Ketamine for MS Fatigue

Overseen By Joanna Cooper, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Alta Bates Summit Medical Center

Must not be taking: Ketamine interactors

Disqualifiers: Sleep apnea, Hypertension, Liver disease, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if ketamine, an anesthetic, can reduce the fatigue often associated with Multiple Sclerosis (MS). Researchers will compare a low dose of ketamine to a placebo (a harmless saline solution) to assess safety and effectiveness. Individuals with MS who experience fatigue impacting their daily life may be suitable candidates, particularly if their condition has remained stable. As an Early Phase 1 trial, this research seeks to understand how ketamine functions in people, providing participants an opportunity to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are taking medications that may interact with ketamine.

Is there any evidence suggesting that ketamine is likely to be safe for humans?

Research shows that ketamine, when given in low doses, is usually well-tolerated. Studies have found that recipients of low-dose ketamine infusions generally do not experience serious side effects. In trials examining fatigue in people with multiple sclerosis (MS), participants did not report major side effects from single doses of ketamine.

Moreover, the FDA has already approved ketamine for other uses, such as anesthesia and treating depression that doesn't respond to other treatments. This approval suggests that its safety is well-understood. While this is reassuring for its use at low doses, different conditions can react differently. Overall, evidence indicates that low-dose ketamine is safe for many people, but individual experiences can vary. It's always important to discuss potential risks with a healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for MS fatigue?

Unlike standard treatments for multiple sclerosis (MS) fatigue, which often rely on medications like amantadine or modafinil to boost energy, ketamine offers a unique approach. Ketamine is known for its rapid-acting antidepressant effects and works by blocking NMDA receptors in the brain, which could help alleviate fatigue differently than traditional stimulants. Researchers are excited because ketamine might provide quicker relief and a new mechanism to target MS fatigue, potentially offering benefits for patients who haven't responded well to conventional treatments.

What evidence suggests that ketamine might be an effective treatment for MS fatigue?

This trial will compare the effects of ketamine with a placebo for reducing fatigue in people with Multiple Sclerosis (MS). Research has shown that ketamine might reduce tiredness by affecting certain brain pathways. Early studies suggested that ketamine can lower fatigue levels over time, even though the immediate effects remain unclear. Ketamine increases a brain chemical called glutamate, crucial for nerve function, in a brain region involved in complex behaviors. This increase in glutamate may help reduce the tiredness often experienced by people with MS. While more research is needed to confirm these findings, the initial results appear promising. ^{1 3 4 6 7}

Who Is on the Research Team?

Deepak Soneji, MD

Principal Investigator

Sutter East Bay Medical Foundation

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-65 with any form of chronic MS, who suffer from fatigue that affects their quality of life. Participants must have been stable on disease-modifying therapy for at least three months, not be pregnant or breastfeeding, use contraception, and not have had an MS relapse in the last 90 days.

Inclusion Criteria

I have been on the same disease-modifying treatment for at least 3 months.

I haven't had an MS flare-up in the last 3 months.

Must agree to practice an acceptable method of contraception

Exclusion Criteria

I have been diagnosed with Sleep Apnea but haven't received treatment.

My blood pressure is not controlled and is above 160/100.

I have a liver condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Cycle 1

Participants receive either ketamine or placebo infusion on Day 1, followed by follow-up visits on Days 7 and 28

4 weeks

3 visits (in-person)

Treatment Cycle 2

Participants crossover to the other treatment group and receive the alternate infusion on Day 1, followed by follow-up visits on Days 7 and 28

4 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine

Trial Overview The study tests if a low dose of ketamine can alleviate fatigue in MS patients by increasing glutamate in the prefrontal cortex. It's a crossover study where participants randomly receive either ketamine or placebo first, then switch to the other after a period.

How Is the Trial Designed?

Group I: Ketamine (active treatment) Active Control 1 Intervention

dose of 0.5 mg/kg intravenously over 40 minutes on day 1

Group II: Saline (placebo treatment) Placebo Group 1 Intervention

Placebo (saline solution) over 40 minutes on day 1

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Alta Bates Summit Medical Center

Lead Sponsor

Trials

5

Recruited

310+

Published Research Related to This Trial

K.Vita, a medical food with a specific ratio of fatty acids, was well accepted and tolerated by individuals with drug-resistant epilepsy, with 66% of children and 69% of adults completing the study despite some gastrointestinal disturbances that decreased over time.

The dietary intervention with K.Vita led to a significant 50% reduction in seizure frequency, suggesting it may be an effective alternative for those who cannot tolerate ketogenic diets, with potential mechanisms of action that do not rely on achieving ketosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

K.Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Schoeler, NE., Orford, M., Vivekananda, U., et al.[2022]

In a study of 90 patients, both intravenous thiamylal and ketamine significantly reduced the increases in serum myoglobin and creatine kinase levels caused by succinylcholine under halothane anesthesia, indicating their protective effects against muscle damage.

Thiamylal and ketamine also prevented the rise in potassium levels associated with succinylcholine use, suggesting they can help avoid complications like myoglobinemia during anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of ketamine or thiamylal on succinylcholine-induced myoglobinemia under halothane anesthesia in adults. Noguchi, I., Sankawa, H., Andou, M.[2019]

Vitamin K2 (VK2) significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, when administered prophylactically, but was ineffective when given after symptoms began.

VK2 treatment led to decreased inflammatory cell infiltration and reduced expression of harmful proteins in the spinal cords of treated rats, suggesting a potential mechanism for its protective effects in multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin K2 ameliorates experimental autoimmune encephalomyelitis in Lewis rats. Moriya, M., Nakatsuji, Y., Okuno, T., et al.[2006]

In a study involving 80 healthy older adults, the medium-chain triglyceride GSK2981710 increased plasma β-hydroxybutyrate (BHB) levels but did not lead to significant improvements in cognitive function or memory-related neuronal activity over 14 days.

The most common side effect was diarrhea, affecting 100% of participants in the initial part of the study, indicating that while GSK2981710 is generally well-tolerated, it may cause gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. O'Neill, BV., Dodds, CM., Miller, SR., et al.[2020]

In a study involving 9 healthy adults, C8 (a medium-chain triglyceride) was found to be the most effective at increasing plasma ketone levels, significantly outperforming coconut oil (CO) in terms of ketogenic effect over an 8-hour period.

While C8 produced the highest overall ketone levels, coconut oil resulted in a greater increase in the acetoacetate-to-β-hydroxybutyrate ratio, suggesting that different types of MCTs may have unique benefits for brain health, especially in aging populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults. Vandenberghe, C., St-Pierre, V., Pierotti, T., et al.[2020]

In a study involving 18-month-old Sprague-Dawley rats, ketone ester (KE) supplementation significantly delayed the onset of seizures caused by central nervous system oxygen toxicity (CNS-OT) during hyperbaric oxygen exposure, with delays of up to 219% in some combinations.

All treatment groups showed elevated blood levels of D-beta-hydroxybutyrate (D-βHB), but only KE alone and in combination with medium-chain triglycerides (MCT) effectively reduced seizure severity, indicating that KE may be a promising intervention for managing CNS-OT risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delaying latency to hyperbaric oxygen-induced CNS oxygen toxicity seizures by combinations of exogenous ketone supplements. Ari, C., Koutnik, AP., DeBlasi, J., et al.[2023]

The combination of medetomidine and ketamine provides effective anesthesia for cats undergoing ovariectomy, offering longer duration and better muscle relaxation compared to acepromazine/ketamine and zolazepam/tiletamine combinations, based on a study involving 60 cats.

This medetomidine/ketamine combination also delivers superior analgesia in deep organs while balancing the heart rate effects, making it a suitable choice for veterinary anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medetomidine/ketamine anaesthesia in cats. Verstegen, J., Fargetton, X., Ectors, F.[2013]

In a study involving 18 cats, it was found that administering xylazine before ketamine significantly prolonged the duration of anesthesia and increased the plasma half-life of ketamine, indicating a potential for enhanced sedation effects.

Xylazine also delayed the production of norketamine, the primary metabolite of ketamine, suggesting that the combination of these drugs could alter the metabolism and effectiveness of ketamine in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of premedication with xylazine on the distribution and metabolism of intramuscularly administered ketamine in cats. Waterman, AE.[2016]

Methyl ethyl ketone (MEK) and diethyl ketone (DEK) demonstrated broad-spectrum anticonvulsant effects in various mouse seizure models, effectively suppressing seizures induced by different methods such as pentylenetetrazole and electroshock.

In comparison to clonazepam, a standard anticonvulsant, MEK and DEK showed similar or better efficacy across all seizure models tested, suggesting they could be promising alternatives for seizure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticonvulsant effects of methyl ethyl ketone and diethyl ketone in several types of mouse seizure models. Hasebe, N., Abe, K., Sugiyama, E., et al.[2016]

Multiple sclerosis (MS) patients have significantly lower serum levels of Vitamin K2 (VK2) compared to healthy controls, suggesting a potential link between VK2 deficiency and MS, with levels averaging 235 ng/ml in MS patients versus 812 ng/ml in controls.

The study found that lower VK2 levels in MS patients correlated with increased disease activity, such as more frequent attacks, indicating that VK2 may play a role in the disease's progression and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin K2 in multiple sclerosis patients. Lasemi, R., Kundi, M., Moghadam, NB., et al.[2019]

This pilot study will assess the feasibility of using ketamine infusions to reduce postoperative depressive symptoms in 32 patients with a history of depression, potentially leading to a larger clinical trial.

Participants will receive either ketamine or a placebo after surgery, with depressive symptoms measured over 14 days, aiming to determine if ketamine can provide lasting antidepressant effects in the postoperative setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol for the Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) feasibility study: A randomized clinical trial. Fritz, BA., Tellor Pennington, BR., Palanca, BJA., et al.[2023]

Ketamine has been shown to have antidepressant effects in palliative care patients, with all 11 studies reviewed reporting positive outcomes, including one randomized controlled trial (RCT).

While ketamine may be effective for treating depression, its efficacy for physical pain relief is less clear, with recent RCTs indicating no significant analgesic effect, although some patients did experience pain relief with specific administration methods like epidural or intrathecal ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. Goldman, N., Frankenthaler, M., Klepacz, L.[2020]

Maintenance ketamine treatment, delivered through various methods such as intravenous and intranasal, shows promise in sustaining antidepressant effects for patients with treatment-resistant depression, based on a review of multiple studies including three randomized controlled trials.

The treatment appears to have a favorable safety profile, with serious side effects like addiction and renal issues being uncommon, although further long-term studies are needed to fully establish its efficacy and role in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Smith-Apeldoorn, SY., Veraart, JK., Spijker, J., et al.[2022]

A case series involving three hospice patients demonstrated that a single subcutaneous dose of ketamine (0.5 mg/kg) followed by daily oral ketamine (0.5 mg/kg) led to rapid improvement in depression symptoms, as measured by various assessment tools.

This approach offers a potentially effective and convenient method for managing depression in hospice patients, providing quicker relief compared to traditional antidepressant therapies, although further prospective studies are needed to optimize dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single Subcutaneous Ketamine Dose Followed by Oral Ketamine for Depression Symptoms in Hospice Patients: A Case Series. Latuga, NM., Luczkiewicz, DL., Grant, PC., et al.[2021]

In a study of 24 patients with major depressive disorder, activity in the pregenual anterior cingulate cortex (pgACC) was found to predict how well patients would respond to ketamine treatment, suggesting its importance in personalizing depression therapy.

The study also revealed that increased pgACC activity was linked to higher levels of glutamate 24 hours after ketamine infusion, which correlated with better clinical outcomes, indicating a potential biomarker for early treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker. Weigand, A., Gärtner, M., Scheidegger, M., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36738917/

Low-dose ketamine infusion for the treatment of multiple ... This study can show whether intervening in the glutamatergic pathways would improves MS fatigue.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06064162

Study Details | NCT06064162 | Ketamine for MS Fatigue The purpose of this study is to see whether using ketamine to increase glutamate in the prefrontal cortex can reduce Multiple Sclerosis (MS) related fatigue ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7790846/

Pilot randomized active-placebo controlled trial of low-dose ... While no change in DFS after seven days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer-term fatigue severity in ...

4. researchgate.net researchgate.net/publication/368232548_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

Low-dose ketamine infusion for the treatment of multiple ... The secondary and exploratory outcomes (measured four weeks after the second infusion) will show how long the effects of a single infusion last ...

5. nationalmssociety.org nationalmssociety.org/how-you-can-help/get-involved/participate-in-research-studies/participate-in-clinical-trials/ct-ketamine-for-multiple-sclerosis-fatigue

Clinical Trial: Ketamine for MS Fatigue In this study, we aim to show the effect of ketamine on fatigue in 110 people with MS and fatigue, ages 18 to 65.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03500289

NCT03500289 | Ketamine for Treatment of MS Fatigue The primary objective of this study is to determine if modulating glutamatergic transmission with ketamine is safe and efficacious in improving MS-related ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05378100/ketamine-for-multiple-sclerosis-fatigue?q=midazolam

Ketamine for Multiple Sclerosis Fatigue The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in ...