Ketamine: From club drug to antidepressant?
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It’s been theorized that ketamine works by blocking a brain receptor called GluN1-2B-2D. Here, we see one of the many ways the drug’s chemical molecules (yellow) can bind to a specific part (the gray web) of the brain receptor.
view moreCredit: Furukawa lab/CSHL
Ketamine has received a Hollywood makeover. It used to be known as a rave drug (street name special K) and cat anesthetic. However, in recent years, some doctors have prescribed ketamine to treat conditions from post-traumatic stress disorder to depression. “The practice is not without controversy,” notes Cold Spring Harbor Laboratory (CSHL) Professor Hiro Furukawa.
‘Should we give a hallucinogen to patients in compromised mental states?’ wonder ketamine’s skeptics. The controversy came to a head in 2024 following the death of Matthew Perry. The popular TV actor, best known as Chandler on NBC’s Friends, died from a ketamine overdose. One person charged in connection with Perry’s death was the doctor who’d prescribed him ketamine for depression and anxiety.
“Even putting this aside, many questions remain regarding how ketamine affects the brain,” says Furukawa. “It’s been suggested for over a decade that the drug blocks a specific kind of NMDA receptor (NMDAR), called GluN1-2B-2D.” There was one big problem with this theory. Scientists weren’t quite sure that GluN1-2B-2D existed. A new study from the Furukawa lab shines much-needed light on the situation.
In a paper published in the journal Neuron, Furukawa and postdoc Hyunook Kang prove that GluN1-2B-2D does exist in the mammal brain. They then reconstruct a human version of GluN1-2B-2D. They don’t stop there. Using electron cryo-microscopy (cryo-EM), they capture GluN1-2B-2D in action. The neuroscientists identify the tension-and-release mechanism that controls GluN1-2B-2D movements. They can now see how this mysterious NMDAR opens and closes its ion channel pore. And they go another step further. They reveal several ways ketamine may bind to GluN1-2B-2D.
A series of stunningly detailed visualizations show ketamine molecules becoming attached to specific parts of GluN1-2B-2D. “It’s like a mesh,” explains Furukawa. “Over tiny fractions of a second, ketamine can latch onto these sections and close off the channel.” Furukawa and his colleagues captured four binding patterns. However, they believe there are many other ways ketamine can take hold.
It’s thought that ketamine may ease symptoms of depression and anxiety by affecting GluN1-2B-2D movement. But for how long should the channel remain open or closed? “This likely varies per patient,” Furukawa says. Likewise, side effects of ketamine therapy can range from mild hallucinations to full-on psychosis. However, if scientists can determine how GluN1-2B-2D movements affect the brain, they may be able to synthesize new versions of the drug with fewer harmful side effects. That could offer hope for millions of people living with depression and anxiety. So, that’s where Furukawa and his colleagues at CSHL will set their sights next.
GluN1-2B-2D movements [VIDEO] |
This 3D animation, from Cold Spring Harbor Laboratory Professor Hiro Furukawa and postdoc Hyunook Kang, illustrates the tension-and-release mechanism that controls how brain receptor GluN1-2B-2D opens and closes its ion channel pore.
Journal
Neuron
Article Title
Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor
Article Publication Date
14-Feb-2025
Major trial to determine if ketamine can stop deadly epilepsy seizures
University of Virginia Health System
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“We wish to determine whether adding ketamine to existing treatment would terminate status epilepticus in more patients than the current treatment,” said neurologist Jaideep Kapur, MD, PhD, co-director of the University of Virginia’s Brain Institute and an epileptologist (epilepsy expert) at UVA Health and the UVA School of Medicine. “Our hope is that this trial can improve treatment guidelines for patients suffering from these dangerous seizures.”
view moreCredit: UVA Health
University of Virginia Brain Institute and School of Medicine researchers have received an initial $9.3 million award from the National Institutes of Health for a $30 million clinical trial to determine if the powerful anesthetic ketamine can save patients from prolonged, life-threatening grand mal seizures that won’t respond to other treatments.
“Status epilepticus,” as the seizures are known, are seizures that last more than five minutes or that strike repeatedly without the person regaining consciousness between seizures. These ceaseless seizures are considered a medical emergency and can require intubation and lead to permanent brain damage or even death.
The seizures are typically treated with anticonvulsants called benzodiazepines. However, many patients – both adults and children – don’t respond to those drugs.
UVA’s new trial, called the Ketamine add-on therapy for the Established Status Epilepticus Treatment Trial, or KESETT, will evaluate whether adding ketamine to the standard treatment helps improve outcomes for patients suffering status epilepticus.
“We wish to determine whether adding ketamine to existing treatment would terminate status epilepticus in more patients than the current treatment,” said neurologist Jaideep Kapur, MD, PhD, co-director of UVA’s Brain Institute and an epileptologist (epilepsy expert) at UVA Health and the School of Medicine. “Our hope is that this trial can improve treatment guidelines for patients suffering from these dangerous seizures.”
Stopping Status Epilepticus
UVA’s new trial builds on its previous Established Status Epilepticus
Treatment Trial (ESETT), which provided the first definitive answers about how and when three drugs commonly used to treat status epilepticus should be used. Prior to the trial, doctors had little understanding of the drugs’ effectiveness or when each should be deployed. In the end, the researchers determined that the drugs – levetiracetam, fosphenytoin and valproate – were all about equally effective but that they stopped status epilepticus in only about 47% of adult trial participants and 52% of children.
The Brain Institute’s massive new trial seeks to improve those outcomes. The randomized, double-blinded trial will evaluate whether adding 1 mg or 3 mg of ketamine can stop the prolonged seizures in more patients than the existing treatments alone.
In particular, the trial will look at outcomes in children 1 year and older. The researchers expect children ages 1-17 will make up approximately a third of the hundreds of participants they plan to enroll in the trial.
The Potential of Ketamine
The researchers believe ketamine could be beneficial based on recent human studies, extensive drug modeling and other factors, including safety data. While the drug has recently received much attention in the news, emergency physicians have used it safely and effectively as a sedative for decades. It is also a known anti-convulsant.
The trial is expected to take place at approximately 60 sites over the next several years.
“Each year, as many as 160,000 Americans suffer from status epilepticus, and this trial promises to bring new and improved treatment for them,” Kapur said. “The University of Virginia team is grateful for the opportunity to partner with our colleagues at other leading institutions to perform this groundbreaking work.”
Funding for the trial is provided by the NIH’s National Institute of Neurological Disorders and Stroke, grant No. UG3NS131532.
About UVA Brain Institute
UVA’s Brain Institute is an interdisciplinary program that connects researchers across Grounds to tackle some of the biggest and most complex problems in neuroscience for the benefit of society.
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