Plain Language Summary:

This study is a clinical trial to see if ketamine can help treat symptoms of Long COVID, especially fatigue and problems with thinking clearly (often called "brain fog"). Long COVID is a condition that affects people even after they have recovered from COVID-19, causing ongoing health issues like tiredness, memory problems, and difficulty concentrating. Right now, there are very few treatments available for these symptoms, and many people are looking for new options to feel better.

What is the study trying to find out? Does ketamine help reduce fatigue and improve thinking skills in people with Long COVID? Does ketamine improve overall quality of life and mental health for people with Long COVID? Is ketamine safe and well-tolerated for people with Long COVID? How does ketamine affect the body's biological processes, like inflammation and brain function? How will the study work?

The study will include 20 adults between 18 and 65 years old who have Long COVID symptoms like fatigue or brain fog.

Participants will first meet with researchers to answer health questions, take surveys about their symptoms, and do tests to check their thinking skills. All participants will also have a brain scan (MRI) and give a blood sample to look at markers of inflammation.

Participants will then receive four ketamine treatments over two weeks at a specialized clinic. The ketamine will be given as an injection, with the dose slightly increasing during the treatment period.

After six weeks, participants will return for follow-up tests to see if their symptoms have improved. This includes repeating the surveys, thinking tests, MRI and blood test.

Why ketamine? Ketamine is a medicine originally used for anesthesia but has also been found to help with depression and other mental health issues. Researchers think it might help with Long COVID symptoms because it can reduce inflammation in the brain and improve how the brain functions. People with Long COVID often have signs of inflammation and changes in brain chemicals, which ketamine might help balance.

What are the potential benefits? Participants might experience less fatigue and clearer thinking after ketamine treatment. They could also feel better overall in terms of mood and quality of life. Since ketamine can work quickly, some people may notice improvements shortly after starting the treatment.

What are the risks? Ketamine can cause side effects like feeling dizzy, anxious, or having an unusual sense of reality (sometimes called dissociation). It may also cause temporary increases in blood pressure or heart rate. All treatments will be carefully monitored by healthcare professionals to ensure safety.

Who can participate? Adults aged 18-65 with Long COVID who have significant fatigue or thinking problems can join. People will not be able to participate if they have certain health conditions like severe heart disease, uncontrolled high blood pressure, or a history of severe mental health disorders.

Why is this study important? Long COVID affects millions of people, and many are struggling to find treatments that work. This study is one of the first to explore ketamine as a potential treatment for Long COVID symptoms. If ketamine helps, it could lead to more research and eventually new treatment options for people living with Long COVID.

Inclusion Criteria:

• Adults aged 18-65 years diagnosed with LC and possess a documented history of positive COVID-19 diagnostic testing or a probable infection as determined by a healthcare provider.
• One persistent symptom of fatigue or neurocognitive dysfunction as defined by rating their symptoms as moderate to severe on the screening form.
• English as a primary language OR comprehension of English suitable to understand research staff instructions.
• All participants must be eligible for MRI and will undergo MRI scans pre- and post-treatment

Exclusion Criteria:

Contraindications to ketamine therapy:

• Current substance use disorder
• Current mania or psychosis
• Recent myocardial infarction or stroke (within 1 year)
• Unstable cardiovascular disease (including uncontrolled high blood pressure > 180/110 mmHg)
• Uncontrolled seizure disorder
• Pregnancy

Additional exclusion criteria include:

• Recent COVID-19 infection or reinfection within 8 weeks

• Prior receipt of ketamine treatment

• History of treatment resistant depression (TRD) prior to development of LC

  • Defined as completing a trial (2 months of treatment at highest tolerated dose) of 3 or more psychotropic medications from at least 2 classes of medications (i.e. SSRIs, SNRIs, antipsychotic medications, or mood stabilizers such as lithium, lamotrigine, Depakote, or oxcarbazepine)
  • Psychotropic medications used during treatment of LC will not be counted as medications used for TRD

• Current severe depression or anxiety, and/or active suicidal ideation

  • Severe depression and anxiety defined as scoring > 19 on PHQ-9 screening or > 14 on GAD-7 screening.
  • Active suicidal ideation is defined as answering "yes" to question #9 on the PHQ-9

• History of bipolar disorder, schizophrenia, or schizoaffective disorder

• History of suicide attempt or psychiatric hospitalization for any reason in the last 5 years

• Current benzodiazepine or naltrexone medication use within 4 weeks of enrollment as these may decrease or block the therapeutic effect of ketamine treatment

Individual Participant Data (IPD) to be shared will include de-identified data related to primary and secondary outcomes, such as patient-reported outcomes (e.g., PROMIS Fatigue and Cognitive Function scores), objective cognitive assessments from the BrainCheck battery, and adverse event reports. Additionally, de-identified neuroimaging data (for participants undergoing MRI) and biomarker data from blood samples will be included. Only data used in the results publication and relevant to the study's primary and secondary outcomes will be shared. All shared data will be stripped of personal identifiers to maintain participant confidentiality, following HIPAA guidelines.

The de-identified IPD will be made available beginning 6 months after publication of the primary study results. Data will be available for a period of 3 years following this initial release.

Data will be shared with qualified researchers affiliated with academic institutions, healthcare organizations, or other research entities conducting studies related to Long COVID, neurocognitive function, or ketamine treatment. Researchers must submit a formal data request, including a summary of the proposed research and intended use of the data. Requests will be reviewed by the study's principal investigator and research team to ensure alignment with ethical guidelines and scientific merit. Approved researchers will be required to sign a data use agreement to ensure proper handling and confidentiality of the data.