, and obsessive-compulsive activity like overexercising, as well as mood disorders such as depression and anxiety. It is notoriously difficult to treat. Even after patients recover in terms of their food intake, body weight, and exercise level, mood problems often persist. The condition can be treated with psychotherapy and nutritional support, but these interventions have low efficacy and high relapse rates. There is no medication available for AN.

The activity-based anorexia model is a well-established model in which mice are kept in an apparatus with a running wheel. By withholding food from mice and only making it available for two hours a day for three days, researchers can induce anorexia behavior. The mice quickly reduce their food intake, lose body weight, and exhibit obsessive-compulsive wheel-running behavior. After three days, the researchers resume normal feeding.

Huang’s team took measurements during both the restrictive and recovery periods. Mice that were administered Bobcat339 through intraperitoneal injections showed significantly higher food intake and lower compulsive wheel running than untreated mice during the restrictive period. Upon resuming normal feeding, although mice in the untreated control group regained their body weight, they still exhibited depressive and anxious behaviors.

“In humans, AN usually manifests during puberty, but mood problems often persist through adulthood. A similar thing happened with our mouse model,” says Huang.

In contrast, mice treated with Bobcat339 showed fewer of these behaviors. “This small molecule helps mice maintain their food intake, maintain their body weight, and inhibit compulsive behaviors,” she says. “This drug is also working in mitigating anxious and depressive-like behaviors.”

The team hopes that the molecule may also be useful in treating humans struggling with anorexia nervosa, as well as those struggling with mood disorders. In contrast to typical anti-depressants, which can need weeks to take effect, Bobcat339 was found to improve problems associated with mood in as little as a day. The team also plans to conduct future studies evaluating its ability to mitigate cancer-induced anorexia and depression.

Featured in this article

• Yingqun Huang, MD, PhD Professor, Obstetrics, Gynecology & Reproductive Sciences
• Tamas Horvath, DVM, PhD Jean and David W. Wallace Professor of Comparative Medicine and Professor of Neuroscience and of Obstetrics, Gynecology, and Reproductive Sciences; Chair, Comparative Medicine

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2020 Breakthrough Research in Anorexia Nervosa: Drs. Cynthia Bulik and Walter Kaye

Anorexia Nervosa (AN) is a puzzle for many reasons. What is it, and what can we do to treat it are commonly asked questions by students and health professionals alike? While we do not have a blood or other test to make a diagnosis, the combination of signs and symptoms are classic and are virtually identical to those seen centuries ago.

AN was the same in 1689 as it was in 1873 as it was in 1983 when Karen Carpenter died of this disease [1]. It is the same today. AN appears to be a biopsychosocial determined disease with important genetic and neurobiological roots.

Anorexia Nervosa occurred as part of religious fasting dating from the Hellenistic era. Mary, Queen of Scots, among others, appears to have suffered from AN. The English physician Richard Morton described AN in 1689, but the medical profession did not consider it seriously until the late 19th century.

In 1873, Queen Victoria’s physicians, Sir William Gull, published the classic, seminal paper which established the term anorexia nervosa. He described cases and treatments. In the same year, French physician Ernest-Charles Lasègue similarly published details of several cases in a paper entitled De l’Anorexie Hystérique.

In an addendum to his Anorexia Nervosa paper, Sir William Gull provides the following comment on Lasègue’s work: “It is understandable that Dr. Lasègue and I have the same sickness in mind, though the forms of our illustrations are different.

Dr. Lasègue does not refer to my address at Oxford, and it is most likely he knew nothing of it. There is, therefore, the more value in his paper, as our observations have been made independently. We have both chosen the same expression to characterize the malady.

In the address at Oxford, I used the term Apepsia hysterica, but before seeing Dr. Lasègue’s paper, it had equally occurred to me that Anorexia would be more correct ” [2]. Still, awareness of AN limited to MDs until the latter part of the 20th century, when German-American psychoanalyst Hilde Bruch published her famous work “The Golden Cage: the Enigma of Anorexia Nervosa” in 1978.

Anorexia Nervosa

The National Eating Disorders Association (NEDA) estimates that between 0.3 and 0.4 percent of all young women and 0.1 percent of young men suffer from AN on this or any day. They estimate that approximately 1 percent of women and 0.3 percent of men reported Anorexia during their lifetimes.

AN is a major cause of death among adolescents and young adults. Young people between the ages of 15 and 24 with AN are estimated to be at ten times greater risk of dying compared to same-aged peers. Although the disorder also affects males, the overwhelming predominance of women is undeniable.

Bulik has led many of the recent efforts. Bulik and her collaborators have a long history of reporting new data, which is really significant progress in AN genetic research. Most recently, with her collaborators, in Nature Genetics [3].

Quick Summary-Review of AN

Mitchell & Peterson’s 2020 review in the New England Journal of Medicine [4] reminds us that AN is often fatal. About 10% of those patients with Anorexia Nervosa will die of the disease. Medical complications, suicide, and co-occurring substance use disorders (SUD) are all too commonly reported.

• Anorexia nervosa is a severe, sometimes fatal, psychiatric disorder characterized by starvation and malnutrition
• Weight preoccupation, overvaluation, and dissatisfaction are related to eating disorders, but no one body image construct can capture clinical risk in eating disorders.
• Preoccupation is the best-studied, most consistent concurrent and longitudinal predictor
• Coexisting psychiatric conditions often accompany Anorexia Nervosa
• AN is a disease that is usually progressive, difficult to treat with episodes where there is no response to treatment, frequent medical complications, and a substantial risk of death.
• Anorexia nervosa has two subtypes, but can progress from one sub-type to another: binge eating, purging, or both, and food restricting only
• AN patients are often hospitalized, which can be life-saving as they have severe starvation, dehydration hypotension, electrolyte abnormalities, arrhythmias or severe bradycardia, suicide risk. Just having a body-mass index (the weight in kilograms divided by the square of the height in meters) of 15 or less is a significant concern.
• Several psychotherapeutic approaches are commonly used in treatment by psychologists and psychiatrists
• Psychotropic medications are generally ineffective in promoting weight gain, reducing depressive symptoms, or preventing relapse in patients with anorexia nervosa.
• While current treatment is psychological and not personalized or informed by genes or improved by medications, about half of adolescents recover, and another 30% significantly improve

Scientific Progress: 2020

New insights will eventually lead to new treatments . Medications, psychedelic medicine, and deep brain stimulation may offer hope and help us to understand which diseases are the most like Anorexia Nervosa, major depression, OCD, or SUDs.

Scientific progress seen in the rest of psychiatry is finding its way to Anorexia Nervosa. The more researchers look into this disease, the more it appears to have important genetic and neurobiological causes. The circuitry of the brain’s reward system behaves differently in unaffected volunteers than in people with Anorexia and those who have recovered.

We have studied eating, eating sugar, and compared food and sugar rewards to those naturally occurring species survival reinforcement [5]. Hunger drives a search for food, eating, and makes food more rewarding. This is a well-known fact because starvation activates brain circuits that motivate eating.

One group of women had been diagnosed with AN, but were in remission (RAN); the other group did not have AN. The RAN group showed reduced neural activation to taste stimulation in the brain’s anterior insula and reduced connectivity between the right anterior and mid-dorsal insula and ventral caudal putamen.

This circuitry involves connected regions that are important for recognizing the feeling of hunger. This circuit typically would drive us to want to eat when we are starving or deprived of food. Most people report that hunger increases the reward and pleasure of food, and thus drives the motivation to eat.

Individuals with AN, however, tend to have a disconnect in this process. Anorexia Nervosa patients are obsessed with food, yet do not eat. Failure to launch this food reward circuit in people with AN may be a key to AN restrictive eating and severe weight loss in persons.

Anorexia Nervosa may be a disease where perceptions of hunger persist in a vacuum disconnected the motivation to eat. Patients with AN describe increased discomfort, anxiety, and panic when they eat, even when they are starving. Profound anxiety may contribute to starvation because it impairs the ability to start eating.

Bulik and others published in Nature Genetics the most extensive genetics study on the disease, analyzing the genomes of nearly 17,000 people with Anorexia and more than 55,000 people without. Eight risk loci for anorexia nervosa were identified that were predictive of other psychiatric disorders, a low BMI, and metabolic derangement.

This study showed that there was also a link to the ability to metabolize fats and sugars [7]. Who knows what this means other than the metabolic problems in AN could be produced by a biological predisposition.

Researchers identified other patterns of genetic associations similar to those found in other psychiatric illnesses, including OCD and depression. We had suspected that the brain’s reinforcement systems might reinforce disordered eating very early on and thought similarities to substance use disorders might offer a clue and endogenous opioid-dopamine targets.

There may be genetic and risk profile similarities between Anorexia and Bulimia Nervosa [8], which relate to genetics, reward deficiency, and early bad learning. Early starvation or dieting might be a trigger like teen cigarette smoking, early-onset binge drinking, or illicit drug use triggers .

Concluding Remarks

Psychedelic medicine [9] trials are also underway for mescaline, psilocybin, nitrous oxide, and others for depression and PTSD. Treatments for SUDs have changed dramatically over this time as well.

Reward deficiency syndrome [10] has been proposed to explain some of the patients with SUDs and brain circuits involved in naturally occurring pleasure and SUD related hijacking. Animal models for SUD have been quite good at predicting treatments, and many are currently in use. TMS [11], DBS [12], and even Vaccines based on these models may be the next for SUDs.

Many of these novel treatment approaches may be helpful in Anorexia Nervosa, Bulimia Nervosa , and other eating disorders.

1. https://www.npr.org/2013/02/04/171080334/remembering-karen-carpenter-30-years-later

2. https://en.wikipedia.org/wiki/History_of_anorexia_nervosa

3. Watson, H.J., Yilmaz, Z., Thornton, L.M. et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet 51, 1207–1214 (2019). https://doi.org/10.1038/s41588-019-0439-2

4. Mitchell JE, Peterson CB. Anorexia Nervosa.N Engl J Med. 2020 Apr 2;382(14):1343-1351. doi: 10.1056/NEJMcp1803175

5. Murray S, Tulloch A, Gold MS, Avena NM Hormonal and neural mechanisms of food reward, eating behaviour and obesity. Nat Rev Endocrinol. 2014 Sep;10(9):540-52. doi: 10.1038/nrendo.2014.91. Epub 2014 Jun 24.

6. Kaye WH, Wierenga CE, Bischoff-Grethe A, Berner LA, Ely AV, Bailer UF, Paulus MP, Fudge JL. Neural Insensitivity to the Effects of Hunger in Women Remitted From Anorexia Nervosa. Am J Psychiatry. 2020 Mar 12

7. Watson, H.J., Yilmaz, Z., Thornton, L.M. et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet 51, 1207–1214 (2019). https://doi.org/10.1038/s41588-019-0439-2

8. Yao, S., Larsson, H., Norring, C., Birgegård, A., Lichtenstein, P., DʼOnofrio, B., . . . Kuja-Halkola, R. (2019). Genetic and environmental contributions to diagnostic fluctuation in anorexia nervosa and bulimia nervosa. Psychological Medicine, 1-8. doi:10.1017/S0033291719002976

9. https://www.jns-journal.com/article/S0022-510X(20)30051-4/fulltext Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J Neurol Sci. 2020 Apr 15;411:116715. doi: 10.1016/j.jns.2020

10. Blum K, Baron D, McLaughlin T, Gold MS.Molecular neurological correlates of endorphinergic/dopaminergic mechanisms in reward circuitry linked to endorphinergic deficiency syndrome (EDS). J Neurol Sci. 2020 Apr 15;411:116733. doi: 10.1016/j.jns.2020.116733. Epub 2020 Feb 14

11. https://niaaa.scienceblog.com/67/rehabilitating-the-addicted-brain-with-transcranial-magnetic-stimulation/

12. https://www.sciencealert.com/surgeon-attempting-deep-brain-stimulation-as-last-resort-for-opioid-addict

About the Author:

Dr. Gold was the first Faculty from the College of Medicine to be selected as a University-wide Distinguished Alumni Professor and served as the 17th University of Florida’s Distinguished Alumni Professor. Learn more about Mark S. Gold, MD

The opinions and views of our guest contributors are shared to provide a broad perspective of eating disorders. These are not necessarily the views of Eating Disorder Hope, but an effort to offer a discussion of various issues by different concerned individuals.

We at Eating Disorder Hope understand that eating disorders result from a combination of environmental and genetic factors. If you or a loved one are suffering from an eating disorder, please know that there is hope for you, and seek immediate professional help .

Published on May 7, 2020. Reviewed & Approved on May 7, 2020, by Jacquelyn Ekern MS, LPC

Published on EatingDisorderHope.com

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New Research Unveils the Gut’s Surprising Role in Anorexia

By University of Copenhagen - The Faculty of Health and Medical Sciences May 5, 2023

Using DNA technology and advanced bioinformatics analyses, the researchers identified distinct and marked changes in composition and function of the intestines’ trillions of bacteria and viruses in cases with anorexia nervosa. Credit: Søren Vestergaard/University of Copenhagen

Contrary to common belief, anorexia nervosa is not just a desire to be skinny. Rather, it is a complicated mental illness that alters the brain’s control over hunger and self-perception of one’s body.

Individuals with anorexia nervosa experience a transformation in their brain’s reward mechanism, making weight loss their primary focus. This results in drastic behavioral changes, including a drastic reduction in caloric intake. Approximately 1% of young people develop anorexia nervosa, and for about one in five, it becomes a chronic and potentially fatal condition. The majority of those diagnosed with anorexia nervosa are young females in their teenage years or early adulthood, accounting for about 90% of cases.

The incidence of anorexia nervosa is too upward.

The disease is caused by a complex interaction between various so-called vulnerability genes and environmental influences. However, it now also appears to be a result of a severe imbalance in the intestinal ecosystem of trillions of bacteria and viruses.

This is the conclusion of a new study conducted by an international team headed by Danish scientists. The study involved 77 Danish girls and young women suffering from anorexia nervosa and 70 healthy individuals of the same gender. The results suggest that severe changes in the intestinal microbes and corresponding gut microbiome-produced metabolites in the blood may directly affect the development and retention of anorexia nervosa.

To demonstrate this, the researchers transplanted stools from anorexia cases and healthy individuals, respectively, to bacteria-free mice, explains Professor and Principal Investigator Oluf Borbye Pedersen from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen .

“The mice receiving stools from individuals with anorexia nervosa had trouble gaining weight, and analyses of gene activities in certain parts of their brain revealed changes in various genes regulating appetite. In addition, the mice that had been given stools from individuals affected with anorexia nervosa showed increased activity of genes regulating fat combustion likely contributing to their lower body weight,” explains Oluf Pedersen, who is the lead investigator of the study together with Clinical Professor René Støvring, who specializes in anorexia nervosa.

Intestinal bacteria produce reduced amounts of important vitamin

Using DNA technology and advanced bioinformatics analyses, the researchers identified distinct and marked changes in the composition and function of the intestines’ trillions of bacteria and viruses in cases with anorexia nervosa.

Researchers compared the disruptions of the gut microbiome with blood molecules (metabolites) produced by the gut microbiome demonstrating associations between specific changes of the gut bacteria, blood bacterial molecules, and a number of personality traits such as distorted body image, drive for thinness, and refusal to eat in those affected by anorexia nervosa.

“We also discovered that specific gut bacteria in women with anorexia nervosa produce less vitamin B1. Deficiency of B1 may lead to loss of appetite, various intestinal symptoms, anxiety, and isolating social behavior,” says Assistant Professor Yong Fan from the Novo Nordisk Foundation Center for Basic Metabolic Research, a leading young researcher of the study.

“Moreover, our analysis of the intestinal microbiome revealed in anorexia cases different virus particles able to decompose lactic acid -producing bacteria in the intestines. Both findings may form the basis of future clinically controlled trials with B1 vitamin supplements and fermented food or probiotics containing various types of lactic acid bacteria,” he says.

Years of clinically controlled studies are ahead

The new study is an example of basic research meant to explore whether a disturbed microbial ecosystem of the gut is a contributory factor in the development or retention of a chronic disease. And this may potentially be the case for anorexia nervosa.

The next question is whether basic research can lay the foundation for clinically controlled trials exploring if current treatment for anorexia nervosa – involving psychotherapy, family counseling, and attempts to change the patient’s eating and exercise habits – may benefit from additional treatment aimed at normalizing the intestinal microbiome.

“A complex disease like anorexia nervosa calls for personalized and multifactorial treatment. Our findings suggest that disruptions of the communities of gut bacteria and viruses and their functions as mirrored in altered microbiome-synthesized blood metabolites may be involved in the development and retention of the disease, providing a rationale for initiating clinically controlled trials. In such trials, clinical investigators will likely test the potential effects of an initial antibiotics intervention to reset the aberrant gut microbiome followed by weekly fecal microbiota transplantation (FMT) from young healthy donors for months. Such FMTs might be supplemented with B1 vitamin and multistrain probiotics. Whether interventions like the suggested will qualify for future adjunctive therapy to current conventional intervention, remain to be shown”, says Oluf Pedersen.

Reference: “The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice” by Yong Fan, René Klinkby Støving, Samar Berreira Ibraim, Tuulia Hyötyläinen, Florence Thirion, Tulika Arora, Liwei Lyu, Evelina Stankevic, Tue Haldor Hansen, Pierre Déchelotte, Tim Sinioja, Oddny Ragnarsdottir, Nicolas Pons, Nathalie Galleron, Benoît Quinquis, Florence Levenez, Hugo Roume, Gwen Falony, Sara Vieira-Silva, Jeroen Raes, Loa Clausen, Gry Kjaersdam Telléus, Fredrik Bäckhed, Matej Oresic, S. Dusko Ehrlich and Oluf Pedersen, 17 April 2023, Nature Microbiology . DOI: 10.1038/s41564-023-01355-5

The international research team comprised Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, the University of Southern Denmark and Odense University Hospital, Aalborg University Hospital, Aarhus University Hospital, the National Research Institute for Agriculture, Food and Environment in France, Center for Microbiology, VIB, Leuven, Belgium, University of Gothenburg and Ørebro University in Sweden, Turku University in Finland and Leiden University in the Netherlands.

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Press Release Jan | 4 | 2024

Study Reveals New Genetic Link Between Anorexia Nervosa and Being an Early Riser

Key takeaways.

• Investigators have discovered that anorexia nervosa is associated with morning chronotype, or a propensity for earlier sleep and activity timing
• They also observed a relationship between the eating disorder and insomnia
• The findings could direct future investigations into circadian- and sleep-based therapies for anorexia nervosa

BOSTON – New research indicates that the eating disorder anorexia nervosa is associated with being an early riser, unlike many other disorders that tend to be evening-based such as depression, binge eating disorder and schizophrenia.

The study, which is published in JAMA Network Open  and led by investigators at Massachusetts General Hospital (MGH), in collaboration with University College London and the University of the Republic in Uruguay, also revealed a link between anorexia nervosa and insomnia risk.

Previous research has suggested a possible connection between eating disorders and the body’s internal clock, or circadian clock, which controls a wide range of biological functions such as sleep and affects nearly every organ in the body.

This study aimed to further understand this relationship by assessing genes associated with anorexia nervosa, the circadian clock and several sleep traits including insomnia.

The investigators used a statistical method called Mendelian Randomization to see how genes that are associated with a certain trait affect other traits of interest. For example, examining the sleep patterns of people with genetic differences that makes them more likely to have anorexia nervosa, this provides evidence on the relationship between anorexia nervosa and sleep.

They found a two-way association between genes associated with anorexia nervosa and genes associated with morning chronotype (waking early and going to bed early).

In other words, the findings suggest that being an early riser could increase the risk for having anorexia nervosa, and having anorexia nervosa could lead to an earlier wake time. The team also found an association between anorexia nervosa and insomnia.

When they further assessed the insomnia connection using the Mass General Brigham Biobank  by developing a “genetic risk score” for anorexia nervosa, the scientists found that the genetic risk score was indeed associated with higher insomnia risk.

“Our findings implicate anorexia nervosa as a morning disorder in contrast to most other evening-based psychiatric diseases and support the association between anorexia nervosa and insomnia as seen in earlier studies,” says senior author Hassan S Dashti, PhD, RD , an assistant investigator in the Department of Anesthesia, Critical Care and Pain Medicine at MGH and an assistant professor of anesthesia at Harvard Medical School.

Treatments for anorexia nervosa are limited and current treatments have relapse rates of up to 52%. In addition, the cause of the disease is still unclear.

With anorexia nervosa having the second highest mortality rate of psychiatric diseases, more research is desperately needed into new prevention strategies and treatments.

“The clinical implications of our new findings are currently unclear; however, our results could direct future investigations into circadian-based therapies for anorexia nervosa prevention and treatment,” says Hannah Wilcox, lead author of the study and researcher at MGH.

Additional authors include Valentina Paz, MSc, Richa Saxena, PhD, John W. Winkelman, MD, PhD, and Victoria Garfield, PhD.

This research was supported by the National Institutes of Health.

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• Early Life Trauma and Binge-Eating Disorder
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• Anorexia: Stark Changes in Brain Structure

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Monday, March 28, 2022

• The Hidden Issue of Anorexia in Pregnancy

Tuesday, March 15, 2022

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Monday, February 28, 2022

• Diminished Activation of Specific Prefrontal Brain Region May Directly Contribute to Binge Eating in Bulimia Nervosa

Wednesday, February 23, 2022

• Eating Disorders Linked to Diabetic Eye Issues

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• Rates of Type 2 Diabetes Are Higher in People With One of Various Common Psychiatric Disorders

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Treatment of Anorexia Nervosa-New Evidence-Based Guidelines

Affiliations.

• 1 Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tuebingen, Osianderstr. 5, 72076 Tuebingen, Baden-Wuerttemberg, Germany. [email protected].
• 2 Department of Psychosomatic Medicine and Psychotherapy, LWL University Hospital, Ruhr-University Bochum, Alexandrinenstr. 1-3, Nordrhein-Westfalen, 55791 Bochum, Germany. [email protected].
• 3 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of the RWTH Aachen, Neuenhofer Weg 21, Nordrhein-Westfalen, 52074 Aachen, Germany. [email protected].
• 4 Department of Psychosomatic Medicine and Psychotherapy, University Hospital Freiburg, Hauptstr. 8, Baden-Wuerttemberg, 79104 Freiburg, Germany. [email protected].
• PMID: 30700054
• PMCID: PMC6406277
• DOI: 10.3390/jcm8020153

Anorexia nervosa is the most severe eating disorder; it has a protracted course of illness and the highest mortality rate among all psychiatric illnesses. It is characterised by a restriction of energy intake followed by substantial weight loss, which can culminate in cachexia and related medical consequences. Anorexia nervosa is associated with high personal and economic costs for sufferers, their relatives and society. Evidence-based practice guidelines aim to support all groups involved in the care of patients with anorexia nervosa by providing them with scientifically sound recommendations regarding diagnosis and treatment. The German S3-guideline for eating disorders has been recently revised. In this paper, the new guideline is presented and changes, in comparison with the original guideline published in 2011, are discussed. Further, the German guideline is compared to current international evidence-based guidelines for eating disorders. Many of the treatment recommendations made in the revised German guideline are consistent with existing international treatment guidelines. Although the available evidence has significantly improved in quality and amount since the original German guideline publication in 2011, further research investigating eating disorders in general, and specifically anorexia nervosa, is still needed.

Keywords: anorexia nervosa; evidenced-based; guidelines; treatment.

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Eating Disorders

What are eating disorders.

There is a commonly held misconception that eating disorders are a lifestyle choice. Eating disorders are actually serious and often fatal illnesses that are associated with severe disturbances in people’s eating behaviors and related thoughts and emotions. Preoccupation with food, body weight, and shape may also signal an eating disorder. Common eating disorders include anorexia nervosa, bulimia nervosa, and binge-eating disorder.

What are the signs and symptoms of eating disorders?

Anorexia nervosa.

Anorexia nervosa is a condition where people avoid food, severely restrict food, or eat very small quantities of only certain foods. They also may weigh themselves repeatedly. Even when dangerously underweight, they may see themselves as overweight.

There are two subtypes of anorexia nervosa: a "restrictive "  subtype and a "binge-purge " subtype.

• In the restrictive subtype of anorexia nervosa, people severely limit the amount and type of food they consume.
• In the binge-purge  subtype of anorexia nervosa, people also greatly restrict the amount and type of food they consume. In addition, they may have binge-eating and purging episodes—eating large amounts of food in a short time followed by vomiting or using laxatives or diuretics to get rid of what was consumed.

Anorexia nervosa can be fatal. It has an extremely high death (mortality) rate compared with other mental disorders. People with anorexia are at risk of dying from medical complications associated with starvation. Suicide is the second leading cause of death for people diagnosed with anorexia nervosa.

If you or someone you know is struggling or having thoughts of suicide, call or text the 988 Suicide & Crisis Lifeline   at 988 or chat at 988lifeline.org   . In life-threatening situations, call 911.

Symptoms include:

• Extremely restricted eating
• Extreme thinness (emaciation)
• A relentless pursuit of thinness and unwillingness to maintain a normal or healthy weight
• Intense fear of gaining weight
• Distorted body image, a self-esteem that is heavily influenced by perceptions of body weight and shape, or a denial of the seriousness of low body weight

Other symptoms may develop over time, including:

• Thinning of the bones (osteopenia or osteoporosis)
• Mild anemia and muscle wasting and weakness
• Brittle hair and nails
• Dry and yellowish skin
• Growth of fine hair all over the body (lanugo)
• Severe constipation
• Low blood pressure
• Slowed breathing and pulse
• Damage to the structure and function of the heart
• Brain damage
• Multiorgan failure
• Drop in internal body temperature, causing a person to feel cold all the time
• Lethargy, sluggishness, or feeling tired all the time
• Infertility

Bulimia nervosa

Bulimia nervosa is a condition where people have recurrent and frequent episodes of eating unusually large amounts of food and feeling a lack of control over these episodes. This binge-eating is followed by behavior that compensates for the overeating such as forced vomiting, excessive use of laxatives or diuretics, fasting, excessive exercise, or a combination of these behaviors. People with bulimia nervosa may be slightly underweight, normal weight, or over overweight.

• Chronically inflamed and sore throat
• Swollen salivary glands in the neck and jaw area
• Worn tooth enamel and increasingly sensitive and decaying teeth as a result of exposure to stomach acid
• Acid reflux disorder and other gastrointestinal problems
• Intestinal distress and irritation from laxative abuse
• Severe dehydration from purging of fluids
• Electrolyte imbalance (too low or too high levels of sodium, calcium, potassium, and other minerals) which can lead to stroke or heart attack

Binge-eating disorder

Binge-eating disorder is a condition where people lose control over their eating and have reoccurring episodes of eating unusually large amounts of food. Unlike bulimia nervosa, periods of binge-eating are not followed by purging, excessive exercise, or fasting. As a result, people with binge-eating disorder often are overweight or obese. Binge-eating disorder is the most common eating disorder in the U.S.

• Eating unusually large amounts of food in a specific amount of time, such as a 2-hour period
• Eating even when you're full or not hungry
• Eating fast during binge episodes
• Eating until you're uncomfortably full
• Eating alone or in secret to avoid embarrassment
• Feeling distressed, ashamed, or guilty about your eating
• Frequently dieting, possibly without weight loss

Avoidant restrictive food intake disorder

Avoidant restrictive food intake disorder (ARFID), previously known as selective eating disorder, is a condition where people limit the amount or type of food eaten. Unlike anorexia nervosa, people with ARFID do not have a distorted body image or extreme fear of gaining weight. ARFID is most common in middle childhood and usually has an earlier onset than other eating disorders. Many children go through phases of picky eating, but a child with ARFID does not eat enough calories to grow and develop properly, and an adult with ARFID does not eat enough calories to maintain basic body function.

• Dramatic restriction of types or amount of food eaten
• Lack of appetite or interest in food
• Dramatic weight loss
• Upset stomach, abdominal pain, or other gastrointestinal issues with no other known cause
• Limited range of preferred foods that becomes even more limited (“picky eating” that gets progressively worse)

What are the risk factors for eating disorders?

Eating disorders can affect people of all ages, racial/ethnic backgrounds, body weights, and genders. Eating disorders frequently appear during the teen years or young adulthood but may also develop during childhood or later in life.

Researchers are finding that eating disorders are caused by a complex interaction of genetic, biological, behavioral, psychological, and social factors. Researchers are using the latest technology and science to better understand eating disorders.

One approach involves the study of human genes. Eating disorders run in families. Researchers are working to identify DNA variations that are linked to the increased risk of developing eating disorders.

Brain imaging studies are also providing a better understanding of eating disorders. For example, researchers have found differences in patterns of brain activity in women with eating disorders in comparison with healthy women. This kind of research can help guide the development of new means of diagnosis and treatment of eating disorders.

How are eating disorders treated?

It is important to seek treatment early for eating disorders. People with eating disorders are at higher risk for suicide and medical complications. People with eating disorders can often have other mental disorders (such as depression or anxiety) or problems with substance use. Complete recovery is possible.

Treatment plans are tailored to individual needs and may include one or more of the following:

• Individual, group, and/or family psychotherapy
• Medical care and monitoring
• Nutritional counseling
• Medications

Psychotherapies

Family-based therapy, a type of psychotherapy where parents of adolescents with anorexia nervosa assume responsibility for feeding their child, appears to be very effective in helping people gain weight and improve eating habits and moods.

To reduce or eliminate binge-eating and purging behaviors, people may undergo cognitive behavioral therapy (CBT), which is another type of psychotherapy that helps a person learn how to identify distorted or unhelpful thinking patterns and recognize and change inaccurate beliefs.

Evidence also suggests that medications such as antidepressants, antipsychotics, or mood stabilizers may also be helpful for treating eating disorders and other co-occurring illnesses such as anxiety or depression. The Food and Drug Administration’s (FDA) website  has the latest information on medication approvals, warnings, and patient information guides.

How can I find a clinical trial for an eating disorder?

Clinical trials are research studies that look at new ways to prevent, detect, or treat diseases and conditions. The goal of clinical trials is to determine if a new test or treatment works and is safe. Although individuals may benefit from being part of a clinical trial, participants should be aware that the primary purpose of a clinical trial is to gain new scientific knowledge so that others may be better helped in the future.

Researchers at NIMH and around the country conduct many studies with patients and healthy volunteers. We have new and better treatment options today because of what clinical trials uncovered years ago. Be part of tomorrow’s medical breakthroughs. Talk to your health care provider about clinical trials, their benefits and risks, and whether one is right for you.

To learn more or find a study, visit:

• NIMH’s Clinical Trials webpage : Information about participating in clinical trials
• Clinicaltrials.gov: Current Studies on Eating Disorders  : List of clinical trials funded by the National Institutes of Health (NIH) being conducted across the country

Where can I learn more about eating disorders?

Free brochures and shareable resources.

• Eating Disorders: About More Than Food : A brochure about the common eating disorders anorexia nervosa, bulimia nervosa, and binge-eating disorder, and various approaches to treatment. Also available en español .
• Let’s Talk About Eating Disorders : An infographic with facts that can help shape conversations around eating disorders. Also available in en español .
• Shareable Resources on Eating Disorders : Help support eating disorders awareness and education in your community. Use these digital resources, including graphics and messages, to spread the word about eating disorders.
• Mental Health Minute: Eating Disorders : Take a mental health minute to watch this video on eating disorders.
• Let’s Talk About Eating Disorders with NIMH Grantee Dr. Cynthia Bulik : Learn about the signs, symptoms, treatments, and the latest research on eating disorders.

Research and statistics

• NIMH Eating Disorders Research Program : This program supports research on the etiology, core features, longitudinal course, and assessment of eating disorders.
• Journal Articles   : References and abstracts from MEDLINE/PubMed (National Library of Medicine).
• Statistics: Eating Disorders

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Anorexia nervosa.

Christine A. Moore ; Brooke R. Bokor .

Affiliations

Last Update: August 28, 2023 .

• Continuing Education Activity

Anorexia nervosa is defined by the restriction of nutrient intake relative to requirements, which leads to significantly low body weight. Patients with this eating disorder will have a fear of gaining weight along and a distorted body image with the inability to comprehend the seriousness of their condition. This activity reviews the evaluation and management of anorexia nervosa and highlights the role of the interprofessional team in improving care for patients with this condition.

• Outline the epidemiology of anorexia nervosa.
• Explain the pathophysiology of anorexia nervosa.
• Describe the management of anorexia nervosa.
• Summarize the importance of improving care coordination among the interprofessional team members to enhance the delivery of care for those with anorexia nervosa.
• Introduction

Anorexia nervosa is an eating disorder defined by restriction of energy intake relative to requirements, leading to a significantly low body weight. Patients will have an intense fear of gaining weight and distorted body image with the inability to recognize the seriousness of their significantly low body weight. [1] [2] [3]

The success of many professions depends on a person's weight. Models and actors portray a level of thinness that is difficult to attain, and it is enhanced by make-up and photographic alterations. Athletes in sports such as ballet, long-distance running, and martial arts are pressured to maintain lean body weights to outperform the competition. Media outlets promote diet secrets and weight loss tips in excess. Populations such as maturing females identify thin body types with increased self-esteem and link weight loss with self-control. [4] [5]

• Epidemiology

Anorexia nervosa is more common in females than males. Onset is late adolescence and early adulthood. Lifetime prevalence is 0.3% to 1% (European studies have demonstrated a prevalence of 2% to 4%), irrespective of culture, ethnicity, and race. Risk factors for eating disorders include childhood obesity, female sex, mood disorders, personality traits (impulsivity and perfectionism), sexual abuse, or weight-related concerns from family or peer environments. [6] [7] [8]

• Pathophysiology

Studies demonstrate biological factors play a role in the development of anorexia nervosa in addition to environmental factors. Genetic correlations exist between educational attainment, neuroticism, and schizophrenia. Patients with anorexia nervosa have altered brain function and structure there are deficits in neurotransmitters dopamine (eating behavior and reward) and serotonin (impulse control and neuroticism), differential activation of the corticolimbic system (appetite and fear), and diminished activity among the frontostriatal circuits (habitual behaviors). Patients have co-morbid psychiatric disorders such as major depressive disorder and generalized anxiety disorder.

• History and Physical

Patients will report symptoms such as amenorrhea, cold intolerance, constipation, extremity edema, fatigue, and irritability. They may describe restrictive behaviors related to food like calorie counting or portion control, and purging methods, for example, self-induced vomiting or use of diuretics or laxatives. Many exercise compulsively for extended periods of time. Patients with anorexia nervosa develop multiple complications related to prolonged starvation and purging behaviors.

Workup includes a thorough medical history (comprehensive review of systems, family and social history, medications including nonprescribed, past medical and psychiatric history, prior abuse) and physical exam (looking for complications above). Basic labs include coagulation panel, complete blood count, complete metabolic profile, 25-hydroxyvitamin D, testosterone (males), thyroid-stimulating hormone, and urine testing (beta-hCG [females] and drugs, either illicit or prescription). An electrocardiogram is recommended to assess for life-threatening arrhythmias. Additional studies may be necessary if BMI is less than 14 kg/m, for example, echocardiogram in patients with hemodynamic compromise (dyspnea, murmurs, syncope) or computed tomography of the abdomen to rule out superior mesenteric artery syndrome or amenorrhea more than 9 months (dual-energy x-ray absorptiometry). [9] [8]

Complications of anorexia nervosa are listed:

• Cardiovascular: bradycardia, dilated cardiomyopathy, electrolyte-induced arrhythmias, hypotension, mitral valve prolapse, pericardial effusion
• Constitutional: arrested growth, hypothermia, low body mass index (BMI), muscle wasting
• Dermatologic: carotenoderma, lanugo, xerosis
• Endocrine: hypothalamic hypogonadism, osteoporosis
• Gastrointestinal: constipation (laxative abuse), gastroparesis
• Hematologic: cytopenias (inc. normocytic anemia), bone marrow hypoplasia/aplasia
• Neurologic: brain atrophy, peripheral neuropathy (mineral and vitamin deficiencies)
• Obstetric: antenatal and postnatal complications
• Psychiatric: depression, impaired concentration, insomnia, irritability
• Renal and electrolytes: hypokalemic metabolic acidosis or alkalosis (laxative or diuretic abuse, resp.), prerenal renal failure, refeeding syndrome.

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides the diagnostic criteria for anorexia nervosa (A-C). It classifies the disease by type, status, and severity.

Of note, amenorrhea has been removed from the DSM-5 criteria. Patients who meet the new criteria and continue to menstruate have similar outcomes as those who do not.

Other eating disorders have similar features to anorexia nervosa. Avoidant or restrictive food intake disorder involves food restriction with failure to meet the nutritional need. While patients are often underweight, this disturbance does not meet diagnostic criteria for anorexia nervosa. Individuals with binge eating disorder eat excessive amounts of calories in a short period with a lack of self-control but do not display compensatory behaviors such as purging or restriction. Patients with bulimia nervosa will binge and purge without a corresponding low BMI. Pica refers to chronic ingestion of nonfood substances and may be a manifestation of underlying medical or psychiatric condition. For example, patients with anorexia nervosa may eat toilet paper when they are hungry. Rumination disorder occurs when patients repeatedly regurgitate food for one month when no other medical condition can be identified and does not occur solely during the course of another eating disorder. Other specified feeding or eating disorder refers to conditions with symptoms that impair functioning but do not meet criteria for a specific eating disorder, for example, patients who meet criteria for anorexia nervosa but have BMI more than 18.5 kg/m are classified as “atypical anorexia nervosa.”

Major depressive disorder can cause anorexia and weight loss. However, patients are not obsessed with body habitus. Patients with obsessive-compulsive disorder may have food rituals but maintain a normal weight. Patients who abuse stimulants such as cocaine and methamphetamine experience weight loss through increased metabolism and concentrated efforts to obtain illicit substances rather than consume calories.

Medical conditions can cause weight loss. Examples are celiac disease, hyperthyroidism, inflammatory bowel disease, malignancy, poorly controlled diabetes mellitus, primary adrenal insufficiency, and tuberculosis. The diagnosis will come from the history and physical examination. Order labs as dictated by the clinical picture.

• Treatment / Management

Treatment for anorexia nervosa is centered on nutrition rehabilitation and psychotherapy. Patients who need inpatient treatment have the following characteristics:

• Existing psychiatric disorders requiring hospitalization
• High risk for suicide (intent with highly lethal plan or failed attempt)
• Lack of support system (severe family conflict or homelessness)
• Limited access (lives too far away to participate in a daily treatment program)
• Medically unstable (bradycardia, dehydration, hypoglycemia or poorly controlled diabetes, hypokalemia or other electrolyte imbalances indicative of refeeding syndrome, hypothermia, hypotension, organ compromise requiring acute treatment)
• Poorly motivated to recover (uncooperative, preoccupied with intrusive thoughts)
• Purging behaviors that are persistent, severe, and occur multiple times a day
• Severe anorexia nervosa (less than 70% of ideal body weight or acute weight loss with food refusal)
• Supervised feeding and/or specialized feeding (nasogastric tube) required
• Unable to stop compulsively exercising (not a sole indication for hospitalization).

Outpatient treatment includes intensive therapy (2 to 3 hours per weekday) and partial hospitalization (6 hours per day). Pediatric patients benefit from family-based psychotherapy to explore underlying dynamics and restructure the home environment.

Refeeding syndrome can occur following prolonged starvation. As the body utilizes glucose to produce molecules of adenosine triphosphate (ATP), it depletes the remaining stores of phosphorus. Also, glucose entry into cells is mediated by insulin and occurs rapidly following long periods without food. Both cause electrolyte abnormalities such as hypophosphatemia and hypokalemia, triggering cardiac and respiratory compromise. Patients should be followed carefully for signs of refeeding syndrome and electrolytes closely monitored.

Pharmacotherapy is not used initially. For acutely ill patients who do not respond to initial treatment, olanzapine is a first-line medication. Other antipsychotics have not demonstrated similar effects on weight gain. For patients who are not acutely ill but have co-morbid psychiatric conditions such as generalized anxiety disorder or major depressive disorder, combination therapy with selective serotonin reuptake inhibitors (SSRIs) and therapy is best. Patients who do not respond to SSRIs may need a second-generation antipsychotic. Tricyclic antidepressants (TCAs) are less preferred due to concerns about cardiotoxicity, especially in malnourished patients. Bupropion is contraindicated in patients with eating disorders due to the increased risk of seizures. [10] [11] [12]

• Differential Diagnosis
• Chronic mesenteric ischemia
• Malabsorption
• Hyperthyroidism
• Irritable bowel syndrome
• Celiac disease

Remission in AN varies. Three-fourths of patients treated in out-patient settings remit within 5 years and the same percentage experience intermediate-good outcomes (including weight gain). Relapse is more common in patients who are older with a longer duration of disease or lower body fat/weight at the end of treatment, have co-morbid psychiatric disorders, or receive therapy outside of a specialized clinic. Patients who achieve partial remission often develop another form of eating disorder (ex. bulimia nervosa or unspecified eating disorder).

All-cause mortality is greater in AN compared to the rest of the population. It has one of the highest mortality rates of all eating disorders due to medical complications, substance abuse, and suicide. Patients with AN have increased rates of suicide and this accounts for 25% of deaths associated.

• Complications
• Delayed puberty
• Hypercarotenemia
• Hypothermia
• Hypoglycemia
• Osteoporosis
• Failure to thrive 
• Cardiomyopathy
• Bradycardia
• Arrhythmias
• Renal failure
• Constipation
• Peripheral neuropathy
• Pancytopenia
• Infertility
• Deterrence and Patient Education

Anorexia nervosa is a psychiatric disease in which patients restrict their food intake relative to their energy requirements through eating less, exercising more, and/or purging food through laxatives and vomiting. Despite being severely underweight, they do not recognize it and have distorted body images. They can develop complications from being underweight and purging food. Diagnose by history, physical, and lab work that rules out other conditions that can make people lose weight. Treatment includes gain weight (sometimes in a hospital if severe), therapy to address body image, and management of complications from malnourishment.

• Enhancing Healthcare Team Outcomes

Anorexia nervosa is a serious eating disorder that has very high morbidity. The disorder is usually managed with an interprofessional team that consists of a psychiatrist, dietitian, social worker, internist, endocrinologist, gastroenterologist, and nurses.  The disorder cannot be prevented and there is no cure. Hence patient and family education is key to preventing high morbidity. The dietitian should educate the family on the importance of nutrition and limiting exercise. The mental health nurse should educate the patient on changes in behavior, easing stress, and overcoming any emotional issues. The pharmacist should educate the patient and family on the use of drugs like laxatives and weight loss pills. Only through close follow-up and monitoring can patient outcomes be improved. [13] [14]  [Level 5]

Evidence-based Outcomes

Remission in anorexia nervosa varies. Three-fourths of patients treated in out-patient settings remit within five years and the same percentage experience intermediate-good outcomes, including weight gain. Relapse is more common in patients who are older with a longer duration of disease or lower body fat/weight at the end of treatment, have co-morbid psychiatric disorders, or receive therapy outside of a specialized clinic. Often, patients who achieve partial remission develop another form of eating disorders like bulimia nervosa or unspecified eating disorder.

All-cause mortality is greater in anorexia nervosa compared to the rest of the population. It has one of the highest mortality rates of all eating disorders due to medical complications, substance abuse, and suicide. Patients with anorexia nervosa have increased rates of suicide, and this accounts for 25% of deaths associated with the disorder. [15] [16] [9]  [Level 5]

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Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Criteria for Anorexia Nervosa Contributed by Christine Moore, D.O.

Disclosure: Christine Moore declares no relevant financial relationships with ineligible companies.

Disclosure: Brooke Bokor declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Moore CA, Bokor BR. Anorexia Nervosa. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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