Phase 2 trial to determine if low-dose ketamine eases MS fatigue

Johns Hopkins study enrolling adult patients with fatigue as a main symptom

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A Phase 2 clinical trial evaluating whether a low dose of ketamine can ease fatigue in people with multiple sclerosis (MS) is enrolling patients at Johns Hopkins University in Baltimore.

The study, called INKLING-MS (NCT05378100), is recruiting up to 110 patients, ages 18-65, who have been complaining of fatigue as one of their main symptoms. Full enrollment is expected by mid-2025.

The trial’s protocol was shared in the study, “Low-dose ketamine infusion for the treatment of multiple sclerosis fatigue (INKLING-MS): Study protocol for a randomized, double-blind, active placebo-controlled phase II trial,” which was published in Contemporary Clinical Trials.

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Fatigue Was One of the First ‘Tells’ of My Primary Progressive MS

Ketamine causes a rapid release of glutamate in the prefrontal cortex

Fatigue, a feeling marked by excessive tiredness or lack of energy that can interfere with daily activities and a person’s overall well-being, is common to many people with MS.

A number of medications, as well as non-drug treatments such as cognitive-behavioral approaches and exercise, have been shown to ease disease-associated fatigue.

“However, [cognitive-behavioral treatment] may not be readily available to many patients with MS, and physical disability may prohibit patients from engaging in an effective exercise program,” the researchers wrote.

Ketamine is a psychedelic compound primarily used as an anesthetic. It works by acting on receptors called NMDA receptors, and preventing the neurotransmitter glutamate from sending signals in the brain and throughout nerve cells.

By preventing glutamate from binding to NMDA receptors, more glutamate becomes available in certain areas of the brain.

Notably, ketamine has been shown to cause a rapid release of glutamate in the prefrontal cortex, a brain region that helps with focus and making plans.

In a pilot Phase 1/2 clinical trial, researchers at the Johns Hopkins University School of Medicine showed that a single, low-dose infusion of ketamine helped ease fatigue in people with MS.

The ongoing trial will evaluate low-dose ketamine in a larger sample of people with MS, including those with relapsing and progressive forms of MS.

Participants will be randomly assigned to one of three groups. The first group will receive two intravenous, or into-the-vein, infusions of low-dose ketamine (0.5 mg/kg) four weeks apart.

The other two groups will receive both ketamine and midazolam, an anesthetic that will be used as an active placebo because it mimics some of the expected side effects of ketamine without providing a therapeutic effect.

The second group will receive one infusion of low-dose ketamine followed by an infusion of midazolam (0.05 mg/kg) four weeks later, while those in the third group will be given one infusion of midazolam followed by an infusion of low-dose ketamine four weeks later.

The study’s main goal is to measure changes in the Modified Fatigue Impact Scale (MFIS) — a tool used to evaluate how fatigue affects daily activities — four weeks after the first infusion. This will enable researchers to compare changes in fatigue among the two-thirds of participants given low-dose ketamine in the first infusion with the one-third who received midazolam.

Secondary outcomes include changes in MFIS four weeks after the second infusion, as well as changes after four weeks in other validated measures of fatigue, pain, and depression.

All participants will be monitored for potential side effects over the course of the study.

“If low-dose ketamine is found to be superior to an active placebo, considering the absence of effective medications for MS fatigue, using ketamine as an off-label medication for this symptom may be justifiable,” the researchers wrote.

Moreover, “the results of this study can lead to further research and development of medications that affect the glutamatergic [glutamate-related] system for the treatment of MS fatigue,” they added.