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Ketamine, Glutamate, and Better Mental Health (And a Lesson in Neurotransmitters)

Ketamine may be one of the most talked-about new antidepressants in decades. It seems to do things that no other drug can do, leading to rapid responses even in people who have never responded to anything else.

But Ketamine isn't a panacea. It has significant risks, and the dose, timing, and route of administration are still being worked on. But it offers hope that simply wasn’t there before.


So how does Ketamine work? To answer that, we have to talk a bit about neurotransmitters.


Synapses, Neurotransmitters, Receptors — Oh My


Synapses are the tiny gaps between nerves where chemicals are released. As those chemicals cross over this gap, they carry information and instruction from one nerve to the next — like telling a nerve to switch on or switch off.


These chemicals are neurotransmitters, since they transmit information between nerves, and they allow us to think, feel, and act.


When a neurotransmitter crosses a synapse, it binds to a specific receptor. These have a part sticking outside of the nerve, and a part inside of the nerve, so they get to play in both spaces. Around the nerve cell is a barrier, called the cell membrane, which stops most things coming in and out. The receptors act like a gate that is designed to let only one thing through. And it only opens in very specific circumstances.


Receptor binding is key, and the way that it grabs hold of the neurotransmitter and then makes something happen in the cell can be likened to a game.


Like A Game of Catch


Imagine you’re playing a game where you are kneeling on the grass in front of a tennis net. In your left hand you hold a white tennis ball. When your friend throws a green tennis ball you catch it in your right hand. In this example your right hand is stuck up, so it is above the top of the net (which represents the cell membrane), and as soon as you catch it you drop the white ball that you were holding in the left hand (which represents things happening inside the cell).


Key to understanding is that you can only catch green tennis balls. If they are red, grey, white, or any other colour, you cannot catch them. Your catching hand is very specific for this colour. This is similar to receptors, which will only catch one type of chemical, even if others are similar.


Most of the time a single receptor is enough to have an impact, but occasionally they act together. It’s like you decide to use both hands to catch a larger ball to make sure you don’t drop it. This two-handed catch sometimes occurs when two receptors have to work together. And it may be what makes the effects of psychedelics so powerful: they impact two receptors at the same time. The two receptors are a particular combination of serotonin and glutamate receptors, and this action may underlie some of the key differences between psychedelics and other drugs.


Within the human nervous system there are at least fifty different neurotransmitters, but the most well-known are serotonin, noradrenaline (called norepinephrine in the US), and glutamate.


I’m So Excited — Glutamate


Glutamate is responsible for over 90 percent of excitement in the brain. I’m not talking about a child’s excitement on Christmas morning or the excitement you feel when you hit the jackpot.


Glutamate excites the nerves. When nerves are switched on or activated, we say that the nerve has been excited, and usually what has excited the nerve is glutamate. When you move your fingers that’s glutamate in action. Same for breathing in, or even blinking!


Glutamate and Mental Health


Since glutamate is so prevalent in the brain, it makes sense that it is involved in so many areas of mental health. Despite its important role in many brain activities, altering glutamate has not proved so far to be effective in the treatment of mood disorders and depression. That is, until recently.


Ketamine was the first compound to usher in the psychedelic era and has been called the most important breakthrough in antidepressant treatment in decades. And Ketamine acts mainly on glutamate. It may also impact other receptors including, but not limited to, serotonin and noradrenaline (norepinephrine). This mixed picture may be what makes Ketamine unique.


It’s now widely available. Many clinics offer it for the treatment of depression. Used carefully under medical supervision it can be transformational. Research is beginning to show that its clinical benefits can be enhanced by appropriate psychotherapy, but there’s more work to be done to determine the most effective approaches.


But remember that I said it isn’t a panacea and it has significant risks? You can learn more about those risks, as well as the benefits, in my soon-to-be-released book: The Promise of Psychedelics, Science Based Hope for Better Mental Health.




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