clinical case studies psychology

5 Fascinating Clinical Psychology Case Studies

If you pursue work as a clinical psychologist, you’ll be able to make a major difference in people’s lives. In most cases, these psychologists are the first practitioners to recognize and diagnose mental health disorders. Many clinical psychologists also practice “talk therapy,” where they talk through issues with patients and help them develop better coping mechanisms. But what’s it really like to work in clinical psychology? Take a look at each case study psychology below to get an idea.

A Day in the Life of a Clinical Psychologist

As you might be able to tell from the name, a clinical psychologist applies psychology knowledge in a clinical setting. Using their knowledge of different mental disorders and how they present, clinical psychologists help patients identify and then treat mental health disorders. They also can help patients work through psychological issues even if no disorder is present.

However, it’s important to note that clinical psychologists do not prescribe medication. Often, once a clinical psychologist makes a diagnosis that requires medication, they will refer a patient to a psychiatrist. The psychiatrist handles the medication, but a clinical psychologist will often help a patient manage some of their symptoms through some form of talk therapy. In the case of some complex disorders, a psychologist may be able to coordinate with the patient’s psychiatrist in order to ensure the best care possible.

Some people believe that talk therapy is just a patient talking while the psychologist listens. However, this couldn’t be further from the truth. Clinical psychologists are tasked with assessing each patient and developing an individualized treatment plan. Often, that plan includes delving into the patient’s issues and helping them understand their roots. From there, the psychologist can help the patient develop healthier coping mechanisms for dealing with those issues.

Usually, clinical psychologists primarily work with patients on an individual basis. They do this either as part of a group practice or in private practice. Sometimes, they may teach classes, although this usually isn’t the bulk of their workload. Clinical psychologists often will conduct and publish research that sometimes involves case studies of patients.

Becoming a Clinical Psychologist

To become a clinical psychologist, you will need to pursue a doctoral degree. Most clinical psychologists have either a Ph.D. or a PsyD, though the Ph.D. is more common in the field and will usually afford you more career opportunities. PsyD programs tend to accept more applicants than Ph.D. programs. A PsyD degree places more focus on applying concepts of psychology to the clinical setting. A Ph.D. program certainly applies concepts of psychology as well, but it has much more of a focus on research than PsyD programs do.

Regardless of which program you choose, becoming a clinical psychologist involves a considerable time commitment. The first step is obtaining a four-year bachelor’s degree. From there, some candidates pursue a master’s degree, while others go straight into a Ph.D. training program.

Most PsyD programs take four to five years to complete, while most Ph.D. programs take between five and seven years. In the case of a Ph.D., graduates will need to complete a residency program much like medical doctors. Residency programs usually last about one to three years. During that time, new psychologists are overseen by an experienced psychologist. Upon completion of the residency, a clinical psychologist must also take and pass a licensure exam in order to practice in their state. Most states will also allow you to obtain different certifications in specialized areas.

As you can see, the decision to become a clinical psychologist isn’t one to make on a whim. Usually, though, you’ll be able to get a sense of the field from the undergraduate courses you take early on.

What’s a Case Study?

In a moment, we’ll take you through five interesting case studies from real clinical psychologists. But what exactly is a case study?

Simply put, a case study is a very detailed account of an individual patient’s case. (The case studies below are abbreviated versions of case studies.) Psychologists usually keep notes on all patients, but a case study is much more formal. Each study is an in-depth exploration of a patient’s disorder, and it usually contains information on the patient’s personal history as well as how their disorder presents. Most case studies also have information on treatments that have worked (and those that have not worked) for a given patient.

So why is a single case study valuable, especially when most studies survey larger groups of patients? For one, case studies are extremely valuable in the case of rare conditions. With very rare mental health disorders, it can be near-impossible to find larger studies. With case studies, it’s still possible to get an accurate picture of the disorder and what it looks like in different patients.

Case studies can also help future clinical psychologists to sharpen their diagnostic skills. In a broader study, you might learn about some of the common symptoms of a diagnose. But individual patients have their own quirks, and the same disorder can look different from patient to patient. Reading case studies can be a great way to see how different mental health issues can look in different people.

Lastly, case studies can be useful in supporting or refuting existing research. In some cases, they may point to issues that need to be researched further.

To really start to get a sense of what it’s like to be a clinical psychologist, check out these five interesting case studies reported by actual clinicians:

Wishing for Death

Even if you seem to have a promising future, it’s still possible to deal with severe depression. This is what happened to Jessica, a woman who had successfully completed medical school and obtained a residency at a large hospital. In Jessica’s case, her mental state declined seemingly overnight; she awoke one day feeling especially sad. But instead of lifting, that sadness continued and even worsened.

As is the case with many people with depression, Jessica lost interest in things she had previously enjoyed. She stopped having sex with her husband and even found interacting with her children to be a chore. She even found that her job was in jeopardy, as she stopped caring about work and began missing shifts.

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Often, people suffering from severe depression will consider suicide. Some will go as far as making and going through with suicide plans. Jessica wasn’t considering or fantasizing about suicide. But she did begin to wish she was dead, and these thoughts slowly became all-consuming. Despite feeling drained from her low mood, Jessica still had trouble sleeping at night. This is when her thoughts of death were at their worst.

Jessica continued to insist that nothing was wrong. But her coworkers at the hospital saw that something was off. Jessica wasn’t being lazy or slacking for no reason; it was clear her mental health was suffering. Her colleagues were able to convince Jessica to see a mental health professional. She was diagnosed with major depressive disorder, a mental health disorder that causes severe and persistent sadness and loss of interest.

College Struggles

Many mental health issues present themselves when people are college-aged, and this is what happened to Gerry, a 21-year-old college student who got good grades. Gerry got along well with his friends and roommates until he started having trouble sleeping. At night, his thoughts began to race and felt as though they were spinning out of control.

But that wasn’t all. Gerry was usually a kind and mild-mannered person, but he began calling his friends at all hours of the night, becoming angry if they didn’t give him the attention he wanted. Within a few days, Gerry started to believe his roommates were spying on him. He told them as much. Instead of writing it off as simply a quirk, his friends became very concerned. They talked to Gerry and explained the strange changes they’d been seeing in his behavior. Ultimately, they were able to convince Gerry to seek mental health help.

After talking with a clinician, Gerry was ultimately diagnosed with bipolar disorder. It can be an intimidating diagnosis to receive, but Gerry was referred to a psychiatrist who could work with him to find the right medication. The combination of medication and cognitive-behavioral therapy helped him to return back to his normal self.

A Case of Obsession

Plenty of people are fastidious about certain things, but one salesman took it a little too far. The salesman was having trouble leaving his house on time to get to work because he had an overwhelming and obsessive need to follow a set of rituals. Many of them were about securing the home. It started with double-checking and triple-checking that doors were locked.

The salesman also became incredibly worried about the electrical wiring in the home. He began to obsess over whether it would cause an electrical fire. If he didn’t complete the various rituals he felt compelled to do, the man believed he would experience bad luck.

Once he saw a psychologist, the man was diagnosed with obsessive-compulsive disorder. Since this disorder involves holding onto irrational beliefs, cognitive-behavioral therapy is essential. The man’s psychologist worked with him through therapy and helped him to manage and then overcome his obsessive thoughts. Ultimately, the salesman was able to get back to a much more normal life.

Unexpected Panic

Panic disorders and anxiety disorders can seem to poison your life. That’s what it felt like for one forest ranger. Up until his mid-30s, he didn’t suffer from more than normal anxiety. But one day, while standing in line at the grocery store, he suddenly felt an overwhelming wave of panic. His heart rate went up and he started sweating. The panic attack was so bad that the forest ranger thought he would pass out, so he abandoned his shopping cart and returned to the car.

Naturally, the forest ranger didn’t want the same thing to happen again. Because that first panic attack had occurred in a grocery store, he began avoiding supermarkets. But that didn’t help for long. He began to experience intense anxiety in many areas of his life. His symptoms were so severe that his family life began to suffer, so he sought help.

The forest ranger saw a psychologist and was diagnosed with an anxiety disorder. Though some people with anxiety disorders benefit from medication, the forest ranger was able to work through and manage his symptoms through cognitive behavioral therapy.

Bizarre Behaviors

Most severe mental disorders don’t start in childhood. When they do appear, these disorders often involve someone who previously seemed outwardly normal suddenly exhibiting strange behaviors. This is what happened to a 21-year-old business student. He suddenly began becoming agitated for no ostensible reason. During his bouts of agitation, other people heard him whispering angrily to himself.

The young man’s friends and family were very concerned, but they were unable to reach him by phone. He explained that aliens had placed a chip in his brain and that it would explode if he answered his phone.

Sometimes, symptoms like those the young man had can be caused or made worse by abusing alcohol or drugs. However, the young man didn’t abuse either. A family history of mental illness can sometimes be a risk factor, and the man did say he had an aunt who had been treated at psychiatric hospitals several times.

Thanks in part to the concern of his friends and family, the young man talked to a psychologist and gave a detailed account of his symptoms. He was diagnosed with paranoid schizophrenia. This is a difficult diagnosis to receive. But as the young man found, schizophrenia is possible to manage with good care. The young man’s psychologist was able to continue therapy, and he was also referred to a psychiatrist for help with medication. Often, for those diagnosed with paranoid schizophrenia, a combination of therapy and the right medications can effectively manage symptoms.

Each case study psychology above is just a short introduction to the types of cases you may encounter working as a clinical psychologist. And when working in the field, you’ll be asked to write your own case studies, too. While in school, you’ll learn the correct way to write case studies and how sharing case studies with other psychologists can help the field grow as a whole. Hopefully, these case studies have also shed some light on one of the best parts of working as a clinical psychologist — you can help people confront and work through mental health challenges and work toward healthier, happier lives.

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Case Study Research Method in Psychology

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

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Olivia Guy-Evans, MSc

Associate Editor for Simply Psychology

BSc (Hons) Psychology, MSc Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

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Case studies are in-depth investigations of a person, group, event, or community. Typically, data is gathered from various sources using several methods (e.g., observations & interviews).

The case study research method originated in clinical medicine (the case history, i.e., the patient’s personal history). In psychology, case studies are often confined to the study of a particular individual.

The information is mainly biographical and relates to events in the individual’s past (i.e., retrospective), as well as to significant events that are currently occurring in his or her everyday life.

The case study is not a research method, but researchers select methods of data collection and analysis that will generate material suitable for case studies.

Freud (1909a, 1909b) conducted very detailed investigations into the private lives of his patients in an attempt to both understand and help them overcome their illnesses.

This makes it clear that the case study is a method that should only be used by a psychologist, therapist, or psychiatrist, i.e., someone with a professional qualification.

There is an ethical issue of competence. Only someone qualified to diagnose and treat a person can conduct a formal case study relating to atypical (i.e., abnormal) behavior or atypical development.

 Famous Case Studies

• Anna O – One of the most famous case studies, documenting psychoanalyst Josef Breuer’s treatment of “Anna O” (real name Bertha Pappenheim) for hysteria in the late 1800s using early psychoanalytic theory.
• Little Hans – A child psychoanalysis case study published by Sigmund Freud in 1909 analyzing his five-year-old patient Herbert Graf’s house phobia as related to the Oedipus complex.
• Bruce/Brenda – Gender identity case of the boy (Bruce) whose botched circumcision led psychologist John Money to advise gender reassignment and raise him as a girl (Brenda) in the 1960s.
• Genie Wiley – Linguistics/psychological development case of the victim of extreme isolation abuse who was studied in 1970s California for effects of early language deprivation on acquiring speech later in life.
• Phineas Gage – One of the most famous neuropsychology case studies analyzes personality changes in railroad worker Phineas Gage after an 1848 brain injury involving a tamping iron piercing his skull.

Clinical Case Studies

• Studying the effectiveness of psychotherapy approaches with an individual patient
• Assessing and treating mental illnesses like depression, anxiety disorders, PTSD
• Neuropsychological cases investigating brain injuries or disorders

Child Psychology Case Studies

• Studying psychological development from birth through adolescence
• Cases of learning disabilities, autism spectrum disorders, ADHD
• Effects of trauma, abuse, deprivation on development

Types of Case Studies

• Explanatory case studies : Used to explore causation in order to find underlying principles. Helpful for doing qualitative analysis to explain presumed causal links.
• Exploratory case studies : Used to explore situations where an intervention being evaluated has no clear set of outcomes. It helps define questions and hypotheses for future research.
• Descriptive case studies : Describe an intervention or phenomenon and the real-life context in which it occurred. It is helpful for illustrating certain topics within an evaluation.
• Multiple-case studies : Used to explore differences between cases and replicate findings across cases. Helpful for comparing and contrasting specific cases.
• Intrinsic : Used to gain a better understanding of a particular case. Helpful for capturing the complexity of a single case.
• Collective : Used to explore a general phenomenon using multiple case studies. Helpful for jointly studying a group of cases in order to inquire into the phenomenon.

Where Do You Find Data for a Case Study?

There are several places to find data for a case study. The key is to gather data from multiple sources to get a complete picture of the case and corroborate facts or findings through triangulation of evidence. Most of this information is likely qualitative (i.e., verbal description rather than measurement), but the psychologist might also collect numerical data.

1. Primary sources

• Interviews – Interviewing key people related to the case to get their perspectives and insights. The interview is an extremely effective procedure for obtaining information about an individual, and it may be used to collect comments from the person’s friends, parents, employer, workmates, and others who have a good knowledge of the person, as well as to obtain facts from the person him or herself.
• Observations – Observing behaviors, interactions, processes, etc., related to the case as they unfold in real-time.
• Documents & Records – Reviewing private documents, diaries, public records, correspondence, meeting minutes, etc., relevant to the case.

2. Secondary sources

• News/Media – News coverage of events related to the case study.
• Academic articles – Journal articles, dissertations etc. that discuss the case.
• Government reports – Official data and records related to the case context.
• Books/films – Books, documentaries or films discussing the case.

3. Archival records

Searching historical archives, museum collections and databases to find relevant documents, visual/audio records related to the case history and context.

Public archives like newspapers, organizational records, photographic collections could all include potentially relevant pieces of information to shed light on attitudes, cultural perspectives, common practices and historical contexts related to psychology.

4. Organizational records

Organizational records offer the advantage of often having large datasets collected over time that can reveal or confirm psychological insights.

Of course, privacy and ethical concerns regarding confidential data must be navigated carefully.

However, with proper protocols, organizational records can provide invaluable context and empirical depth to qualitative case studies exploring the intersection of psychology and organizations.

• Organizational/industrial psychology research : Organizational records like employee surveys, turnover/retention data, policies, incident reports etc. may provide insight into topics like job satisfaction, workplace culture and dynamics, leadership issues, employee behaviors etc.
• Clinical psychology : Therapists/hospitals may grant access to anonymized medical records to study aspects like assessments, diagnoses, treatment plans etc. This could shed light on clinical practices.
• School psychology : Studies could utilize anonymized student records like test scores, grades, disciplinary issues, and counseling referrals to study child development, learning barriers, effectiveness of support programs, and more.

How do I Write a Case Study in Psychology?

Follow specified case study guidelines provided by a journal or your psychology tutor. General components of clinical case studies include: background, symptoms, assessments, diagnosis, treatment, and outcomes. Interpreting the information means the researcher decides what to include or leave out. A good case study should always clarify which information is the factual description and which is an inference or the researcher’s opinion.

1. Introduction

• Provide background on the case context and why it is of interest, presenting background information like demographics, relevant history, and presenting problem.
• Compare briefly to similar published cases if applicable. Clearly state the focus/importance of the case.

2. Case Presentation

• Describe the presenting problem in detail, including symptoms, duration,and impact on daily life.
• Include client demographics like age and gender, information about social relationships, and mental health history.
• Describe all physical, emotional, and/or sensory symptoms reported by the client.
• Use patient quotes to describe the initial complaint verbatim. Follow with full-sentence summaries of relevant history details gathered, including key components that led to a working diagnosis.
• Summarize clinical exam results, namely orthopedic/neurological tests, imaging, lab tests, etc. Note actual results rather than subjective conclusions. Provide images if clearly reproducible/anonymized.
• Clearly state the working diagnosis or clinical impression before transitioning to management.

3. Management and Outcome

• Indicate the total duration of care and number of treatments given over what timeframe. Use specific names/descriptions for any therapies/interventions applied.
• Present the results of the intervention,including any quantitative or qualitative data collected.
• For outcomes, utilize visual analog scales for pain, medication usage logs, etc., if possible. Include patient self-reports of improvement/worsening of symptoms. Note the reason for discharge/end of care.

4. Discussion

• Analyze the case, exploring contributing factors, limitations of the study, and connections to existing research.
• Analyze the effectiveness of the intervention,considering factors like participant adherence, limitations of the study, and potential alternative explanations for the results.
• Identify any questions raised in the case analysis and relate insights to established theories and current research if applicable. Avoid definitive claims about physiological explanations.
• Offer clinical implications, and suggest future research directions.

5. Additional Items

• Thank specific assistants for writing support only. No patient acknowledgments.
• References should directly support any key claims or quotes included.
• Use tables/figures/images only if substantially informative. Include permissions and legends/explanatory notes.
• Provides detailed (rich qualitative) information.
• Provides insight for further research.
• Permitting investigation of otherwise impractical (or unethical) situations.

Case studies allow a researcher to investigate a topic in far more detail than might be possible if they were trying to deal with a large number of research participants (nomothetic approach) with the aim of ‘averaging’.

Because of their in-depth, multi-sided approach, case studies often shed light on aspects of human thinking and behavior that would be unethical or impractical to study in other ways.

Research that only looks into the measurable aspects of human behavior is not likely to give us insights into the subjective dimension of experience, which is important to psychoanalytic and humanistic psychologists.

Case studies are often used in exploratory research. They can help us generate new ideas (that might be tested by other methods). They are an important way of illustrating theories and can help show how different aspects of a person’s life are related to each other.

The method is, therefore, important for psychologists who adopt a holistic point of view (i.e., humanistic psychologists ).

Limitations

• Lacking scientific rigor and providing little basis for generalization of results to the wider population.
• Researchers’ own subjective feelings may influence the case study (researcher bias).
• Difficult to replicate.
• Time-consuming and expensive.
• The volume of data, together with the time restrictions in place, impacted the depth of analysis that was possible within the available resources.

Because a case study deals with only one person/event/group, we can never be sure if the case study investigated is representative of the wider body of “similar” instances. This means the conclusions drawn from a particular case may not be transferable to other settings.

Because case studies are based on the analysis of qualitative (i.e., descriptive) data , a lot depends on the psychologist’s interpretation of the information she has acquired.

This means that there is a lot of scope for Anna O , and it could be that the subjective opinions of the psychologist intrude in the assessment of what the data means.

For example, Freud has been criticized for producing case studies in which the information was sometimes distorted to fit particular behavioral theories (e.g., Little Hans ).

This is also true of Money’s interpretation of the Bruce/Brenda case study (Diamond, 1997) when he ignored evidence that went against his theory.

Breuer, J., & Freud, S. (1895).  Studies on hysteria . Standard Edition 2: London.

Curtiss, S. (1981). Genie: The case of a modern wild child .

Diamond, M., & Sigmundson, K. (1997). Sex Reassignment at Birth: Long-term Review and Clinical Implications. Archives of Pediatrics & Adolescent Medicine , 151(3), 298-304

Freud, S. (1909a). Analysis of a phobia of a five year old boy. In The Pelican Freud Library (1977), Vol 8, Case Histories 1, pages 169-306

Freud, S. (1909b). Bemerkungen über einen Fall von Zwangsneurose (Der “Rattenmann”). Jb. psychoanal. psychopathol. Forsch ., I, p. 357-421; GW, VII, p. 379-463; Notes upon a case of obsessional neurosis, SE , 10: 151-318.

Harlow J. M. (1848). Passage of an iron rod through the head.  Boston Medical and Surgical Journal, 39 , 389–393.

Harlow, J. M. (1868).  Recovery from the Passage of an Iron Bar through the Head .  Publications of the Massachusetts Medical Society. 2  (3), 327-347.

Money, J., & Ehrhardt, A. A. (1972).  Man & Woman, Boy & Girl : The Differentiation and Dimorphism of Gender Identity from Conception to Maturity. Baltimore, Maryland: Johns Hopkins University Press.

Money, J., & Tucker, P. (1975). Sexual signatures: On being a man or a woman.

Further Information

• Case Study Approach
• Case Study Method
• Enhancing the Quality of Case Studies in Health Services Research
• “We do things together” A case study of “couplehood” in dementia
• Using mixed methods for evaluating an integrative approach to cancer care: a case study

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• > Critical Thinking in Psychology
• > The Case Study Perspective on Psychological Research

Book contents

• Frontmatter
• List of Illustrations and Tables
• List of Contributors
• 1 The Nature and Nurture of Critical Thinking
• 2 Evaluating Experimental Research
• 3 Critical Thinking in Quasi-Experimentation
• 4 Evaluating Surveys and Questionnaires
• 5 Critical Thinking in Designing and Analyzing Research
• 6 The Case Study Perspective on Psychological Research
• 7 Informal Logical Fallacies
• 8 Designing Studies to Avoid Confounds
• 9 Evaluating Theories
• 10 Not All Experiments Are Created Equal
• 11 Making Claims in Papers and Talks
• 12 Critical Thinking in Clinical Inference
• 13 Evaluating Parapsychological Claims
• 14 Why Would Anyone Do or Believe Such a Thing?
• 15 The Belief Machine
• 16 Critical Thinking and Ethics in Psychology
• 17 Critical Thinking in Psychology
• Author Index
• Subject Index

6 - The Case Study Perspective on Psychological Research

Published online by Cambridge University Press:  05 June 2012

The case study approach has a rich history in psychology as a method for observing the ways in which individuals may demonstrate abnormal thinking and behavior, for collecting evidence concerning the circumstances and consequences surrounding such disorders, and for providing data to generate and test models of human behavior (see Yin, 1998, for an overview). Nevertheless, the most typical methods for scientifically studying human cognition involve testing groups of healthy people – typically, college undergraduates. In their statistics and research methods courses, psychology students are trained to study the effects of manipulations that are significant across groups of participants despite considerable variation at the level of the individual. They are trained to be skeptical of reasoning from an individual case that goes against the general trend, and to be suspicious of the compelling anecdote that may be introduced to defend some position about how cognition or social interactions might work. Given this state of affairs, are the practitioners of the case study approach misguided, or can valid conclusions be drawn from findings with one patient? Can case reports that detail a client's symptoms and reactions to psychotherapy constitute scientific data? What about case studies that investigate how brain damage affects particular cognitive processes? The goal of this chapter is to demonstrate how single-case-study approaches in clinical psychology and cognitive neuropsychology have contributed to the advancement of theories and models of human cognition and to address the common concerns that researchers often have about case study methodology.

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• The Case Study Perspective on Psychological Research
• By Randi Martin , Rice University, Rachel Hull , Rice University
• Edited by Robert J. Sternberg , Yale University, Connecticut , Henry L. Roediger III , Washington University, St Louis , Diane F. Halpern , Claremont McKenna College, California
• Book: Critical Thinking in Psychology
• Online publication: 05 June 2012
• Chapter DOI: https://doi.org/10.1017/CBO9780511804632.007

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Case Studies in Clinical Psychological Science: Bridging the Gap from Science to Practice

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Case Studies in Clinical Psychological Science demonstrates in detail how the clinical science model can be applied to actual cases. It presents dialogues between leading clinical researchers regarding the treatment of a wide variety of psychological problems, from depression and Alzheimer's disease to Panic Disorder and chronic pain. Chapters describe what evidence-based practice consists of for various clinical problems and are followed by commentary sections in which other leading clinical researchers analyze the case at hand, pointing out additional assessment and treatment options and controversial issues. It examines the application of scientifically based interventions to actual cases and models thoughtful and collegial discussion among prominent clinical researchers

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Clinical Case Studies

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The only journal devoted entirely to psychotherapy case studies, Clinical Case Studies presents innovative psychotherapy cases involving individual, couples, and family therapy. Whether you are a psychologist, counselor, psychiatrist, clinical social worker, family therapist, professor or student of psychotherapy, you’ll find Clinical Case Studies to be a necessary part of your library. The easy-to-follow case presentation format allows you to learn how interesting and challenging cases were assessed and conceptualized, and how treatment followed such conceptualization. This practical format allows clinicians to replicate successful treatments in their own practices. Cases presented in the journal will follow a 12-point format including Title Page, Abstract, and References.

Title Page Abstract

• Theoretical and Research Basis for Treatment 
• Case Introduction
• Presenting complaints
• Case Conceptualization (this is where the clinician’s thinking and treatment selection come to the forefront)
• Course of Treatment and Assessment of Progress
• Complicating Factors
• Access and Barriers to Care
• Treatment Implications of the case
• Recommendations to Clinicians and Students

The journal is multidisciplinary, publishing contributions from practitioners and single case researchers. The journal is sure to be an important tool for the classroom as well as daily practice.

Questions should be directed to the Clinical Case Studies Editorial Office by email: [email protected] . This journal is a member of the Committee on Publication Ethics (COPE) .

Clinical Case Studies seeks manuscripts of innovative and novel psychotherapy treatment cases that articulate various theoretical frameworks (behavioral, cognitive-behavioral, gestalt, humanistic, psychodynamic, rational-emotive therapy, existential, systems, and others). All manuscripts will require an abstract and must adhere to the following format: (1) Theoretical and Research Basis, (2) Case Introduction, (3) Presenting Complaints, (4) History, (5) Assessment, (6) Case Conceptualization (this is where the clinician’s thinking and treatment selection come to the forefront), (7) Course of Treatment and Assessment of Progress, (8) Complicating Factors (including medical management), (9) Access and Barriers to Care, (10) Follow-up (how and how long), (11) Treatment Implications of the Case, (12) Recommendations to Clinicians and Students, and References.

• EMBASE/Excerpta Medica
• Psychological Abstracts

Manuscript submission guidelines can be accessed on Sage Journals .

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The clinical case report: a review of its merits and limitations

Trygve nissen.

1 Department of Clinical Medicine, University of Tromsø, N-9038 Tromsø, Norway

2 Division of General Psychiatry, University Hospital of North Norway, N-9291 Tromsø, Norway

3 Division of Addictions and Specialized Psychiatry, University Hospital of North Norway, N-9291 Tromsø, Norway

The clinical case report has a long-standing tradition in the medical literature. While its scientific significance has become smaller as more advanced research methods have gained ground, case reports are still presented in many medical journals. Some scholars point to its limited value for medical progress, while others assert that the genre is undervalued. We aimed to present the various points of view regarding the merits and limitations of the case report genre. We searched Google Scholar, PubMed and select textbooks on epidemiology and medical research for articles and book-chapters discussing the merits and limitations of clinical case reports and case series.

The major merits of case reporting were these: Detecting novelties, generating hypotheses, pharmacovigilance, high applicability when other research designs are not possible to carry out, allowing emphasis on the narrative aspect (in-depth understanding), and educational value. The major limitations were: Lack of ability to generalize, no possibility to establish cause-effect relationship, danger of over-interpretation, publication bias, retrospective design, and distraction of reader when focusing on the unusual.

Conclusions

Despite having lost its central role in medical literature in the 20th century, the genre still appears popular. It is a valuable part of the various research methods, especially since it complements other approaches. Furthermore, it also contributes in areas of medicine that are not specifically research-related, e.g. as an educational tool. Revision of the case report genre has been attempted in order to integrate the biomedical model with the narrative approach, but without significant success. The future prospects of the case report could possibly be in new applications of the genre, i.e. exclusive case report databases available online, and open access for clinicians and researchers.

Throughout history the clinical case report and case report series have been integral components of medical literature [ 1 ]. The case report genre held a strong position until it was sidelined in the second half of the 20 th century [ 2 , 3 ]. New methodologies for research articles paved the way for evidence-based medicine. Editors had to make space for these research articles and at the same time signaled less enthusiasm for publishing case reports [ 4 ]. This spurred some heated debates in medical journals as readers were worried that the traditional case report was in jeopardy [ 5 , 6 ]. Those who welcomed the new trend with fewer case reports being published pointed mainly to their low quality and inclination to emphasize mere curiosa [ 7 - 9 ]. Some of the proponents of the genre claimed that the case report had been and still was indispensible for furthering medical knowledge and that it was unique in taking care of the detailed study of the individual patient as opposed to the new research methods with their “…nomothetic approach [taking] precedence…” [ 5 ]. Still, the case report got a low ranking on the evidence hierarchy. After a decline in popularity a new interest for the case report emerged, probably beginning in the late 1990s [ 2 ]. A peer-reviewed ‘Case reports’ section was introduced in the Lancet in 1995 [ 10 ]. In 2007, the first international, Pubmed-listed medical journal publishing only case reports was established [ 11 , 12 ]. In the following years, several similar journals, for the most part online and open-access, have been launched.

The present debate is not so much focused on whether case reporting is obsolete or not. Some of the discussions after the turn of the century have been about adapting the case report genre to new challenges. One example is the suggestion of incorporating the narrative, i.e. “… stressing the patient’s story”, in the case report [ 13 ]. The authors termed their initiative “The storied case report”. Their endeavor was not met with success. In analyzing the causes for this, they wondered if “… junior trainees find it too hard to determine what is relevant and senior trainees find it too hard to change their habits” [ 13 ]. A similar attempt was done when the editors of the Journal of Medical Case Reports in 2012 encouraged authors to include the patients’ perspectives by letting patients describe their own experiences [ 14 ].

Notwithstanding, we feel there is much to be gained from having an ongoing discussion highlighting the indications and contraindications for producing case reports. This can to some degree be facilitated by getting an understanding of the merits and limitations of the genre. The objective of this article is to present the merits and limitations of case reports and case series reports.

We adopted Taber’s Cyclopedic Medical Dictionary’s definition of the case report : “A formal summary of a unique patient and his or her illness, including the presenting signs and symptoms, diagnostic studies, treatment course and outcome” [ 15 ]. A case report consists of one or two cases, most often only one. The case series or case series report usually consists of three to ten cases [ 16 ]. (In the following we use the term case report to denote both case reports and case series report). Case reports are most often naturalistic and descriptive. Sometimes, however, they can be prospective and experimental.

As literature specifically dealing with the case report genre seemed harder to elicit from the databases than the vast amount of particular case reports, we performed iterative searches. We searched Google Scholar and PubMed using the search terms ‘case report(s)’, ‘case series’, ‘case series report(s)’, ‘case reporting’ in various combinations with ‘clinical’, ‘medical’, ‘anecdotal’, ‘methodology’, ‘review’, ‘overview’, ‘strengths’, ‘weaknesses’, ‘merits’, and ‘limitations’. Further references were identified by examining the literature found in the electronic searches. We also consulted major textbooks on epidemiology [ 17 , 18 ], some scholars of medical genres [ 19 , 20 ] and a monograph on case reporting by the epidemiologist M. Jenicek [ 16 ]. We delimited our review to the retrospective, naturalistic, and descriptive case report, also labeled the “traditional” or “classic” case report, and case series including such reports. Thus we excluded other types, such as the planned, qualitative case study approach [ 21 ] and simulated cases [ 22 - 24 ]. Finally, we extracted the relevant data and grouped the merits and limitations items in rank order with the items we judged to be the most important first.

New observations

The major advantage of case reporting is probably its ability to detect novelties [ 16 ]. It is the only way to present unusual, uncontrolled observations regarding symptoms, clinical findings, course of illness, complications of interventions, associations of diseases, side effects of drugs, etc. In short, anything that is rare or has never been observed previously might be important for the medical community and ought to be published. A case report might sensitize readers and thus facilitate detection of similar or identical cases.

Generating hypotheses

From a single, or preferably several single case reports or a case series, new hypotheses could be formulated. These could then be tested with formal research methods that are designed to refute or confirm the hypotheses, i.e. comparative (observational and experimental) studies.

There are numerous examples of new discoveries or major advancements in medicine that started with a case report or, in some cases, as humbly as a letter to the editor. The first concern from the medical community about the devastating side effect of thalidomide, i.e. the congenital abnormalities, appeared as a letter to the editor in the Lancet in 1961 [ 25 ]. Soon thereafter, several case reports and case series reports were published in various journals. Case reporting is thus indispensable in drug safety surveillance (pharmacovigilance) [ 26 ].

Sometimes significant advancements in knowledge have come not from what researchers were pursuing, but from “accidental discoveries”, i.e. by serendipity. The story of Alexander Fleming’s discovery of penicillin in 1928 is well known in the medical field [ 27 ]. Psychiatry has profited to a large degree from this mode of advancing medical science as many of the drugs used for mental disorders have been discovered serendipitously [ 27 ]. One notable example is the discovery of the effect of lithium on manic episodes in patients with manic-depressive disorder [ 28 ]. A more recent discovery is the successful treatment of infantile hemangiomas with systemic propranolol. This discovery was published, as a case series report, in the correspondence section in New England Journal of Medicine [ 29 ]. However, the evidence for the effect of this treatment is still preliminary, and several randomized trials are under way [ 30 , 31 ].

Clear and operational entities are prerequisites for doing medical research. Descriptions must come before understanding. Clinical observations that lead to new disorders being described are well suited for case reporting. The medical literature is replete with case-based articles describing new diseases and syndromes. One notable example is the first description of neurasthenia by G. Beard in Boston Medical and Surgical Journal in 1869 [ 32 ].

Researching rare disorders

For rare disorders randomized controlled trials (RCTs) can be impossible to run due to lack of patients to be enrolled. Research on drug treatment and other kinds of interventions must therefore be based on less rigorous methodologies, among them case series and case reports. This would be in accordance with the European Commission’s recommendation to its members to improve health care for those with rare disorders [ 33 ].

Solving ethical constraints

Case reporting can be valuable when ethical constraints prohibit experimental research. Take as an example the challenge of how to manage the side effects of accidental extravasation of cytotoxic drugs. As RCTs on humans seem unethical in this clinical situation the current guidelines rest on small observational studies, case reports and animal studies [ 34 ]. Or another example: Physical restraint is sometimes associated with sudden, unexpected death. The cause or causes for this are to some degree enigmatic, and it is hard to conceive of a controlled study that could be ethical [ 35 , 36 ]. Case reports and case series being “natural experiments” might be the only evidence available for guiding clinical practice.

In-depth narrative case studies

Case reporting can be a way of presenting research with an idiographic emphasis. As contrasted to nomothetic research, an idiographic approach aims at in-depth understanding of human phenomena, especially in the field of psychology and psychiatry. The objective is not generalizable knowledge, but an understanding of meaning and intentionality for an individual or individuals. Sigmund Freud’s case studies are relevant examples. This usage of case reports borders on qualitative research. Qualitative studies, although developed in the social sciences, have become a welcome contribution within health sciences in the last two decades.

Educational value

Clinical medical learning is to a large degree case-based. Typical case histories and vignettes are often presented in textbooks, in lectures, etc. Unusual observations presented as published case reports are important as part of doctors’ continuing medical education, especially as they demonstrate the diversity of manifestations both within and between medical diseases and syndromes [ 37 , 38 ]. Among the various medical texts, the case report is the only one that presents day-to-day clinical practice, clinicians’ diagnostic reasoning, disease management, and follow-up. We believe that some case reports that are written with the aim of contributing to medical knowledge turn out to be of most value educationally because the phenomena have already been described elsewhere. Other case reports are clearly primarily written for educational value [ 37 ]. Some journals have regular sections dedicated to educational case reports, e.g. The Case Records of the Massachusetts General Hospital in the New England Journal of Medicine and the Clinical Case Conference found in the American Journal of Psychiatry.

The cost of doing a case report is low compared to planned, formal studies. Most often the necessary work is probably done in the clinical setting without specific funding. Larger studies, for instance RCTs, will usually need an academic setting.

Fast publication

The time span from observation to publication can be much shorter than for other kinds of studies. This is obviously a great advantage as a case report can be an important alert to the medical community about a serious event. The unexpected side effects of the sedative-antinauseant thalidomide on newborn babies is a telling story. The drug had been prescribed during pregnancy to the babies’ mothers. After the first published observation of severe abnormalities in babies appeared as a letter to the editor of the Lancet in December 16 th , 1961 [ 25 ], several case reports and series followed [ 39 , 40 ]. It should be mentioned though that the drug company had announced on December 2 nd , 1961, i.e. two weeks before the letter from McBride [ 25 ], that it would withdraw the drug form the market immediately [ 41 ].

Flexible structure

Riaz Agha, editor of the International Journal of Surgery Case Reports suggests that the case report, with its less rigid structure is useful as it “… allows the surgeon(s) to discuss their diagnostic approach, the context, background, decision-making, reasoning and outcomes” [ 42 ]. Although the editor is commenting on the surgical case report, the argument can be applied for the whole field of clinical medicine. It should be mentioned though, that other commentators have argued for a more standardized, in effect more rigid, structure [ 43 ].

Clinical practice can be changed

Case reporting can lead to or contribute to a change in clinical practice. A drug might be withdrawn from the market. Or a relabeling might change the attitude to and treatment of a condition. During Word War I the shell shock syndrome was labeled and described thoroughly in several articles in the Lancet , the first of them appearing in February 1915 [ 44 ]. The author was the British captain and military doctor Charles S. Myers. Before his efforts to bring good care and treatment to afflicted soldiers there had been a common misconception that many of these dysfunctional soldiers were malingerers or cowards.

Exercise for novice researchers

The case report format is well suited for young doctors not yet trained as researchers. It can be an opportunity for a first exercise in authoring an article and a preparation for a scientific career [ 37 , 45 , 46 ].

Communication between the clinical and academic fields

Articles authored by clinicians can promote communication between practicing clinicians and academic researchers. Observations published can generate ideas and be a trigger for further studies. For instance, a case series consisting of several similar cases in a short period can make up the case-group for a case–control study [ 47 ]. Clinicians could do the observation and publish the case series while the case–control study could be left to the academics.

Entertainment

Some commentators find reading case reports fun. Although a rather weak argument in favor of case reporting, the value of being entertained should not be dismissed altogether. It might inspire physicians to spend more time browsing and reading scientific literature [ 48 ].

Studying the history of medicine

Finally, we present a note on a different and unintended aspect of the genre. The accumulated case reports from past eras are a rich resource for researching and understanding medical history [ 49 , 50 ]. A close study of old case reports can provide valuable information about how medicine has been practiced through the centuries [ 50 , 51 ].

Limitations

No epidemiological quantities.

As case reports are not chosen from representative population samples they cannot generate information on rates, ratios, incidences or prevalences. The case or cases being the numerator in the equation, has no denominator. However, if a case series report consists of a cluster of cases, it can signal an important and possibly causal association, e.g. an epidemic or a side effect of a newly marketed drug.

Causal inference not possible

Causality cannot be inferred from an uncontrolled observation. An association does not imply a cause-effect relationship. The observation or event in question could be a mere coincidence. This is a limitation shared by all the descriptive studies [ 47 ]. Take the thalidomide tragedy already mentioned as an example; Unusual events such as congenital malformations in some of the children born to mothers having taken a specific drug during pregnancy does not prove that the drug is the culprit. It is a mere hypothesis until further studies have either rejected or confirmed it. Cause-effect relationships require planned studies including control groups that to the extent possible control for chance, bias and confounders [ 52 ].

Generalization not possible

From the argument above, it follows that findings from case reports cannot be generalized. In order to generalize we need both a cause-effect relationship and a representative population for which the findings are valid. A single case report has neither. A case series, on the other hand, e.g. many “thalidomide babies” in a short time period, could strengthen the suspicion of a causal relationship, demanding further surveillance and research.

Publication bias could be a limiting factor. Journals in general favor positive-outcome findings [ 53 ]. One group of investigators studying case reports published in the Lancet found that only 5% of case reports and 10% of case series reported treatment failures [ 54 ]. A study of 435 case reports from the field of dentistry found that in 99.1%, the reports “…clearly [had] a positive outcome and the intervention was considered and described as successful by the authors” [ 55 ].

Overinterpretation

Overinterpretation or misinterpretation is the tendency or temptation to generalize when there is no justification for it. It has also been labeled “the anecdotal fallacy” [ 56 ]. This is not a shortcoming intrinsic to the method itself. Overinterpretation may be due to the phenomenon of case reports often having an emotional appeal on readers. The story implicitly makes a claim to truth. The reader might conclude prematurely that there is a causal connection. The phenomenon might be more clearly illustrated by the impact of the clinician’s load of personal cases on his or her practice. Here exemplified by a young doctor’s confession: “I often tell residents and medical students, ‘The only thing that actually changes practice is adverse anecdote.’” [ 57 ].

Emphasis on the rare

As case reporting often deals with the rare and atypical, it might divert the readers’ attention from common diseases and problems [ 58 ].

Confidentiality

Journals today require written informed consent from patients before publishing case reports. Both authors and publishers are responsible for securing confidentiality. A guarantee for full confidentiality is not always possible. Despite all possible measures taken to preserve confidentiality, sometimes the patient will be recognized by someone. This information should be given to the patient. An adequately informed patient might not consent to publication. In 1995 in an Editorial in the British Journal of Psychiatry one commentator, Isaac Marks, feared that written consent would discourage case reports being written [ 59 ]. Fortunately, judged form the large number of reports being published today, it seems unlikely that the demand for consent has impeded their publication.

Other methodological limitations

Case reports and series are written after the relevant event, i.e. the observation. Thus, the reports are produced retrospectively. The medical record might not contain all relevant data. Recall bias might prevent us from getting the necessary information from the patient or other informants such as family members and health professionals.

It has also been held against case reporting that it is subjective. The observer’s subjectivity might bias the quality and interpretation of the observation (i.e. information bias).

Finally, the falsification criterion within science, which is tested by repeating an experiment, cannot be applied for case reports. We cannot design another identical and uncontrolled observation. However, unplanned similar “experiments” of nature can be repeated. Several such observations can constitute a case series that represents stronger indicative evidence than the single case report.

The major advantages of case reporting are the ability to make new observations, generate hypotheses, accumulate scientific data about rare disorders, do in-depth narrative studies, and serve as a major educational tool. The method is deficient mainly in being unable to deliver quantitative data. Nor can it prove cause-effect relationship or allow generalizations. Furthermore, there is a risk of overinterpretation and publication bias.

The traditional case report does not fit easily into the qualitative-quantitative dichotomy of research methods. It certainly shares some characteristics with qualitative research [ 16 ], especially with regard to the idiographic, narrative perspective – the patient’s “interior world” [ 60 ] – that sometimes is attended to. Apart from “The storied case report” mentioned in the Background-section, other innovative modifications of the traditional case report have been tried: the “evidence-based case report” [ 61 ], the “interactive case report” [ 62 ] and the “integrated narrative and evidence based case report” [ 63 ]. These modifications of the format have not made a lasting impact on the way case reports in general are written today.

The method of case reporting is briefly dealt with in some textbooks on epidemiology [ 17 , 18 ]. Journals that welcome case reports often put more emphasis on style and design than on content in their ‘instruction to authors’ section [ 64 ]. As a consequence, Sorinola and coworkers argue for more consensus and more consistent guidance on writing case reports [ 64 ]. We feel that a satisfactory amount of guidance concerning both style and content now exists [ 12 , 16 , 65 , 66 ]. The latest contribution, “The CARE guidelines”, is an ambitious endeavor to improve completeness and transparency of reports [ 66 ]. These guidelines have included the “Patient perspective” as an item, apparently a bit half-heartedly as this item is placed after the Discussion section, thus not allowing this perspective to influence the Discussion and/or Conclusion section. We assume this is symptomatic of medicine’s problem with integrating the biomedical model with “narrative-based medicine”.

In recent years the medical community has taken an increased interest in case reports [ 2 ], especially after the surge of online, exclusive case report journals started in 2007 with the Journal of Medical Case Reports (which was the first international, Pubmed-listed medical journal publishing only case reports) as the first of this new brand. The climate of skepticism has been replaced by enthusiasm and demand for more case reports. A registry for case reports, Cases Database, was founded in 2012 [ 67 ]. On the condition that it succeeds in becoming a large, international database it could serve as a register being useful for clinicians at work as well as for medical research on various clinical issues. Assuming Pamela P. Powell’s assertion that “[a]lmost all practicing physicians eventually will encounter a case worthy of being reported” [ 60 ] is valid, there should be no shortage of potential cases waiting to be reported and filed in various databases, preferably online and open access.

Limitations of this review

There are several limitations to this study. It is a weakness that we have not been able to review all the relevant literature. The number of publications in some way related to case reports and case report series is enormous, and although we have attempted to identify those publications relevant for our purpose (i.e. those that describe the merits and limitations of the case report genre), we might have missed some. It was difficult to find good search terms for our objective. Still, after repeated electronic searches supplemented with manual searches in reference lists, we had a corpus of literature where essentially no new merits or limitations emerged.

As we point out above, the ranking of merits and limitations represents our subjective opinion and we acknowledge that others might rank the importance of the items differently.

The perspective on merits and limitations of case reporting has been strictly medical. As a consequence we have not analyzed or discussed the various non-medical factors affecting the publication of case reports in different medical journals [ 2 ]. For instance, case reports are cited less often than other kinds of medical research articles [ 68 ]. Thus they can lower a journal’s impact factor, potentially making the journal less attractive. This might lead some high-impact journals to publish few or no case reports, while other journals have chosen to specialize in this genre.

Before deciding on producing a case report or case series based on a particular patient or patients at hand, the observant clinician has to determine if the case report method is the appropriate article type. This review could hopefully assist in that judgment and perhaps be a stimulus to the continuing debate in the medical community on the value of case reporting.

Competing interests

The authors declare that there are no competing interests.

Authors’ contributions

TN contributed to the conception, drafting, and revision of the article. RW contributed to the conception, drafting, and revision of the article. Both authors approved the final manuscript.

Acknowledgements

There was no specific funding for this study.

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CASE STUDY John (obsessive-compulsive disorder)

Case study details.

John is a 56-year-old man who presents to you for treatment. His symptoms started slowly; he tells you that he was always described as an anxious person and remembers being worried about a lot of things throughout his life. For instance, he reported he was very afraid he’d contract HIV by touching doorknobs, even though he tells you he knew this was “irrational.” He tells you that about 10 years ago, following a few life stressors, his anxiety and intrusive thoughts worsened significantly. He tells you he began washing his hands excessively. He reports he developed an intense fear that someone would break into the house and it would be his fault because he left something unlocked. He states that this fear led him to repeatedly check doors and windows before sleep in a specific order, which was a source of contention with his wife. He says that his fear of making a mistake also leads him to be slow to turn in work for his job, checking many times to make sure there are no mistakes, for which he gets reprimanded on occasion.

John reports that his symptoms are getting worse, which is why he has sought treatment. For example, currently he washes his hands until he finishes the whole soap bar, and his hands are cracked because they are so dry. He says he continues to check the doors and windows of his house numerous times throughout the day, not just at night, and has on occasion driven home from work to be sure everything truly was locked. If he notices even a speck of dust on the floor, he states he has the urge to clean the whole house and he often complies with that urge.

John expresses significant distress over these symptoms, as they are taking up more of his time and robbing him of his confidence, as he is increasingly distracted at work and in his family life.

• Compulsions
• Concentration Difficulties
• Intrusive Thoughts
• Ruminations

Diagnoses and Related Treatments

1. obsessive-compulsive disorder.

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Clinical Psychology Case Study: Allison

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Personality and Mental Health

Theo Ingenhoven

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This study examined the usefulness of the SCID-PQ on a sample of 82 inpatients as a screening measure for Axis II disorders. The SCID-PQ proved effective (i.e., resulted in a very low false negatives and moderate false positives) in screening for seven of the 11 DSM-III-R personality disorders. Of the four remaining disorders, minor modifications were suggested which resulted in improved classification rates for dependent and schizoid personality disorders.

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This is the case description of an elderly lady with long standing pattern of maladapted behavior and thinking process that showed a sudden change in response to a potential change in her way of life. The patient was treated like an axis-I disorder but showed minimal response to drug therapy. Discussed here are challenges in terms of diagnosis and management of such patients along with the need for research and investigation that builds further understanding of the complex issues in this patient population.

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Ongoing research demonstrates a striking tendency for personality disorders and mental illness to co-occur, almost all Axis I categories being associated with maladaptive personality traits/criteria across the three personality disorder clusters. The high comorbidity rates between the two axes can be explained by models of association, the structure of personality and even common genetic vulnerabilities. As these links are being identified, the distinction between Axis I and Axis II traditional diagnostic formulations are becoming increasingly blurred, indicating the need for new nosological systems. We present a brief review on the implications of Axis II comorbidity in diagnosis, treatment and prognosis of mental disorders.

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New msu study finds systematic biases at play in clinical trials.

July 1, 2024 - Shelly DeJong

Randomized controlled trials, or RCTs, are believed to be the best way to study the safety and efficacy of new treatments in clinical research. However, a recent study from Michigan State University found that people of color and white women are significantly underrepresented in RCTs due to systematic biases. 

The study , published in the Journal of Ethnicity in Substance Abuse, reviewed 18 RCTs conducted over the last 15 years that tested treatments for post-traumatic stress and alcohol use disorder. The researchers found that despite women having double the rates of post-traumatic stress and alcohol use disorder than men, and people of color having worse chronicity than white people, most participants were white (59.5%) and male (about 78%). 

“Because RCTs are the gold standard for treatment studies and drug trials, we rarely ask the important questions about their limitations and failings,” said   NiCole Buchanan , co-author of the study and professor in MSU’s Department of Psychology. “For RCTs to meet their full potential, investigators need to fix barriers to inclusion. Increasing representation in RCTs is not simply an issue for equity, but it is also essential to enhancing the quality of our science and meeting the needs of the public that funds these studies through their hard-earned tax dollars.”

The researchers found that the design and implementation of the randomized controlled trials contributed to the lack of representation of people of color and women. This happened because trials were conducted in areas where white men were the majority demographic group   and study samples almost always reflected the demographic makeup where studies occurred. Additionally, those designing the studies seldom acknowledged race or gender differences, meaning they did not intentionally recruit diverse samples.

Furthermore, the journals publishing these studies did not have regulations requiring sample diversity, equity or inclusion as appropriate to the conditions under investigation.

“Marginalized groups have unique experiences from privileged groups, and when marginalized groups are poorly included in research, we remain in the dark about their experiences, insights, needs and strengths,” said   Mallet Reid , co-author of the study and doctoral candidate in MSU’s Department of Psychology. “This means that clinicians and researchers may unknowingly   remain ignorant to how to attend to the trauma and addiction challenges facing marginalized groups and may unwittingly perpetuate microaggressions against marginalized groups in clinical settings or fail to meet their needs.”

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• Published: 02 July 2024

A rapid narrative review of the clinical evolution of psychedelic treatment in clinical trials

• Ronit Kishon 1 , 2 ,
• Nadav Liam Modlin 3 , 4 ,
• Yael M. Cycowicz 1 , 2 ,
• Hania Mourtada 2 , 5 ,
• Tayler Wilson 2 ,
• Victoria Williamson 3 , 6 ,
• Anthony Cleare 3 , 4 &
• James Rucker 3 , 4  

npj Mental Health Research volume  3 , Article number:  33 ( 2024 ) Cite this article

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Pre-prohibition psychedelic research with complex psychiatric patients generated a wealth of treatment methodologies and practices, providing invaluable clinical insights pertaining to the medical administration of psychedelics in various mental health diagnoses. Building upon these early studies, which lack the rigor and research tools available today, contemporary psychedelic research has focused on investigating the safety and efficacy of psychedelics in randomized controlled trials via psychometric measures and symptom assessments. Both then and now, the treatment context and the role of clinicians in psychedelic treatment has been recognized as an essential feature for positive patient outcomes. To broaden the knowledge base of modern psychedelic research and support the training of clinicians conducting medically supervised psychedelic research studies, this paper provides a review of pre-prohibition clinical research narratives pertaining to the phenomenology of psychedelic treatment and the role of the non-pharmacological treatment factors in the patient experience. Lastly, this paper explores a range of clinician perspectives and psychological interventions employed in pre-prohibition psychedelic research to inform future research directions and best practice guidelines.

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Introduction.

Medical reports concerning the effects of psychedelics such as 3,4,5-trimethoxyphenethylamine (mescaline) date back to the 1890s, noting their profound effects on perception, cognition, and potential ‘value for psychology’ 1 . However, scientific research remained sporadic until the synthesis of lysergic acid diethylamide (LSD) by Dr. Hofmann in 1938 2 , 3 which marked the beginning of the pre-prohibition era of psychedelic research. During this prolific period of clinical experimentation and scientific inquiry, clinicians and researchers studied the use of LSD and other classical psychedelics in the treatment of a range psychiatric disorders 4 . However, increased recreational use, concerns about safety and abuse, and shifting political attitudes led to the prohibition of psychedelics by the late 1960s and early 1970s.

Clinically, the unique phenomenology of LSD inspired hypotheses regarding its potential psychiatric applications 5 . The pharmaceutical company Sandoz pursued research in this domain by distributing LSD to investigators worldwide free of charge. Sandoz recommended its use as an aid to psychotherapy, referred to as the “psycholytic” 6 . The treatment involved administrating small, gradually increasing doses of psychedelics alongside established psychoanalytic treatment, to patients diagnosed with difficult-to-treat conditions 7 . Subsequently, many pre-prohibition, predominantly psychoanalytically oriented psychiatrists, noted psychedelics’ therapeutic potential 8 , highlighting their capacity to stimulate the emergence of unconscious material by enhancing the transference and eliciting highly associative states 9 .

As the clinical use of psychedelics increased across residential 9 , 10 and outpatient settings 11 , in individual 12 or group-based 13 treatment protocols (Table 1 ), psychedelics appeared to challenge the prevailing psychoanalytic theories regarding the etiology of mental illness. LSD’s psychosis-like effects led some to propose biological models where endogenous compounds similar to mescaline and LSD caused psychotic disorders 14 , challenging traditional psychoanalytic conceptualizations of mental illnesses 15 and adding to the evolving field of neuropsychiatry. This paradigm shift enabled the introduction of the first antipsychotic in 1952, superseding psychoanalytic schizophrenia treatment 16 . Further, LSD’s structural serotonin resemblance sparked hypothesizing in 1954 that serotonin dysfunction played a pathogenic role in affective illnesses 17 , shifting perspectives further toward biological frameworks. However, despite these novel perspectives, pre-prohibition researchers consistently emphasized the significance of psychological interventions to positive treatment outcomes 18 , 19 .

Correspondingly, psychedelic treatment presented two distinct factors that necessitated careful clinical consideration. First, psychedelics appeared to induce a phenomenology that encompassed biological, psychological, interpersonal, and spiritual dimensions. Reported effects appeared dose-dependent and included sensory distortions, synesthesia, mystical-type experiences, intensification of affect, and increased suggestibility 9 , 20 . These effects were at once potentially destabilizing and therapeutic, compelling patients to confront disturbing and repressed content contributing to psychopathology 21 , 22 . Meaning-making capacities also appeared to intensify, with the memorable subjective effects produced by psychedelics appearing necessary to clinical gains 9 , 23 . Crucially, patients’ interpretation of psychedelics’ phenomenology seemed to highly depend on the nature and quality of the treatment’s non-pharmacological factors 24 , 25 . For example, music may be imbued with layers of significance and evoke transcendent wonder 21 . Correspondingly, the terms ‘set’ and ‘setting’ eventually evolved to describe the various psychological and environmental influences on psychedelic treatment 26 , 27 . ‘Setting’ refers to the clinical and environmental context in which the treatment occurs. The mind ‘set’ refers to the expectations, beliefs, and any pre-existing psychological factors (including psychopathology) the patient brings to the treatment session 28 , 29 .

The second factor during psychedelic treatment is the therapist’s unique role, which does not overlap with the conventional roles of psychiatrists and psychotherapists. In psychedelic treatment, researchers found, the clinician is compelled to work alongside and follow the patients’ responses to the psychedelic effects, promoting a sense of safety, rather than directing the patient toward insight 30 . Correspondingly, as psychedelics’ enhanced patients’ sensitivity to the staff, pre-prohibition clinicians discovered that the quality of their interpersonal skills impacted patients’ experience during the acute drug effects 31 . The necessity to mitigate potential psychological and behavioral risks, along with the need to support patients to reflect on their psychedelic experience to elicit therapeutic effects, led to the development of a common way of administrating the drug treatment. It included three phases: preparation, psychedelic treatment session, and integration, occurring after the drug administration session 30 , 32 .

Since 2006, clinical research with psychedelics has seen a revival after years of inactivity; recent studies indicate their potential efficacy in treating a range of severe psychiatric conditions, including treatment-resistant depression, anxiety disorders, and alcohol and substance use disorders 33 , 34 . In the renewed era of psychedelic research, trial protocols have upheld the imperative need for psychological care during the three phases 35 . Modern psychedelic research studies and their associated clinical frameworks are presented in Table 2 . The chosen articles provide a representative sample of modern psychedelic research across indications, compounds, and therapeutic methodologies. In line with pre-prohibition research, contemporary studies highlight the significance of set and setting factors to clinical improvements 27 . Moreover, psychedelics may support therapeutic processes by temporarily relaxing rigid thinking patterns 36 , inducing non-dual awareness 37 , facilitating emotional breakthroughs 38 , and increasing psychological insight 39 . However, there is still a lack of sound empirical data supporting integrative models of care delineating specific ‘set and setting’ factors to optimize outcomes. Further, the therapist’s role and the benefits of integrating psychological tools during treatment remains understudied 1 , 40 .

As psilocybin in the treatment of depression 41 and MDMA-assisted therapy for post-traumatic stress disorder (PTSD) 42 are investigated in phase II and III studies and with their supervised use approved in Oregon and Australia 43 , 44 there is a need for rigorous research to evaluate the impact and therapist effects and associated interventions. To that end, a review of the pre-prohibition period becomes crucial, as it originally inspired sophisticated reflections on the intricate relationship between biological and psychological factors in treating mental illness. Despite the limitations of that period, marked by poor controls, inconsistent diagnoses, unvalidated outcomes and lack of adverse effect reporting 3 , revisiting the two aforementioned fundamental factors can inform current and future research in this evolving field.

In this article, we examine selected pre-prohibition trials, explore clinician and patient narratives pertaining to the treatment process, and discuss their relevance to modern research. We gathered articles from the pre-prohibition era that showcase this period’s diverse perspectives and therapy methods. The chosen articles provide a clinically meaningful, representative sample of the essential aspects that defined psychedelic research and treatment during this period. Our aim is to trace the evolution of contemporary psychedelic treatment protocols, as observed in modern randomized clinical trials (RCTs). This includes an analysis of various components from the pre-prohibition era including clinician-reported psychedelic phenomenology, preparation, treatment sessions, and integration practices. The overarching objective is to contribute valuable insights to inform best practices and guide future research endeavors.

Pre-prohibition clinician-reported psychedelic phenomenology

During the midcentury era, the use of psychedelics in psychiatry typically followed one of two models: the psycholytic and the psychedelic. In the psycholytic approach, low to moderate doses (e.g., LSD 25–200 µg) of psychedelics were used as an adjunct to conventional psychotherapy, aiming to facilitate access to unconscious material and to enhance the traditional psychodynamic treatment process 6 . The underlying assumption of the psycholytic approach was that therapeutic progress relies more on the psychodynamic process occurring during and between the non-drug psychotherapy sessions than on the experience induced by the psychedelic medication. In contrast, the psychedelic approach aimed to instigate therapeutic gains by eliciting intense transcendental and affective states through the administration of high doses of psychedelics (e.g., LSD > 200 µg), over 1–3 treatment sessions. Within the psychedelic approach, there were two methods of treatment: psychedelic chemotherapy 32 and psychedelic-peak therapy 9 , 30 . In these approaches, therapeutic gains were directly attributed to the profound and cathartic impact of experiencing dramatic, unitive, and visionary states, with less emphasis on the core tenets of relationally driven forms of person-centered counseling or psychoanalytic psychotherapy.

The difference in the dose quantity between these two psychedelic models mirrors their distinct approaches to facilitating positive psychological shifts. In the psycholytic model, mental changes were anticipated to unfold more subtly yet with the potential for meaningful impact, as the biochemical psychedelic effects aid insight-oriented psychoanalysis. Whereas the psychedelic approach relied on intense and immersive psychedelic states that elicit profound and disruptive mystical-type experiences, often accompanied by emotional breakthroughs, shifts in belief systems and self-narratives, serving as the primary catalysts for change. We now describe the manifestation of the states of consciousness in each model using a range of selected researcher narratives from pre-prohibition trials.

Clinician-reported phenomenology in psycholytic therapy

Pre-prohibition researchers aligned with the psycholytic model 9 , 24 , 45 , 46 extensively detailed the physiological and psychological effects of LSD. The description underscored LSD’s characteristic outcomes, including heightened distortion of perception and enhanced emotion, as well as the elicitation of introspection and the unveiling of the individual’s unconscious during the drug treatment session. While toxicity from small-moderate doses of LSD were rare, reported adverse effects included nausea, dizziness, sensations of heat/cold, and sweating. Despite the drug’s intended goal of aiding psychological treatment, specific psychological effects, often linked to the patient’s characteristics, at times proved counterproductive for psychoanalytic psychotherapy. For example, in psycholytic sessions, the influence of LSD could exacerbate pre-existing neurotic symptoms, heightening anxiety and causing bodily trembling 46 . During these instances, some patients craved human contact, while some withdrew and became increasingly unreachable, potentially undermining the therapeutic process 24 . Although ego functions largely persisted, allowing for the internal registration of the psychedelic experience, patients oscillated between mentally exploring immersive inner realms and experiencing moments of uncontrollable psychic overwhelm as ego barriers dissolved 46 . However, often enough, three main phenomena occurred during the most potent moments of the drug action, shaping the therapeutic session and potentially contributing to improving disease symptoms:

Non-specific hallucinations: Psychedelics induce sensory experiences, such as visions of animals, people, and shapes, even in the absence of external stimuli. Patients may withdraw into timeless worlds with ancient atmospheres, alternating between immersive hallucinatory periods where time ceases and reality breaks down, occasionally accompanied by moments of realization that their mind had constructed an unreal realm 11 , 24 . Some patients reported assigning roles to those present in the treatment room based on the emerging inner drama, which were classified into two major types: Identification and Projection 24 . Identifying with the emergent phenomenon appeared to help bring resolution to internal conflicts. During the Projection processes, people and places in the immediate surroundings could represent the patient’s unsolved developmental and oedipal conflicts.

Reliving repressed memories: Repressed memories spanning the patient’s lifespan could surface, but some believed that LSD enabled the vivid recall of childhood traumatic memories, allowing the patient to re-experience their body and affective state at the time of traumatization 25 . Therefore, psycholytic treatment sessions could elicit potent recollections of childhood trauma, providing full sensory immersion into the traumatized self-identity.

Impersonal archetypal unconscious imagery: Profound emotions can accompany vivid unconscious imagery and symbols emerging during psychedelic states. These included typical primal patterns and universal themes (e.g., ancient landscapes, religious iconography, visions of the natural world and the cosmos) that resonated across cultures 11 , 22 .

Based on this phenomenology, psycholytic researchers considered psychedelics’ primary function as an adjunct to on-going psychotherapy, asserting, “the reaction which was desired was to make the patient more accessible but was not of such intensity as to create hallucinations” 47 . In turn, psycholytic treatment aimed to increase patient openness to therapist interpretations, mobilize the patient’s ego functions and strengths, enable rapid insight, and facilitate confrontation with repressed traumatic events through concurrent psychoanalytical psychotherapy 11 , 48 . As the primary mechanism of change in the psycholytic model focused on facilitating the transference, intense, psychedelic-induced subjective experiences, such as ego dissolution, disembodiment, and a sense of unity with nature and humanity 49 , at times, defied the more traditional psychoanalytic, neutral and interpretative clinical stance.

Clinician-reported phenomenology in psychedelic ‘peak’ therapy

In modern-day research, extensive literature has documented alterations in consciousness during intense psychedelic treatment sessions 50 , 51 . Lacking sophisticated neurobiological research tools and methods, pre-prohibition researchers relied on patient reports and clinical observations to understand the medical psychedelic experience 21 . For example, Alnæs 30 reported observations of 20 patients and 20 volunteers who were administered high doses (<250 mcg LSD) during treatment. Focusing on the profound psychedelic effects, Alnaes reported three phases:

The initial phase involved various physical experiences leading to so-called ego death and dissolution - sensations of cold clamminess, bodily pressure, trembling, nausea, and vibrations were reported. At the precipice of ego death, subjects reported perceiving a clear light, aligning with descriptions in Tibetan literature of the process of dying 29 . The second phase included immersive visions and mythic content. These included feelings of mind/body separation, visions filled with light, and encounters with mythic heroes/demons. Further, symbolic birth themes were reported in psychedelic sessions, featuring canyon-like passages 52 , 53 . The third phase included re-orientation and integration of insights. At this stage, guided self-insight, in which patients were supported to reach their own conclusions about their experience, appeared invaluable 48 . During this phase, suggestibility and memory increased, and repressed material arose. More specifically, patients were more receptive to novel ideas, environmental cues, and divergent thinking, with their entrenched worldviews becoming more malleable to change 9 , 11 , 30 , 32 .

To conclude, during the pre-prohibition era, methodological questions concerning the nature, timing, and focus of clinical interventions aimed at leveraging the potential therapeutic effects associated with psychedelic peak experiences were raised. In contemporary research, largely concerned with establishing an evidence base for the safety and efficacy of psychedelics, these questions have yet to be the focus of rigorous empirical studies. Noting that some patients suffered adverse events and struggled to leverage revelatory shifts without ongoing care, pre-prohibition clinicians explored, and modern-day researchers are asking, what, if any, type of psychological interventions are optimal during and following psychedelic treatments that may dissolve ego structures and abruptly overhaul rigidly held worldviews.

In the next section, we will discuss the paradigm of psychedelic treatment: preparation -> treatment session -> integration as it was created at the time and the therapist’s role in each phase.

Therapist’s role: preparation, psychedelic treatment, and integration sessions

In the 1950s and 1960s, researchers recognized the complex interactivity between psychedelics’ pharmacological properties, patients’ intrapsychic dispositions, and the treatment’s non-pharmacological factors 3 . By 1965 three broad treatment methods based on dosage and therapy techniques existed:

“Psycholytic” protocols that involved multiple low to moderate doses (25–200 μg) and psychodynamic psychotherapy interventions to promote gradual personality changes.

“Psychedelic chemotherapy” sessions that involved a single high dose of LSD (200+ μg) in medical settings with limited psychological interventions, prioritizing the patient’s physical safety and relying on the acute effects of the drug.

“Psychedelic Peak Therapy” which consolidated intentional patient preparation, empathetic support during heightened suggestible ego-dissolved states, and integration processes after the psychedelic treatment session to promote enduring psychological and spiritual transformations regarding self-concept, relationships, and meaning.

In this section, we will explore how psychedelic chemotherapy evolved into psychedelic-peak therapy, using the three-part method of psychedelic treatment: preparation, treatment session, and integration. Additionally, we will explore how psycholytic therapy integrated itself into this treatment method.

Preparation

The current framework for the administration of psychedelics in research settings was developed to address the challenges that were identified during early research. The challenges were exemplified in Smith’s 32 , 54 report on using LSD or mescaline in psychedelic chemotherapy for patients with alcohol use disorder (AUD).

In Smith’s protocol, patients were initially admitted to a 1-week evaluation and professional rapport-building in a psychiatric ward. Smith stressed retroactively the importance of introducing encouragement, enticement, and directive guidance prior to drug administration to prime patients to benefit from the drug treatment. Distinguishing the psychedelic approach from psycholytic models, Smith also asserted that there less need to provide insights (or psychoanalytic interpretations) to patients as many seemed to have gained a better understanding of themselves due to the psychedelic experience. Further, if patients perceived their therapists as distant or disinterested, they tended to be more anxious or paranoid, therefore having difficulties immersing in the experience. Similarly, Smart et al 55 . who treated 30 AUD patients with a long history of uncontrolled drinking, noted “the role of the therapists’ conviction and personal commitment to a treatment approach has rarely been investigated as a factor in success but it might well be important”. Acknowledging the therapists’ role in supporting treatment success via establishing trust and safety, Smart also provided patients with information concerning the drug effects during the preparation phase.

Drawing from insights gained from the psychedelic chemotherapy modality, the psychedelic-peak approach developed a clinically meaningful understanding of the non-pharmacological factors influencing patient outcomes. Researchers adjusted the treatment environment, staff training, and instituted guidelines regarding interpersonal interactions with patients 21 , 30 . Over time, researchers discerned that effective preparation played a pivotal role in guiding patients through inner explorations by employing diverse approaches such as aesthetic appreciation, the area of philosophy that studies the nature of beauty and art 30 , 56 . Alnaes conducted preparation sessions based on principles ‘The Tibetan Book of the Dead’ 29 . In this approach, the same preparation used by the Tibetans before death served as an informative introduction in preparation for psychedelic experiences. Further, Abramson detailed additional preparation activities, such as establishing trust between the patient and therapist, conducting group preparation sessions, and employing techniques such as picture imagination, in which therapists helped patients focus on mental images in order to evoke feelings of relaxation 57 . Further, autogenic training, a therapeutic technique designed to help patients achieve a calm state by focusing on specific sensations and imagery or occasionally hypnosis with posthypnotic suggestions, was employed.

Accordingly, the primary goal of the preparation phase was to support patients to accept the drug’s effects without fear, emphasizing a readiness to experience the expected and unexpected somatic and psychic effects. Importantly, in cases lacking adequate preparation, researchers observed that most patients struggled counterproductively, experiencing increasing dysregulation, avoidance, and despair during the psychedelic treatment session 7 , 9 , 30 . Conversely, patients who were more amenable to temporarily relinquish their familiar ego functions and accept the experience appeared more likely to achieve positive outcomes 9 , 24 , 32 .

Psychedelic treatment session

Due to the high dosage and its often dramatic effects, psychodynamic interventions were not feasible or advisable during drug administration 30 . However, it soon became evident that patients required specific forms of support during the acute drug effects. Staff members with LSD experiences or those frequently observing LSD sessions were thought to be better suited to support patients during psychedelic treatment 32 . Researchers also observed that personnel maintaining neutrality during the acute phase of the drug effects were more likely to provoke fear and hostility in patients 55 . Correspondingly, Parley described how nurses carefully prepared patients for their LSD treatment, providing reassurance and guidance throughout the treatment session, and helping patients process their emotions and insights afterwards 58 . She emphasized the importance of the nurse-patient relationship and the need for empathy, intuition, and creativity in this unique therapeutic context. Far from being mere observers, these nurses acted as companions, guides, and anchors for patients receiving psychedelic treatment, providing reassurance, support, and understanding throughout the drug administration session. Further, by 1958, psychedelic treatment clinics began emphasizing the importance of “set and setting” in achieving desired outcomes 9 , 24 , 30 , 59 . Auditory stimuli, such as relaxing classical and semi-classical music, enhanced perception and diverted attention from self-focused fears induced by the experience 21 . Visual stimuli, like artwork or personal photographs prompted emotional reflection on unhealthy attitudes and relational dynamics, contributing to post-session reflection 46 . Lastly, it became apparent that the patient-reported phenomenology often entailed encounters with psychospiritual states that diverged from traditional psychiatric and psychoanalytic frameworks.

Correspondingly, to accommodate the distinct phenomenology of the psychedelic state, researchers administering psychedelic-peak treatment sought additional frameworks that expanded on traditional psychoanalytic practices 18 . For instance, Chwelos et al. 21 encouraged patients to accept themselves without rationalizations, meaning-making, or guilt over emerging material during peak emotional periods. Similarly, Chandler asserted, “It is best to let the fantasy unfold its meaning by encouraging the patient to go along with it and see it through to the end.” 11 This approach emphasized the utility of patients’ courage, willingness to surrender to the drug effects, self-acceptance, and responsibility for change 59 . Following psychedelic treatment sessions, many patients engaged in spiritual or religious discussions exploring the spiritual implications of their experiences 22 , 30 , 60 .

These discussions highlighted the contrast between biological and psychoanalytic conceptualizations of pathology and mystical-type experiences, there by redirecting the clinical focus to interventions concerned with leveraging transpersonal states for therapeutic gains 21 . Correspondingly, discussing treatment responders, Pahnke stated, “If the psychedelic peak experience is achieved and stabilized, the clinical picture can be described as follows: Mood is elevated and energetic; there is a relative freedom from concerns of the past, from guilt and anxiety, and the disposition and capacity to enter close interpersonal relationships is enhanced” 61 . However, the acute and potentially highly distressing treatment effects were noted across studies. Coupled with experimental and unsubstantiated interventions delivered to treatment-resistant and complex patient populations, including schizophrenia, adverse events were under reported, however, certainly present and many patients did not improve 62 , 63 .

Integration

Once the psychedelic effects subsided, patients undergoing psychedelic chemotherapy were transferred to regular hospital beds where they spent the night 32 , 55 . If necessary, patients were given anxiolytics and released to the clinic the next day 55 or referred to primary care, including alcoholics anonymous groups 9 . During regular individual or group meetings, patients were free to discuss any insights associated with their treatment sessions, however, therapists did not direct patients to examine their experiences unless they initiated it themselves 9 , 30 . As for the patients undergoing psychedelic peak therapy, the impact of psychedelic experiences was thought to extend beyond the treatment sessions, compelling the integration of events spanning from the psychedelic treatment session to the present reality 64 . As Maclean noted, patients “may become aware of those archetypal or universal meanings which underlie all human feeling and thinking 60 . The symbols provide intermediate points of reference creating a bridge between the habitual self-concept and a new concept based on self-understanding and self-acceptance.” Correspondingly, to promote psychological safety and effectiveness, in the days and weeks after psychedelic treatment sessions, clinicians recognized that patients required structured procedures. These included interviews with clinicians, peer-to-peer discussions, artistic expression, and guiding patients to write accounts of their experiences 30 , 31 , 46 , 60 .

This narrative review highlights the wealth of insights garnered from the utilization of psychedelics in the treatment of mental disorders during the pre-prohibition era. While acknowledging that pre-prohibition research methodologies do not align with contemporary randomized control trial (RCTs) standards, the valuable clinical observations made by researchers in that era, benefiting from freedom and flexibility in drug access and administration, informed modern clinical trials and could inform future investigations and care models. For example, modern researchers may draw inspiration from the pre-prohibition era to help optimize the treatments’ non-pharmacological factors. This may include experimenting with different treatment approaches (e.g., individual vs. group-based treatment protocols) and the investigation of more flexible psychotherapeutic techniques before and after the psychedelic treatment session. Further, pre-prohibition researchers produced rich case reports describing their observations of patients undergoing psychedelic treatment. Despite changes to theoretical conceptualizations of mental ill health and advances in evidence-based clinical technique, modern researchers and clinicians may gain insight into the potential complexities of the treatment process by reviewing these reports. In turn, this may promote better safety outcomes and contribute to the design of best practice and ethical guidelines. Further, by combining the insights from pre-prohibition studies with the methodological rigor of modern RCTs, researchers can develop a comprehensive, evidence-based approach to psychedelic forms of therapy. This synthesis may lead to innovative treatment models that are tailored to individual needs while maintaining scientific integrity.

The profound effects reported by pre-prohibition patients undergoing psychedelic treatment coupled with heightened patient suggestibility and regression potential 65 , compelled clinicians to organically devise specialized protocols for administrating psychedelics. Regardless of the chosen treatment model (e.g., psycholytic or psychedelic), practitioners converged on common core principles for treatment 66 . Clinicians understood that adequate preparation encompassing psychoeducation, establishing patient-therapist rapport and clearly defining the role of therapists was crucial. Providing a comfortable physical setting and an accepting and encouraging interpersonal atmosphere were essential. Further, clinicians came to appreciate patients’ need to intentionally reflect on their experience and develop a clinically meaningful narrative of their subjective experience. Similarly, the standard modern psychedelic RCT model of preparation – > treatment -> integration was established. Further, in the psychedelic model, clinicians moved from a largely interpretive clinical position to a more explicitly supportive stance; implicitly suggesting that the patient’s internal resources, rather than therapist’s theoretical perspectives, are the primary driver of positive change. In the psycholytic approach, psychoanalytically oriented clinicians, primarily focused on psychodynamic explorations of the patients’ unconscious via the transference/countertransference phenomena, expanded their clinical repertoire to accommodate patient reports of psychospiritual states associated with the treatment 18 , 67 .

Modern psychedelic RCTs are designed to support regulatory approval of the compound and, therefore, are focused on generating replicable and generalizable safety and efficacy data. Further, in a medication RCT, all non-drug factors must be standardized and held fixed to isolate the drug effects. Correspondingly, to reduce treatment variables, standardized models of psychological support 68 , 69 or psychotherapy 70 , 71 , 72 have been implemented across trials. This necessary approach is appropriate for the developmental stage of psychedelic treatments in mental health, which is reaching the milestone of acceptance and adoption within medicine. Alongside this process, literature is emerging regarding the type of psychological interventions that might be safe and effective in psychedelic treatment 73 , 74 , 75 . Further, integrative psychotherapeutic approaches, incorporating interpretations of findings from empirical research, have also been suggested 76 . Yet sound empirical data that will inform the utility of these approaches is currently limited. To that end, a mature and evidence-based form of psychotherapy utilizing psychedelics, which would require specific research, could turn to pre-prohibition trials for guidance and inspiration.

Reviewing the plethora of convergent and divergent perspectives of pre-prohibition clinicians, who were not limited by the legality of psychedelics in clinical practice, suggests that if certain psychedelics were to receive regulatory approval, a new era of rigorous research, focused on adjunct psychological interventions, therapist effects and modulation of the treatment’s non-pharmacological factors will be feasible, warranted and needed to promote positive and durable patient outcomes. Pre-prohibition perspectives could help design studies investigating the relevance, selection, and significance of psychological interventions in psychedelic treatment. Additionally, the clinical richness of pre-prohibition perspectives could inform studies assessing the impact of therapist effects, guiding the development of evidence-based training and supervision protocols to optimize clinical outcomes.

Further, pre-prohibition treatment was administered in both inpatient and outpatient settings, in individual or group-based treatment protocols and consisting of single to multiple psychedelic treatment sessions. Clinician and patient testimonials, and pre-prohibition treatment protocols may serve as valuable guidance for designing future studies, delineating the roles of various staff members, defining the treatment environment and procedures, and determining treatment frequency. For example, studies generating data pertaining to the effects of different compounds, under specific clinical conditions, in various patient populations, utilizing more sophisticated psychological assessments, could inform whether and how psychological interventions should be tailored to enhance patient outcomes.

Correspondingly, contemporary research utilizes psychometric measures, such as the Altered States of Consciousness Questionnaire 77 , to assess peak states. While this detailed exploration provides valuable insights, using additional research methodologies could increase the ability to discover novel perspectives associated with psychedelic treatment. The rich descriptions of the pre-prohibition era allowed clinicians to observe more closely patients’ subjective experiences, informing potential interventions. In modern trials, investigating patients’ experiences through qualitative research methodologies and natural language processing may offer a more nuanced understanding of peak states and optimize research and treatment protocols. Importantly, novel measures that are based on clinical observations assessing patients’ readiness for psychedelic treatment 78 and follow-up assessments capturing biopsychosocial changes and integration processes 79 may optimize screening, preparation, and post-treatment care where indicated.

Further, during the pre-prohibition era, the effects of psychedelics were primarily characterized in terms of psychological changes, especially with respect to the dramatic alterations in consciousness. Today, with advancements in neuroimaging and molecular biology, we have modern tools that can aid in understanding the neurobiological alterations in the nervous system underlying the observed psychological phenomena 80 , 81 . Correspondingly, this may support the development of a more comprehensive, biopsychosocial understanding of mental ill health and approach to psychedelic treatment, enabling the identification of biomarkers informing patient suitability for treatment and predictors of response to inform precision treatment planning.

In summary, clinician and patient-reported qualitative narratives of psychological processes of change were predominant in pre-prohibition research, playing a crucial role in the evolution of psychedelic research and treatment. However, in the modern era, the emphasis has shifted, and evidence-based research now heavily relies on psychometric measures and symptom assessments. Whether investigating psychedelics as a standalone treatment with psychological support 82 or considering their application as an adjunct to psychotherapy 75 , 83 , it is essential to recognize that the nuanced understanding and rich clinical narratives derived from pre-prohibition data can significantly contribute to the design and implementation of future investigations. This, in turn, holds the potential to advance contemporary psychedelic treatment and care paradigms.

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Ronit Kishon & Yael M. Cycowicz

New York State Psychiatric Institute, New York, NY, USA

Ronit Kishon, Yael M. Cycowicz, Hania Mourtada & Tayler Wilson

The Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Nadav Liam Modlin, Victoria Williamson, Anthony Cleare & James Rucker

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Nadav Liam Modlin, Anthony Cleare & James Rucker

Department of Clinical Psychology, Teachers College, Columbia University, New York, NY, USA

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Contributions

R.K. and N.L.M.: idea, method, data selection and extraction, quality appraisal, analysis, writing, drafting, and revising of the review paper and contributed substantially to the discussion. Both authors contributed equally. Y.M.C.: quality appraisal validated the work done by R.K. and N.L.M. in study selection, writing, drafting, and revising of the review paper and contributed substantially to the discussion. H.M. and T.W.: helped with data extraction, validated the work done by R.K. and N.L.M. in study selection, reviewed and edited the manuscript, and contributed to the manuscript. V.W. A.C. and J.R.: supervised the work progress, reviewed, and edited the manuscript, proofread the manuscript, and contributed substantially to the discussion.

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Correspondence to Nadav Liam Modlin .

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Competing interests.

No shareholdings in pharmaceutical companies. No shareholdings in companies developing psychedelics. J.R. and N.L.M. provide services for the psychoactive trials group at King’s College London. The psychoactive trials group at King’s College London receives grant funding (received and managed by King’s College London) from Compass Pathways, Supporting Wounded Veterans, Multidisciplinary Association for Psychedelic Studies, Beckley PsyTech and National Institute for Health Research. J.R. is supported by the U.K. National Institute for Health Research (NIHR) via Clinician Scientist Fellowship Awards to J.R. (CS-2017-17-007) and by the NIHR Biomedical Research Centre at South London, Maudsley National Health Service Foundation Trust, and King’s College London. J.R. has attended trial-related meetings paid for by Compass Pathways, Ltd. He has consulted for Beckley PsyTech and Clerkenwell Health; and he is employed by Sapphire Medical Clinics, a private medical clinic. A.C. has received honoraria for presentations and/or serving on advisory boards from the following pharmaceutical companies: Janssen, Lundbeck, Allergan, and Livanova. N.L.M. has received consulting fees (PAST) from Compass Pathways PLC, Small Pharma Ltd and Beckley Psytech Ltd. R.K. provides services for the clinical trials at the Depression Evaluation Service (DES), New York State Psychiatric Institute, Columbia University. The DES receives grant funding from Compass Pathways and Beckley PsyTech.

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Kishon, R., Modlin, N.L., Cycowicz, Y.M. et al. A rapid narrative review of the clinical evolution of psychedelic treatment in clinical trials. npj Mental Health Res 3 , 33 (2024). https://doi.org/10.1038/s44184-024-00068-9

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DOI : https://doi.org/10.1038/s44184-024-00068-9

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Human Subjects Office

Medical terms in lay language.

Please use these descriptions in place of medical jargon in consent documents, recruitment materials and other study documents. Note: These terms are not the only acceptable plain language alternatives for these vocabulary words.

This glossary of terms is derived from a list copyrighted by the University of Kentucky, Office of Research Integrity (1990).

For clinical research-specific definitions, see also the Clinical Research Glossary developed by the Multi-Regional Clinical Trials (MRCT) Center of Brigham and Women’s Hospital and Harvard  and the Clinical Data Interchange Standards Consortium (CDISC) .

Alternative Lay Language for Medical Terms for use in Informed Consent Documents

A   B   C   D   E   F   G   H   I  J  K   L   M   N   O   P   Q   R   S   T   U   V   W  X  Y  Z

ABDOMEN/ABDOMINAL body cavity below diaphragm that contains stomach, intestines, liver and other organs ABSORB take up fluids, take in ACIDOSIS condition when blood contains more acid than normal ACUITY clearness, keenness, esp. of vision and airways ACUTE new, recent, sudden, urgent ADENOPATHY swollen lymph nodes (glands) ADJUVANT helpful, assisting, aiding, supportive ADJUVANT TREATMENT added treatment (usually to a standard treatment) ANTIBIOTIC drug that kills bacteria and other germs ANTIMICROBIAL drug that kills bacteria and other germs ANTIRETROVIRAL drug that works against the growth of certain viruses ADVERSE EFFECT side effect, bad reaction, unwanted response ALLERGIC REACTION rash, hives, swelling, trouble breathing AMBULATE/AMBULATION/AMBULATORY walk, able to walk ANAPHYLAXIS serious, potentially life-threatening allergic reaction ANEMIA decreased red blood cells; low red cell blood count ANESTHETIC a drug or agent used to decrease the feeling of pain, or eliminate the feeling of pain by putting you to sleep ANGINA pain resulting from not enough blood flowing to the heart ANGINA PECTORIS pain resulting from not enough blood flowing to the heart ANOREXIA disorder in which person will not eat; lack of appetite ANTECUBITAL related to the inner side of the forearm ANTIBODY protein made in the body in response to foreign substance ANTICONVULSANT drug used to prevent seizures ANTILIPEMIC a drug that lowers fat levels in the blood ANTITUSSIVE a drug used to relieve coughing ARRHYTHMIA abnormal heartbeat; any change from the normal heartbeat ASPIRATION fluid entering the lungs, such as after vomiting ASSAY lab test ASSESS to learn about, measure, evaluate, look at ASTHMA lung disease associated with tightening of air passages, making breathing difficult ASYMPTOMATIC without symptoms AXILLA armpit

BENIGN not malignant, without serious consequences BID twice a day BINDING/BOUND carried by, to make stick together, transported BIOAVAILABILITY the extent to which a drug or other substance becomes available to the body BLOOD PROFILE series of blood tests BOLUS a large amount given all at once BONE MASS the amount of calcium and other minerals in a given amount of bone BRADYARRHYTHMIAS slow, irregular heartbeats BRADYCARDIA slow heartbeat BRONCHOSPASM breathing distress caused by narrowing of the airways

CARCINOGENIC cancer-causing CARCINOMA type of cancer CARDIAC related to the heart CARDIOVERSION return to normal heartbeat by electric shock CATHETER a tube for withdrawing or giving fluids CATHETER a tube placed near the spinal cord and used for anesthesia (indwelling epidural) during surgery CENTRAL NERVOUS SYSTEM (CNS) brain and spinal cord CEREBRAL TRAUMA damage to the brain CESSATION stopping CHD coronary heart disease CHEMOTHERAPY treatment of disease, usually cancer, by chemical agents CHRONIC continuing for a long time, ongoing CLINICAL pertaining to medical care CLINICAL TRIAL an experiment involving human subjects COMA unconscious state COMPLETE RESPONSE total disappearance of disease CONGENITAL present before birth CONJUNCTIVITIS redness and irritation of the thin membrane that covers the eye CONSOLIDATION PHASE treatment phase intended to make a remission permanent (follows induction phase) CONTROLLED TRIAL research study in which the experimental treatment or procedure is compared to a standard (control) treatment or procedure COOPERATIVE GROUP association of multiple institutions to perform clinical trials CORONARY related to the blood vessels that supply the heart, or to the heart itself CT SCAN (CAT) computerized series of x-rays (computerized tomography) CULTURE test for infection, or for organisms that could cause infection CUMULATIVE added together from the beginning CUTANEOUS relating to the skin CVA stroke (cerebrovascular accident)

DERMATOLOGIC pertaining to the skin DIASTOLIC lower number in a blood pressure reading DISTAL toward the end, away from the center of the body DIURETIC "water pill" or drug that causes increase in urination DOPPLER device using sound waves to diagnose or test DOUBLE BLIND study in which neither investigators nor subjects know what drug or treatment the subject is receiving DYSFUNCTION state of improper function DYSPLASIA abnormal cells

ECHOCARDIOGRAM sound wave test of the heart EDEMA excess fluid collecting in tissue EEG electric brain wave tracing (electroencephalogram) EFFICACY effectiveness ELECTROCARDIOGRAM electrical tracing of the heartbeat (ECG or EKG) ELECTROLYTE IMBALANCE an imbalance of minerals in the blood EMESIS vomiting EMPIRIC based on experience ENDOSCOPIC EXAMINATION viewing an  internal part of the body with a lighted tube  ENTERAL by way of the intestines EPIDURAL outside the spinal cord ERADICATE get rid of (such as disease) Page 2 of 7 EVALUATED, ASSESSED examined for a medical condition EXPEDITED REVIEW rapid review of a protocol by the IRB Chair without full committee approval, permitted with certain low-risk research studies EXTERNAL outside the body EXTRAVASATE to leak outside of a planned area, such as out of a blood vessel

FDA U.S. Food and Drug Administration, the branch of federal government that approves new drugs FIBROUS having many fibers, such as scar tissue FIBRILLATION irregular beat of the heart or other muscle

GENERAL ANESTHESIA pain prevention by giving drugs to cause loss of consciousness, as during surgery GESTATIONAL pertaining to pregnancy

HEMATOCRIT amount of red blood cells in the blood HEMATOMA a bruise, a black and blue mark HEMODYNAMIC MEASURING blood flow HEMOLYSIS breakdown in red blood cells HEPARIN LOCK needle placed in the arm with blood thinner to keep the blood from clotting HEPATOMA cancer or tumor of the liver HERITABLE DISEASE can be transmitted to one’s offspring, resulting in damage to future children HISTOPATHOLOGIC pertaining to the disease status of body tissues or cells HOLTER MONITOR a portable machine for recording heart beats HYPERCALCEMIA high blood calcium level HYPERKALEMIA high blood potassium level HYPERNATREMIA high blood sodium level HYPERTENSION high blood pressure HYPOCALCEMIA low blood calcium level HYPOKALEMIA low blood potassium level HYPONATREMIA low blood sodium level HYPOTENSION low blood pressure HYPOXEMIA a decrease of oxygen in the blood HYPOXIA a decrease of oxygen reaching body tissues HYSTERECTOMY surgical removal of the uterus, ovaries (female sex glands), or both uterus and ovaries

IATROGENIC caused by a physician or by treatment IDE investigational device exemption, the license to test an unapproved new medical device IDIOPATHIC of unknown cause IMMUNITY defense against, protection from IMMUNOGLOBIN a protein that makes antibodies IMMUNOSUPPRESSIVE drug which works against the body's immune (protective) response, often used in transplantation and diseases caused by immune system malfunction IMMUNOTHERAPY giving of drugs to help the body's immune (protective) system; usually used to destroy cancer cells IMPAIRED FUNCTION abnormal function IMPLANTED placed in the body IND investigational new drug, the license to test an unapproved new drug INDUCTION PHASE beginning phase or stage of a treatment INDURATION hardening INDWELLING remaining in a given location, such as a catheter INFARCT death of tissue due to lack of blood supply INFECTIOUS DISEASE transmitted from one person to the next INFLAMMATION swelling that is generally painful, red, and warm INFUSION slow injection of a substance into the body, usually into the blood by means of a catheter INGESTION eating; taking by mouth INTERFERON drug which acts against viruses; antiviral agent INTERMITTENT occurring (regularly or irregularly) between two time points; repeatedly stopping, then starting again INTERNAL within the body INTERIOR inside of the body INTRAMUSCULAR into the muscle; within the muscle INTRAPERITONEAL into the abdominal cavity INTRATHECAL into the spinal fluid INTRAVENOUS (IV) through the vein INTRAVESICAL in the bladder INTUBATE the placement of a tube into the airway INVASIVE PROCEDURE puncturing, opening, or cutting the skin INVESTIGATIONAL NEW DRUG (IND) a new drug that has not been approved by the FDA INVESTIGATIONAL METHOD a treatment method which has not been proven to be beneficial or has not been accepted as standard care ISCHEMIA decreased oxygen in a tissue (usually because of decreased blood flow)

LAPAROTOMY surgical procedure in which an incision is made in the abdominal wall to enable a doctor to look at the organs inside LESION wound or injury; a diseased patch of skin LETHARGY sleepiness, tiredness LEUKOPENIA low white blood cell count LIPID fat LIPID CONTENT fat content in the blood LIPID PROFILE (PANEL) fat and cholesterol levels in the blood LOCAL ANESTHESIA creation of insensitivity to pain in a small, local area of the body, usually by injection of numbing drugs LOCALIZED restricted to one area, limited to one area LUMEN the cavity of an organ or tube (e.g., blood vessel) LYMPHANGIOGRAPHY an x-ray of the lymph nodes or tissues after injecting dye into lymph vessels (e.g., in feet) LYMPHOCYTE a type of white blood cell important in immunity (protection) against infection LYMPHOMA a cancer of the lymph nodes (or tissues)

MALAISE a vague feeling of bodily discomfort, feeling badly MALFUNCTION condition in which something is not functioning properly MALIGNANCY cancer or other progressively enlarging and spreading tumor, usually fatal if not successfully treated MEDULLABLASTOMA a type of brain tumor MEGALOBLASTOSIS change in red blood cells METABOLIZE process of breaking down substances in the cells to obtain energy METASTASIS spread of cancer cells from one part of the body to another METRONIDAZOLE drug used to treat infections caused by parasites (invading organisms that take up living in the body) or other causes of anaerobic infection (not requiring oxygen to survive) MI myocardial infarction, heart attack MINIMAL slight MINIMIZE reduce as much as possible Page 4 of 7 MONITOR check on; keep track of; watch carefully MOBILITY ease of movement MORBIDITY undesired result or complication MORTALITY death MOTILITY the ability to move MRI magnetic resonance imaging, diagnostic pictures of the inside of the body, created using magnetic rather than x-ray energy MUCOSA, MUCOUS MEMBRANE moist lining of digestive, respiratory, reproductive, and urinary tracts MYALGIA muscle aches MYOCARDIAL pertaining to the heart muscle MYOCARDIAL INFARCTION heart attack

NASOGASTRIC TUBE placed in the nose, reaching to the stomach NCI the National Cancer Institute NECROSIS death of tissue NEOPLASIA/NEOPLASM tumor, may be benign or malignant NEUROBLASTOMA a cancer of nerve tissue NEUROLOGICAL pertaining to the nervous system NEUTROPENIA decrease in the main part of the white blood cells NIH the National Institutes of Health NONINVASIVE not breaking, cutting, or entering the skin NOSOCOMIAL acquired in the hospital

OCCLUSION closing; blockage; obstruction ONCOLOGY the study of tumors or cancer OPHTHALMIC pertaining to the eye OPTIMAL best, most favorable or desirable ORAL ADMINISTRATION by mouth ORTHOPEDIC pertaining to the bones OSTEOPETROSIS rare bone disorder characterized by dense bone OSTEOPOROSIS softening of the bones OVARIES female sex glands

PARENTERAL given by injection PATENCY condition of being open PATHOGENESIS development of a disease or unhealthy condition PERCUTANEOUS through the skin PERIPHERAL not central PER OS (PO) by mouth PHARMACOKINETICS the study of the way the body absorbs, distributes, and gets rid of a drug PHASE I first phase of study of a new drug in humans to determine action, safety, and proper dosing PHASE II second phase of study of a new drug in humans, intended to gather information about safety and effectiveness of the drug for certain uses PHASE III large-scale studies to confirm and expand information on safety and effectiveness of new drug for certain uses, and to study common side effects PHASE IV studies done after the drug is approved by the FDA, especially to compare it to standard care or to try it for new uses PHLEBITIS irritation or inflammation of the vein PLACEBO an inactive substance; a pill/liquid that contains no medicine PLACEBO EFFECT improvement seen with giving subjects a placebo, though it contains no active drug/treatment PLATELETS small particles in the blood that help with clotting POTENTIAL possible POTENTIATE increase or multiply the effect of a drug or toxin (poison) by giving another drug or toxin at the same time (sometimes an unintentional result) POTENTIATOR an agent that helps another agent work better PRENATAL before birth PROPHYLAXIS a drug given to prevent disease or infection PER OS (PO) by mouth PRN as needed PROGNOSIS outlook, probable outcomes PRONE lying on the stomach PROSPECTIVE STUDY following patients forward in time PROSTHESIS artificial part, most often limbs, such as arms or legs PROTOCOL plan of study PROXIMAL closer to the center of the body, away from the end PULMONARY pertaining to the lungs

QD every day; daily QID four times a day

RADIATION THERAPY x-ray or cobalt treatment RANDOM by chance (like the flip of a coin) RANDOMIZATION chance selection RBC red blood cell RECOMBINANT formation of new combinations of genes RECONSTITUTION putting back together the original parts or elements RECUR happen again REFRACTORY not responding to treatment REGENERATION re-growth of a structure or of lost tissue REGIMEN pattern of giving treatment RELAPSE the return of a disease REMISSION disappearance of evidence of cancer or other disease RENAL pertaining to the kidneys REPLICABLE possible to duplicate RESECT remove or cut out surgically RETROSPECTIVE STUDY looking back over past experience

SARCOMA a type of cancer SEDATIVE a drug to calm or make less anxious SEMINOMA a type of testicular cancer (found in the male sex glands) SEQUENTIALLY in a row, in order SOMNOLENCE sleepiness SPIROMETER an instrument to measure the amount of air taken into and exhaled from the lungs STAGING an evaluation of the extent of the disease STANDARD OF CARE a treatment plan that the majority of the medical community would accept as appropriate STENOSIS narrowing of a duct, tube, or one of the blood vessels in the heart STOMATITIS mouth sores, inflammation of the mouth STRATIFY arrange in groups for analysis of results (e.g., stratify by age, sex, etc.) STUPOR stunned state in which it is difficult to get a response or the attention of the subject SUBCLAVIAN under the collarbone SUBCUTANEOUS under the skin SUPINE lying on the back SUPPORTIVE CARE general medical care aimed at symptoms, not intended to improve or cure underlying disease SYMPTOMATIC having symptoms SYNDROME a condition characterized by a set of symptoms SYSTOLIC top number in blood pressure; pressure during active contraction of the heart

TERATOGENIC capable of causing malformations in a fetus (developing baby still inside the mother’s body) TESTES/TESTICLES male sex glands THROMBOSIS clotting THROMBUS blood clot TID three times a day TITRATION a method for deciding on the strength of a drug or solution; gradually increasing the dose T-LYMPHOCYTES type of white blood cells TOPICAL on the surface TOPICAL ANESTHETIC applied to a certain area of the skin and reducing pain only in the area to which applied TOXICITY side effects or undesirable effects of a drug or treatment TRANSDERMAL through the skin TRANSIENTLY temporarily TRAUMA injury; wound TREADMILL walking machine used to test heart function

UPTAKE absorbing and taking in of a substance by living tissue

VALVULOPLASTY plastic repair of a valve, especially a heart valve VARICES enlarged veins VASOSPASM narrowing of the blood vessels VECTOR a carrier that can transmit disease-causing microorganisms (germs and viruses) VENIPUNCTURE needle stick, blood draw, entering the skin with a needle VERTICAL TRANSMISSION spread of disease

WBC white blood cell

• Introduction
• Conclusions
• Article Information

The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among individuals older than 40 years of age, there were no more than 8 reports of myocarditis for any individual age after receiving either vaccine. For the BNT162b2 vaccine, there were 114 246 837 first vaccination doses and 95 532 396 second vaccination doses; and for the mRNA-1273 vaccine, there were 78 158 611 and 66 163 001, respectively. The y-axis range differs between panels A and B.

The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among recipients of either vaccine, there were only 13 reports or less of myocarditis beyond 10 days for any individual time from vaccination to symptom onset. The y-axis range differs between panels A and B.

A, For the BNT162b2 vaccine, there were 138 reported cases of myocarditis with known date for symptom onset and dose after 114 246 837 first vaccination doses and 888 reported cases after 95 532 396 second vaccination doses.

B, For the mRNA-1273 vaccine, there were 116 reported cases of myocarditis with known date for symptom onset and dose after 78 158 611 first vaccination doses and 311 reported cases after 66 163 001 second vaccination doses.

eMethods. Medical Dictionary for Regulatory Activities Preferred Terms, Definitions of Myocarditis and Pericarditis, Myocarditis medical review form

eFigure. Flow diagram of cases of myocarditis and pericarditis reported to Vaccine Adverse Event Reporting System (VAERS) after receiving mRNA-based COVID-19 vaccine, United States, December 14, 2020-August 31, 2021.

eTable 1. Characteristics of all myocarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 2. Characteristics of all pericarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 3. Characteristics of myocarditis cases reported to Vaccine Adverse Event Reporting System after mRNA-based COVID-19 vaccination by case definition status.

• Myocarditis and Pericarditis After Vaccination for COVID-19 JAMA Research Letter September 28, 2021 This study investigates the incidence of myocarditis and pericarditis emergency department or inpatient hospital encounters before COVID-19 vaccine availability (January 2019–January 2021) and during a COVID-19 vaccination period (February-May 2021) in a large US health care system. George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD
• Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel JAMA Research Letter April 26, 2022 This study assessed whether a third vaccine dose was associated with the risk of myocarditis among military personnel in Israel. Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD
• Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply JAMA Comment & Response May 24, 2022 Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA
• Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US JAMA Comment & Response May 24, 2022 Sheila R. Weiss, PhD
• JAMA Network Articles of the Year 2022 JAMA Medical News & Perspectives December 27, 2022 This Medical News article is our annual roundup of the top-viewed articles from all JAMA Network journals. Melissa Suran, PhD, MSJ
• Diagnosis and Treatment of Acute Myocarditis—A Review JAMA Review April 4, 2023 This Review summarizes current evidence regarding the diagnosis and treatment of acute myocarditis. Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD
• Patient Information: Acute Myocarditis JAMA JAMA Patient Page August 8, 2023 This JAMA Patient Page describes acute myocarditis and its symptoms, causes, diagnosis, and treatment. Kristin Walter, MD, MS
• Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military JAMA Cardiology Brief Report October 1, 2021 This case series describes myocarditis presenting after COVID-19 vaccination within the Military Health System. Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD
• Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination JAMA Cardiology Brief Report October 1, 2021 This study describes 4 patients who presented with acute myocarditis after mRNA COVID-19 vaccination. Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD
• Association of Myocarditis With BNT162b2 Vaccination in Children JAMA Cardiology Brief Report December 1, 2021 This case series reviews comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine. Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD

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Oster ME , Shay DK , Su JR, et al. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021. JAMA. 2022;327(4):331–340. doi:10.1001/jama.2021.24110

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Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021

• 1 US Centers for Disease Control and Prevention, Atlanta, Georgia
• 2 School of Medicine, Emory University, Atlanta, Georgia
• 3 Children’s Healthcare of Atlanta, Atlanta, Georgia
• 4 Vanderbilt University Medical Center, Nashville, Tennessee
• 5 Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
• 6 Boston Medical Center, Boston, Massachusetts
• 7 Duke University, Durham, North Carolina
• 8 US Food and Drug Administration, Silver Spring, Maryland
• Research Letter Myocarditis and Pericarditis After Vaccination for COVID-19 George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD JAMA
• Research Letter Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD JAMA
• Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA JAMA
• Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US Sheila R. Weiss, PhD JAMA
• Medical News & Perspectives JAMA Network Articles of the Year 2022 Melissa Suran, PhD, MSJ JAMA
• Review Diagnosis and Treatment of Acute Myocarditis—A Review Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD JAMA
• JAMA Patient Page Patient Information: Acute Myocarditis Kristin Walter, MD, MS JAMA
• Brief Report Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD JAMA Cardiology
• Brief Report Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD JAMA Cardiology
• Brief Report Association of Myocarditis With BNT162b2 Vaccination in Children Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD JAMA Cardiology

Question   What is the risk of myocarditis after mRNA-based COVID-19 vaccination in the US?

Findings   In this descriptive study of 1626 cases of myocarditis in a national passive reporting system, the crude reporting rates within 7 days after vaccination exceeded the expected rates across multiple age and sex strata. The rates of myocarditis cases were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively).

Meaning   Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men.

Importance   Vaccination against COVID-19 provides clear public health benefits, but vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19 vaccination are unclear.

Objective   To describe reports of myocarditis and the reporting rates after mRNA-based COVID-19 vaccination in the US.

Design, Setting, and Participants   Descriptive study of reports of myocarditis to the Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19 vaccine administration between December 2020 and August 2021 in 192 405 448 individuals older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021.

Exposures   Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna).

Main Outcomes and Measures   Reports of myocarditis to VAERS were adjudicated and summarized for all age groups. Crude reporting rates were calculated across age and sex strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims data. For persons younger than 30 years of age, medical record reviews and clinician interviews were conducted to describe clinical presentation, diagnostic test results, treatment, and early outcomes.

Results   Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis, the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2 days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19 vaccination exceeded the expected rates of myocarditis across multiple age and sex strata. The rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and 223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately 96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of presenting symptoms by hospital discharge. The most common treatment was nonsteroidal anti-inflammatory drugs (589/676; 87%).

Conclusions and Relevance   Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Myocarditis is an inflammatory condition of the heart muscle that has a bimodal peak incidence during infancy and adolescence or young adulthood. 1 - 4 The clinical presentation and course of myocarditis is variable, with some patients not requiring treatment and others experiencing severe heart failure that requires subsequent heart transplantation or leads to death. 5 Onset of myocarditis typically follows an inciting process, often a viral illness; however, no antecedent cause is identified in many cases. 6 It has been hypothesized that vaccination can serve as a trigger for myocarditis; however, only the smallpox vaccine has previously been causally associated with myocarditis based on reports among US military personnel, with cases typically occurring 7 to 12 days after vaccination. 7

With the implementation of a large-scale, national COVID-19 vaccination program starting in December 2020, the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration began monitoring for a number of adverse events of special interest, including myocarditis and pericarditis, in the Vaccine Adverse Event Reporting System (VAERS), a long-standing national spontaneous reporting (passive surveillance) system. 8 As the reports of myocarditis after COVID-19 vaccination were reported to VAERS, the Clinical Immunization Safety Assessment Project, 9 a collaboration between the CDC and medical research centers, which includes physicians treating infectious diseases and other specialists (eg, cardiologists), consulted on several of the cases. In addition, reports from several countries raised concerns that mRNA-based COVID-19 vaccines may be associated with acute myocarditis. 10 - 15

Given this concern, the aims were to describe reports and confirmed cases of myocarditis initially reported to VAERS after mRNA-based COVID-19 vaccination and to provide estimates of the risk of myocarditis after mRNA-based COVID-19 vaccination based on age, sex, and vaccine type.

VAERS is a US spontaneous reporting (passive surveillance) system that functions as an early warning system for potential vaccine adverse events. 8 Co-administered by the CDC and the US Food and Drug Administration, VAERS accepts reports of all adverse events after vaccination from patients, parents, clinicians, vaccine manufacturers, and others regardless of whether the events could plausibly be associated with receipt of the vaccine. Reports to VAERS include information about the vaccinated person, the vaccine or vaccines administered, and the adverse events experienced by the vaccinated person. The reports to VAERS are then reviewed by third-party professional coders who have been trained in the assignment of Medical Dictionary for Regulatory Activities preferred terms. 16 The coders then assign appropriate terms based on the information available in the reports.

This activity was reviewed by the CDC and was conducted to be consistent with applicable federal law and CDC policy. The activities herein were confirmed to be nonresearch under the Common Rule in accordance with institutional procedures and therefore were not subject to institutional review board requirements. Informed consent was not obtained for this secondary use of existing information; see 45 CFR part 46.102(l)(2), 21 CFR part 56, 42 USC §241(d), 5 USC §552a, and 44 USC §3501 et seq.

The exposure of concern was vaccination with one of the mRNA-based COVID-19 vaccines: the BNT162b2 vaccine (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna). During the analytic period, persons aged 12 years or older were eligible for the BNT162b2 vaccine and persons aged 18 years or older were eligible for the mRNA-1273 vaccine. The number of COVID-19 vaccine doses administered during the analytic period was obtained through the CDC’s COVID-19 Data Tracker. 17

The primary outcome was the occurrence of myocarditis and the secondary outcome was pericarditis. Reports to VAERS with these outcomes were initially characterized using the Medical Dictionary for Regulatory Activities preferred terms of myocarditis or pericarditis (specific terms are listed in the eMethods in the Supplement ). After initial review of reports of myocarditis to VAERS and review of the patient’s medical records (when available), the reports were further reviewed by CDC physicians and public health professionals to verify that they met the CDC’s case definition for probable or confirmed myocarditis (descriptions previously published and included in the eMethods in the Supplement ). 18 The CDC’s case definition of probable myocarditis requires the presence of new concerning symptoms, abnormal cardiac test results, and no other identifiable cause of the symptoms and findings. Confirmed cases of myocarditis further require histopathological confirmation of myocarditis or cardiac magnetic resonance imaging (MRI) findings consistent with myocarditis.

Deaths were included only if the individual had met the case definition for confirmed myocarditis and there was no other identifiable cause of death. Individual cases not involving death were included only if the person had met the case definition for probable myocarditis or confirmed myocarditis.

We characterized reports of myocarditis or pericarditis after COVID-19 vaccination that met the CDC’s case definition and were received by VAERS between December 14, 2020 (when COVID-19 vaccines were first publicly available in the US), and August 31, 2021, by age, sex, race, ethnicity, and vaccine type; data were processed by VAERS as of September 30, 2021. Race and ethnicity were optional fixed categories available by self-identification at the time of vaccination or by the individual filing a VAERS report. Race and ethnicity were included to provide the most complete baseline description possible for individual reports; however, further analyses were not stratified by race and ethnicity due to the high percentage of missing data. Reports of pericarditis with evidence of potential myocardial involvement were included in the review of reports of myocarditis. The eFigure in the Supplement outlines the categorization of the reports of myocarditis and pericarditis reviewed.

Further analyses were conducted only for myocarditis because of the preponderance of those reports to VAERS, in Clinical Immunization Safety Assessment Project consultations, and in published articles. 10 - 12 , 19 - 21 Crude reporting rates for myocarditis during a 7-day risk interval were calculated using the number of reports of myocarditis to VAERS per million doses of COVID-19 vaccine administered during the analytic period and stratified by age, sex, vaccination dose (first, second, or unknown), and vaccine type. Expected rates of myocarditis by age and sex were calculated using 2017-2019 data from the IBM MarketScan Commercial Research Database. This database contains individual-level, deidentified, inpatient and outpatient medical and prescription drug claims, and enrollment information submitted to IBM Watson Health by large employers and health plans. The data were accessed using version 4.0 of the IBM MarketScan Treatment Pathways analytic platform. Age- and sex-specific rates were calculated by determining the number of individuals with myocarditis ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes B33.20, B33.22, B33.24, I40.0, I40.1, I40.8, I40.9, or I51.4) 22 identified during an inpatient encounter in 2017-2019 relative to the number of individuals of similar age and sex who were continually enrolled during the year in which the myocarditis-related hospitalization occurred; individuals with any diagnosis of myocarditis prior to that year were excluded. Given the limitations of the IBM MarketScan Commercial Research Database to capture enrollees aged 65 years or older, an expected rate for myocarditis was not calculated for this population. A 95% CI was calculated using Poisson distribution in SAS version 9.4 (SAS Institute Inc) for each expected rate of myocarditis and for each observed rate in a strata with at least 1 case.

In cases of probable or confirmed myocarditis among those younger than 30 years of age, their clinical course was then summarized to the extent possible based on medical review and clinician interviews. This clinical course included presenting symptoms, diagnostic test results, treatment, and early outcomes (abstraction form appears in the eMethods in the Supplement ). 23

When applicable, missing data were delineated in the results or the numbers with complete data were listed. No assumptions or imputations were made regarding missing data. Any percentages that were calculated included only those cases of myocarditis with adequate data to calculate the percentages.

Between December 14, 2020, and August 31, 2021, 192 405 448 individuals older than 12 years of age received a total of 354 100 845 mRNA-based COVID-19 vaccines. VAERS received 1991 reports of myocarditis (391 of which also included pericarditis) after receipt of at least 1 dose of mRNA-based COVID-19 vaccine (eTable 1 in the Supplement ) and 684 reports of pericarditis without the presence of myocarditis (eTable 2 in the Supplement ).

Of the 1991 reports of myocarditis, 1626 met the CDC’s case definition for probable or confirmed myocarditis ( Table 1 ). There were 208 reports that did not meet the CDC’s case definition for myocarditis and 157 reports that required more information to perform adjudication (eTable 3 in the Supplement ). Of the 1626 reports that met the CDC’s case definition for myocarditis, 1195 (73%) were younger than 30 years of age, 543 (33%) were younger than 18 years of age, and the median age was 21 years (IQR, 16-31 years) ( Figure 1 ). Of the reports of myocarditis with dose information, 82% (1265/1538) occurred after the second vaccination dose. Of those with a reported dose and time to symptom onset, the median time from vaccination to symptom onset was 3 days (IQR, 1-8 days) after the first vaccination dose and 74% (187/254) of myocarditis events occurred within 7 days. After the second vaccination dose, the median time to symptom onset was 2 days (IQR, 1-3 days) and 90% (1081/1199) of myocarditis events occurred within 7 days ( Figure 2 ).

Males comprised 82% (1334/1625) of the cases of myocarditis for whom sex was reported. The largest proportions of cases of myocarditis were among White persons (non-Hispanic or ethnicity not reported; 69% [914/1330]) and Hispanic persons (of all races; 17% [228/1330]). Among persons younger than 30 years of age, there were no confirmed cases of myocarditis in those who died after mRNA-based COVID-19 vaccination without another identifiable cause and there was 1 probable case of myocarditis but there was insufficient information available for a thorough investigation. At the time of data review, there were 2 reports of death in persons younger than 30 years of age with potential myocarditis that remain under investigation and are not included in the case counts.

Symptom onset of myocarditis was within 7 days after vaccination for 947 reports of individuals who received the BNT162b2 vaccine and for 382 reports of individuals who received the mRNA-1273 vaccine. The rates of myocarditis varied by vaccine type, sex, age, and first or second vaccination dose ( Table 2 ). The reporting rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.73 [95% CI, 61.68-81.11] per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.86 [95% CI, 91.65-122.27] per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.43 [95% CI, 45.56-60.33] per million doses of the BNT162b2 vaccine and 56.31 [95% CI, 47.08-67.34] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in adolescent males and young men exceeded the upper bound of the expected rates after the first vaccination dose with the BNT162b2 vaccine in those aged 12 to 24 years, after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 49 years, after the first vaccination dose with the mRNA-1273 vaccine in those aged 18 to 39 years, and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 49 years.

The reporting rates of myocarditis in females were lower than those in males across all age strata younger than 50 years of age. The reporting rates of myocarditis were highest after the second vaccination dose in adolescent females aged 12 to 15 years (6.35 [95% CI, 4.05-9.96] per million doses of the BNT162b2 vaccine), in adolescent females aged 16 to 17 years (10.98 [95% CI, 7.16-16.84] per million doses of the BNT162b2 vaccine), in young women aged 18 to 24 years (6.87 [95% CI, 4.27-11.05] per million doses of the mRNA-1273 vaccine), and in women aged 25 to 29 years (8.22 [95% CI, 5.03-13.41] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in females exceeded the upper bound of the expected rates after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 29 years and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 29 years.

Among the 1372 reports of myocarditis in persons younger than 30 years of age, 1305 were able to be adjudicated, with 92% (1195/1305) meeting the CDC’s case definition. Of these, chart abstractions or medical interviews were completed for 69% (826/1195) ( Table 3 ). The symptoms commonly reported in the verified cases of myocarditis in persons younger than 30 years of age included chest pain, pressure, or discomfort (727/817; 89%) and dyspnea or shortness of breath (242/817; 30%). Troponin levels were elevated in 98% (792/809) of the cases of myocarditis. The electrocardiogram result was abnormal in 72% (569/794) of cases of myocarditis. Of the patients who had received a cardiac MRI, 72% (223/312) had abnormal findings consistent with myocarditis. The echocardiogram results were available for 721 cases of myocarditis; of these, 84 (12%) demonstrated a notable decreased left ventricular ejection fraction (<50%). Among the 676 cases for whom treatment data were available, 589 (87%) received nonsteroidal anti-inflammatory drugs. Intravenous immunoglobulin and glucocorticoids were each used in 12% of the cases of myocarditis (78/676 and 81/676, respectively). Intensive therapies such as vasoactive medications (12 cases of myocarditis) and intubation or mechanical ventilation (2 cases) were rare. There were no verified cases of myocarditis requiring a heart transplant, extracorporeal membrane oxygenation, or a ventricular assist device. Of the 96% (784/813) of cases of myocarditis who were hospitalized, 98% (747/762) were discharged from the hospital at time of review. In 87% (577/661) of discharged cases of myocarditis, there was resolution of the presenting symptoms by hospital discharge.

In this review of reports to VAERS between December 2020 and August 2021, myocarditis was identified as a rare but serious adverse event that can occur after mRNA-based COVID-19 vaccination, particularly in adolescent males and young men. However, this increased risk must be weighed against the benefits of COVID-19 vaccination. 18

Compared with cases of non–vaccine-associated myocarditis, the reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination were similar in demographic characteristics but different in their acute clinical course. First, the greater frequency noted among vaccine recipients aged 12 to 29 years vs those aged 30 years or older was similar to the age distribution seen in typical cases of myocarditis. 2 , 4 This pattern may explain why cases of myocarditis were not discovered until months after initial Emergency Use Authorization of the vaccines in the US (ie, until the vaccines were widely available to younger persons). Second, the sex distribution in cases of myocarditis after COVID-19 vaccination was similar to that seen in typical cases of myocarditis; there is a strong male predominance for both conditions. 2 , 4

However, the onset of myocarditis symptoms after exposure to a potential immunological trigger was shorter for COVID-19 vaccine–associated cases of myocarditis than is typical for myocarditis cases diagnosed after a viral illness. 24 - 26 Cases of myocarditis reported after COVID-19 vaccination were typically diagnosed within days of vaccination, whereas cases of typical viral myocarditis can often have indolent courses with symptoms sometimes present for weeks to months after a trigger if the cause is ever identified. 1 The major presenting symptoms appeared to resolve faster in cases of myocarditis after COVID-19 vaccination than in typical viral cases of myocarditis. Even though almost all individuals with cases of myocarditis were hospitalized and clinically monitored, they typically experienced symptomatic recovery after receiving only pain management. In contrast, typical viral cases of myocarditis can have a more variable clinical course. For example, up to 6% of typical viral myocarditis cases in adolescents require a heart transplant or result in mortality. 27

In the current study, the initial evaluation and treatment of COVID-19 vaccine–associated myocarditis cases was similar to that of typical myocarditis cases. 28 - 31 Initial evaluation usually included measurement of troponin level, electrocardiography, and echocardiography. 1 Cardiac MRI was often used for diagnostic purposes and also for possible prognostic purposes. 32 , 33 Supportive care was a mainstay of treatment, with specific cardiac or intensive care therapies as indicated by the patient’s clinical status.

Long-term outcome data are not yet available for COVID-19 vaccine–associated myocarditis cases. The CDC has started active follow-up surveillance in adolescents and young adults to assess the health and functional status and cardiac outcomes at 3 to 6 months in probable and confirmed cases of myocarditis reported to VAERS after COVID-19 vaccination. 34 For patients with myocarditis, the American Heart Association and the American College of Cardiology guidelines advise that patients should be instructed to refrain from competitive sports for 3 to 6 months, and that documentation of a normal electrocardiogram result, ambulatory rhythm monitoring, and an exercise test should be obtained prior to resumption of sports. 35 The use of cardiac MRI is unclear, but it may be useful in evaluating the progression or resolution of myocarditis in those with abnormalities on the baseline cardiac MRI. 36 Further doses of mRNA-based COVID-19 vaccines should be deferred, but may be considered in select circumstances. 37

This study has several limitations. First, although clinicians are required to report serious adverse events after COVID-19 vaccination, including all events leading to hospitalization, VAERS is a passive reporting system. As such, the reports of myocarditis to VAERS may be incomplete, and the quality of the information reported is variable. Missing data for sex, vaccination dose number, and race and ethnicity were not uncommon in the reports received; history of prior SARS-CoV-2 infection also was not known. Furthermore, as a passive system, VAERS data are subject to reporting biases in that both underreporting and overreporting are possible. 38 Given the high verification rate of reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination, underreporting is more likely. Therefore, the actual rates of myocarditis per million doses of vaccine are likely higher than estimated.

Second, efforts by CDC investigators to obtain medical records or interview physicians were not always successful despite the special allowance for sharing information with the CDC under the Health Insurance Portability and Accountability Act of 1996. 39 This challenge limited the ability to perform case adjudication and complete investigations for some reports of myocarditis, although efforts are still ongoing when feasible.

Third, the data from vaccination administration were limited to what is reported to the CDC and thus may be incomplete, particularly with regard to demographics.

Fourth, calculation of expected rates from the IBM MarketScan Commercial Research Database relied on administrative data via the use of ICD-10 codes and there was no opportunity for clinical review. Furthermore, these data had limited information regarding the Medicare population; thus expected rates for those older than 65 years of age were not calculated. However, it is expected that the rates in those older than 65 years of age would not be higher than the rates in those aged 50 to 64 years. 4

Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Corresponding Author: Matthew E. Oster, MD, MPH, US Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333 ( [email protected] ).

Correction: This article was corrected March 21, 2022, to change “pericarditis” to “myocarditis” in the first row, first column of eTable 1 in the Supplement.

Accepted for Publication: December 16, 2021.

Author Contributions: Drs Oster and Su 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: Oster, Shay, Su, Creech, Edwards, Dendy, Schlaudecker, Woo, Shimabukuro.

Acquisition, analysis, or interpretation of data: Oster, Shay, Su, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Marquez, Strid, Woo, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Drafting of the manuscript: Oster, Shay, Su, Gee, Creech, Marquez, Strid, Woo, Shimabukuro.

Critical revision of the manuscript for important intellectual content: Oster, Shay, Su, Creech, Broder, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Statistical analysis: Oster, Su, Marquez, Strid, Woo, Shimabukuro.

Obtained funding: Edwards, DeStefano.

Administrative, technical, or material support: Oster, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Smith, Baumblatt, Thompson, Reagan-Steiner, DeStefano.

Supervision: Su, Edwards, Soslow, Dendy, Schlaudecker, Campbell, Sperling, DeStefano, Shimabukuro.

Conflict of Interest Disclosures: Dr Creech reported receiving grants from the National Institutes of Health for the Moderna and Janssen clinical trials and receiving personal fees from Astellas and Horizon. Dr Edwards reported receiving grants from the National Institutes of Health; receiving personal fees from BioNet, IBM, X-4 Pharma, Seqirus, Roche, Pfizer, Merck, Moderna, and Sanofi; and receiving compensation for being the associate editor of Clinical Infectious Diseases . Dr Soslow reported receiving personal fees from Esperare. Dr Schlaudecker reported receiving grants from Pfizer and receiving personal fees from Sanofi Pasteur. Drs Barnett, Ruberg, and Smith reported receiving grants from Pfizer. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and receiving grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. No other disclosures were reported.

Funding/Support: This work was supported by contracts 200-2012-53709 (Boston Medical Center), 200-2012-53661 (Cincinnati Children’s Hospital Medical Center), 200-2012-53663 (Duke University), and 200-2012-50430 (Vanderbilt University Medical Center) with the US Centers for Disease Control and Prevention (CDC) Clinical Immunization Safety Assessment Project.

Role of the Funder/Sponsor: The CDC provided funding via the Clinical Immunization Safety Assessment Project to Drs Creech, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, and Lopes. The authors affiliated with the CDC along with the other coauthors conducted the investigations; performed collection, management, analysis, and interpretation of the data; were involved in the preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC or the US Food and Drug Administration. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC or the US Food and Drug Administration.

Additional Contributions: We thank the following CDC staff who contributed to this article without compensation outside their normal salaries (in alphabetical order and contribution specified in parenthesis at end of each list of names): Nickolas Agathis, MD, MPH, Stephen R. Benoit, MD, MPH, Beau B. Bruce, MD, PhD, Abigail L. Carlson, MD, MPH, Meredith G. Dixon, MD, Jonathan Duffy, MD, MPH, Charles Duke, MD, MPH, Charles Edge, MSN, MS, Robyn Neblett Fanfair, MD, MPH, Nathan W. Furukawa, MD, MPH, Gavin Grant, MD, MPH, Grace Marx, MD, MPH, Maureen J. Miller, MD, MPH, Pedro Moro, MD, MPH, Meredith Oakley, DVM, MPH, Kia Padgett, MPH, BSN, RN, Janice Perez-Padilla, MPH, BSN, RN, Robert Perry, MD, MPH, Nimia Reyes, MD, MPH, Ernest E. Smith, MD, MPH&TM, David Sniadack, MD, MPH, Pamela Tucker, MD, Edward C. Weiss, MD, MPH, Erin Whitehouse, PhD, MPH, RN, Pascale M. Wortley, MD, MPH, and Rachael Zacks, MD (for clinical investigations and interviews); Amelia Jazwa, MSPH, Tara Johnson, MPH, MS, and Jamila Shields, MPH (for project coordination); Charles Licata, PhD, and Bicheng Zhang, MS (for data acquisition and organization); Charles E. Rose, PhD (for statistical consultation); and Scott D. Grosse, PhD (for calculation of expected rates of myocarditis). We also thank the clinical staff who cared for these patients and reported the adverse events to the Vaccine Adverse Event Reporting System.

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Supreme Court to weigh whether the FDA was heavy-handed with flavored e-cigarette products

By Associated Press July 2, 2024

W ASHINGTON — The Supreme Court  took up an e-cigarette case Tuesday, weighing Food and Drug Administration decisions blocking the marketing of sweet flavored products amid a surge in vaping by young people.

The FDA is appealing a lower court ruling siding with vape companies who argue the FDA unfairly denied more than a million applications to market fruit or candy flavored versions of nicotine-laced liquid that’s heated by the e-cigarette to create an inhalable aerosol.

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The case comes as the FDA undertakes a sweeping review after years of regulatory delays intended to bring scientific scrutiny to the multibillion-dollar vaping market, which includes thousands of flavored vapes that are technically illegal but are widely available in convenience stores, gas stations and vape shops . The FDA recently approved its first menthol-flavored  electronic cigarettes  for adult smokers.

The agency says the sweet flavored e-liquids pose a “serious, well-documented risk” of enticing more young people to pick up a nicotine habit. In 2020, nearly 20% of high school students and almost 5% of middle-school students used e-cigarettes, and almost all of those kids used flavored products, the agency said in court documents.

Related: Journals issue corrections noting vaping researchers’ undisclosed ties to Juul

The agency says companies were blocked because they couldn’t show the possible benefits for adult smokers outweighed the risk of underage use. The companies say they had prepared detailed plans to avoid appealing to young people.

The companies scored a victory when the 5th U.S. Circuit Court of Appeals sided with the vaping company Triton Distribution and tossed out orders denying the marketing of e-liquids with names like “Jimmy The Juice Man in Peachy Strawberry.”

The 5th Circuit found the agency was unfair because it required the companies, without warning, to present studies showing that flavored products would help with smoking cessation.

The justices are expecting to hear the case in the fall.

Related: Vaping is just as good as Chantix at helping people quit cigarettes, new study finds

Other appeals courts have sided with the FDA, which regulates new tobacco products under a 2009 law aimed at curbing youth tobacco use.

Yolonda Richardson, president and CEO of the Campaign for Tobacco-Free Kids, called on the high court to overturn the appeals-court order, calling it misguided and saying it would “cause significant harm to public health and especially to the health of our kids,” if allowed to stand.

Youth vaping has declined from all-time highs in recent years, but 2.8 million middle and high school students still use it, according to federal survey data.

Vaping companies have long claimed their  products can help blunt the toll of smoking , which is blamed for 480,000 U.S. deaths annually due to cancer, lung disease and heart disease.

The company, Trinton, is looking forward to the Supreme Court hearing the case, attorney Eric Heyer said. He said the FDA had imposed “surprise, after-the-fact … study requirements” and failed to follow its own guidance.

— Lindsay Whitehurst

About the Author Reprints

Associated press.

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