Ketamine: A New Psychedelic Treatment

I’ve been working in the area of mental health treatment and neuroscience for over 35 years, and I now believe that we’re on the cusp of a therapeutic revolution in treatment because of psychedelics. One of these, ketamine, is legally available and may be one of the most talked-about new antidepressants in decades. In some patients with depression who have never responded to anything else, it leads to a rapid response.

But ketamine isn't a panacea. It has significant risks, and the best dose, timing, and individual route of administration are still being worked on. But it offers hope that simply wasn’t there before. And like all psychedelics, outcomes are much better when combined with appropriate therapy. So how does ketamine work, and why is it unique?

Synapses, Neurotransmitters, and Receptors

Synapses are the tiny gaps between nerves where chemical messengers are released. As those chemicals cross over this gap, they carry information and instruction from one nerve to the next, such as telling a nerve to switch on. These chemical messengers are called neurotransmitters since they transmit information between nerves, and they are what 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 chemicals from coming in and out. The receptors act like a gate that is designed to let only one specific type of chemical through. And it only opens in very specific circumstances, after the receptor binds to its specific neurotransmitter. Within the human nervous system, there are at least fifty different neurotransmitters, but some of the most well-known are serotonin, norepinephrine, and glutamate.

I’m So Excited

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 the neurotransmitter which has excited the nerve is glutamate. When you move your hand to move to the next page, blink, or stand up, it is glutamate that is involved.

There are different types of glutamate receptors, but the one that ketamine works most on is the NMDA receptor, while also having some action on another type, the AMPA receptor. It may also have some impact on other types of neurotransmitters as well. This mixed effect could be what makes ketamine so unusual. This mechanism of action is quite different from more typical antidepressants which are thought to work by primarily impacting the serotonin or norepinephrine systems. Ketamine’s effect on glutamate is also very different from the way other psychedelics work.

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 the treatment of depression in decades.

More specifically, the glutamate surge caused by ketamine may result in an increase of brain-derived neurotrophic factor (BDNF), which is thought to specifically increase nerve connectivity and which may be closely associated with ketamine’s antidepressant activity.

Why Are There No Other Drugs Like Ketamine?

A number of ketamine-like drugs have been developed, but it may be difficult to find something that is not problematic. For example, ketamine was originally developed as a replacement for PCP (phenylcyclohexyl piperidine, known as “angel dust”). PCP is chemically similar to ketamine but has a wider range of impacts on different neurotransmitter systems. The effects of PCP can be very varied, and some individuals still use it because it can also lead to euphoria, depersonalization, and a range of hallucinatory experiences. Unfortunately, it can also cause hallucinations, psychotic thoughts, violent behaviour, addiction, and in higher doses it can lead to death.

PCP illustrates the difficulty of finding similar drugs to ketamine that have clinical benefits without significant unintended negative consequences, and this risk of bad outcomes could occur with new ketamine-like drugs, although research continues.

Ketamine Clinics Are Increasingly Available

The good news is that ketamine is increasingly available. Many clinics offer it for the treatment of depression and some other conditions. Used carefully under medical supervision it can be transformational, particularly when combined with appropriate therapy. While some clinics offer ketamine without therapy, this is less effective, so always look for clinics that offer both together.

But remember that I said ketamine isn’t a panacea and has significant risks? One problem with ketamine is that even in responders, this tends to wear off after a few weeks, so longer-term treatment may be needed. You can learn more about those risks, as well as the benefits, in my book: The Promise of Psychedelics, Science-Based Hope for Better Mental Health.