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BUFFALO, N.Y. — In recent years, ketamine — long known for its misuse as a psychedelic party drug — has become a “life-saving” medicine for people battling major depression. Patients praise the drug for producing fast and long-lasting results in low doses. Now, researchers at the University of Buffalo have unlocked the mystery behind ketamine’s effects on the brain at various doses, along with its tremendous impact on mental health.
Their study, published in Molecular Psychiatry, describes where and what receptor ketamine binds to in the brain to provide its anti-depressant effects in as little as a few hours. The research also sheds light on how depression develops in the brain and the potential for other psychedelics to help with other brain conditions.
From Party Drug to Depression Treatment: Ketamine’s Evolution
Ketamine has an interesting history. It first started in the 1960s when doctors used it as an anesthetic. However, ketamine enhances the senses and can make someone experience hallucinations and a feeling of being disconnected from the body at higher doses. This potential for abuse gave ketamine a bad reputation as more people experienced ketamine abuse, and variations of it started showing up as a popular party drug.
Then, in the 2000s, researchers showed evidence of low doses of ketamine quickly relieving symptoms of major depression and suicidal thoughts. Traditional antidepressants take months for people to feel the effects—time that people with suicidal ideation may use to act on their thoughts. Ketamine almost instantly silences those suicidal thoughts, and its antidepressant action can last for several days and up to a week. There are now ketamine clinics nationwide where the drug is given intravenously to treat depression.
Like a lock and key, ketamine binds to the brain via N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are all over the brain and are essential in maintaining consciousness. The study came about from an observation by Sheila Gupta, a UB undergraduate at the time who would go on to co-author the paper.
“Sheila noticed that when applied onto NMDA receptors that were chronically active, ketamine had a stronger inhibitory effect than expected based on the literature,” says Dr. Gabriela K. Popescu, a professor of biochemistry at the University of Buffalo and senior study author, in a press release. “We were curious about this discrepancy.”
A Surprising Scientific Discovery
The study showed that low-dose ketamine alters the activity of certain NMDA receptors, which could contribute to its hallucinatory effects. It’s also the reason drugs that affect all NMDA receptors produce severely harmful psychiatric side effects that distort a person’s reality.
The Buffalo team’s observation was unusual, considering past research into ketamine’s effects on the brain. Years ago, scientists added ketamine to NMDA receptors to study the anesthetic’s antidepressant effect. The drug made little difference.
“This observation caused many experts to turn their attention to receptors located outside synapses, which might be mediating ketamine’s antidepressive effects,” Popescu explains. The discovery prompted the team to look for other mechanisms than a direct current block, which many scientists assume is how ketamine exerts its effect on the brain.
“Because we track activity from a single receptor molecule over an extended period of time, we can chart the entire behavioral repertoire of each receptor and can identify which part of the process is altered when the receptor binds a drug or when it harbors a mutation,” Popescu adds.
At low doses, the authors found ketamine does not work on the main current but currents already activated in the background. It did not affect synaptic receptors, which only activate in short electrical bursts.
“This results in an immediate increase in excitatory transmission, which in turn lifts depressive symptoms,” says Popescu. “Moreover, the increase in excitation initiates the formation of new or stronger synapses, which serve to maintain higher excitatory levels even after ketamine has cleared from the body, thus accounting for the long-term relief observed in patients.”
When you give a little ketamine, it plugs up two spots on NMDA receptors. The binding slows down extra-synaptic receptors to relieve depression symptoms. The areas where ketamine binds to the receptor can only hold so much, so higher doses of ketamine cause a spillage from the area and into the pore, blocking synaptic currents and creating an anesthetic effect.
Understanding Ketamine’s Dual Action
A 3D model of the NMDA receptor was created to help researchers predict where ketamine would bind. “The simulations show that at high concentrations, which is how it is used as an anesthetic, ketamine indeed lodges itself in the central ion-conducting pore of the receptors, where it stops ionic current from flowing through the receptor,” says Popescu.
Meanwhile, ketamine acts differently at low amounts. It binds itself to two symmetrical sites on the side of the pore. The action does not block the current but slows receptors down, so the current is only slightly inhibited.
According to Popescu, finding the exact site where ketamine attaches to the NMDA receptor can help in finding drugs that work in a similar manner. The next step is to identify these drugs and see if they work as well as ketamine without causing potential addiction.
Paper Summary
Methodology
The researchers used a combination of laboratory techniques to study ketamine’s effects on NMDA receptors. They performed whole-cell recordings to measure electrical currents through these receptors in cells, used molecular modeling to predict where ketamine might bind, and conducted single-channel recordings to examine how individual receptors behaved. They tested different concentrations of ketamine and its enantiomers, ranging from 0.002 to 10 microMolar, and examined how various mutations in the receptor affected ketamine’s ability to reduce receptor activity.
Results
The study revealed that ketamine has two distinct effects on NMDA receptors. At higher concentrations (micromolar range), it blocks the receptor’s central pore. At lower concentrations (nanomolar range), it binds to a previously unknown site on the side of the receptor, causing the receptor to become less active through a different mechanism. The R(+) form of ketamine showed stronger interactions with this side site than the S(-) form, and mutations of specific amino acids in this region affected ketamine’s ability to reduce receptor activity at low concentrations.
Limitations
The study was conducted using isolated cells and purified proteins, which may not fully represent how ketamine works in the complex environment of the human brain. The researchers also note that ketamine’s effects can vary depending on factors like pH, membrane composition, and voltage, which could affect its clinical effectiveness in different patients or brain regions.
Discussion and Takeaways
This research provides a molecular explanation for why ketamine’s antidepressant effects occur at lower doses than its anesthetic effects and why similar drugs don’t work as antidepressants. The discovery of a new binding site could lead to the development of more targeted treatments for depression and other neurological conditions. The findings also help explain why ketamine’s effects might vary between individuals based on factors like brain pH and cell membrane composition.
Funding and Disclosures
The research was funded by multiple National Institutes of Health grants (R35NS132248, R01MH118298, and R01NS108750). The authors declared no competing interests.
