Ketamine Studied for Relief of Levodopa-associated Involuntary Movements

A Phase 1 trial will test the potential of ketamine — an analgesic medicine used for depression and pain — at reducing the uncontrollable, jerky movements that arise in Parkinson’s disease patients after long-term treatment with levopoda.

Levodopa, probably the most common treatment for Parkinson’s disease, is effective at improving the stiffness and slowness of movement that characterize the disease.

However, up to 40 percent of long-term users eventually experience dyskinesia, which is the uncontrollable and involuntary movements that may be restricted to certain parts of the body, such as head, arms or legs, or affect the whole body.

“The problem is levodopa works great for a few years — we call that the ‘honeymoon’ period — but then you start getting these side effects,” Scott Sherman, MD, PhD, a neurologist at the University of Arizona College of Medicine – Tucson, said in a press release.

The severity of dyskinesia varies among patients, with some experiencing small jerky movements and others being affected by strong, constant bursts. Unfortunately, these side effects go away only after a patient stops taking levodopa.

So, researchers at the University of Arizona will conduct a small Phase 1 clinical trial with 10 Parkinson’s patients to determine the potential of ketamine for rescuing levopoda-induced dyskinesia.

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The trial follows earlier work by Sherman and Torsten Falk, PhD, the scientists leading the study. They were using ketamine to relieve pain in Parkinson’s disease patients when they noticed an unexpected effect — the treatment also reduced the patients’ uncontrolled movements. One patient was actually free of the jerky movements for several weeks.

The same results were seen in animal models, where treatment led to a significant reduction in abnormal involuntary movements. The reduction was sustained for three days, and 10 days passed before baseline involuntary movements returned.

Ketamine increases blood pressure, but may cause a sensation of “out-of-body” experience, also known as dissociation, Sherman said. “When people describe it, they have told me that they feel like they are in fish bowl,” said Sherman. Ketamine actually has been used as a psychedelic recreational drug, Sherman said, adding that researchers have established preventive measures and he is hopeful those side effects will not affect the clinical trial.

“We are going to monitor blood pressure closely to make sure it doesn’t get high,” Sherman said. “And we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson’s disease will stay well below that level.”

Parallel to the Phase 1 trial, researchers will undertake a rodent study to assess the mechanisms underlying the effects of ketamine in the brain.

“We want to find out exactly what ketamine is doing to have this effect,” Sherman added.

Positive results in both the human trial and the animal study could help researchers establish ketamine as a therapy for patients with Parkinson’s disease.

“Ketamine has been long overlooked. Now it could prove very useful for Parkinson’s patients,” Sherman said.

The Phase 1 human and the animal study are both supported by a $750,000 three-year grant from the Arizona Biomedical Research Commission.