US-based organic chemist Dr Calvin Lee Stevens discovered ketamine in the 1960s but it was only more recently that it was seriously considered as a tool to help treat mental health disorders.

Named because of the ketone and the amine group in its chemical structure, it’s known as a dissociative anaesthetic because it produces a trance-like state when used as an anaesthetic.

After its discovery, it became particularly useful in the Vietnam War because it could be given to wounded soldiers as an analgesic – or pain reliever – without the need for oxygen support.

As an anaesthetic, it’s often the preferred choice for short-term procedures because it’s vasoconstrictive, meaning it doesn’t supress breathing as much as other anaesthetics, making it much safer to use – particularly especially in paediatric medicine.

However, like all drugs, it does carry risks – especially when used at anaesthetic levels. At high doses, ketamine may have a psychotomimetic reaction – which is like slipping into a psychotic state, where some patients have experienced severe hallucinations or delusions.

After the Vietnam War, an interesting trend started to emerge – veterans who received ketamine were statistically less likely to develop post-traumatic stress disorder.

Studies later found that ketamine creates a chemical cascade in the brain that nurtures a rich environment for cells – they become bigger and more communicative, growing new receptors and sprouting new and more complex connections.

However, during the post-war era, social stigma eroded the public perception of ketamine as substance misuse became associated with the party scene.

Throughout this period, ketamine continued to provide promising outcomes in depressed patients who received ketamine for anaesthetic purposes. However, it has taken a while for research to investigate its use as a tool for improving mental health outcomes.

That is starting to change. In 2019, the US’s Federal Drug Administration approved the use of low-dose intranasal ketamine as a treatment for treatment-resistant depression and suicidality.

But here in Australia more research needs to be done.

At the start of 2021, our colleagues at UniSC’s Thompson Institute published a pilot study investigating low-dose oral ketamine as a treatment for chronic suicidality. When we say low dose, we mean participants received about 1/5 of what they would receive at anaesthetic levels.

In our colleagues’ study, over a six-week period, 69 percent of respondents reported positive behavioural changes, meaning they went from experiencing a high level of suicidal ideation to none.

While there is no clear cure for chronic suicidality, our findings suggest ketamine may provide a viable treatment option.

This is very encouraging, particularly due to other potential benefits of low-dose ketamine treatment when compared to conventional antidepressants and anti-anxiety medication:

• it’s rapid acting, taking between days and weeks to relieve depressive symptoms, rather than months for conventional antidepressants; and
• side effects are transient, with symptoms typically reducing within days post-treatment.

These alone makes ketamine very novel or, in other words, unique.

Building on our original study, we assessed changes in brain structure following six weeks of the ketamine treatment to figure out why participants might experience improved behavioural outcomes.

What we found was fascinating – grey matter volume, in areas of the brain associated with suicidality, appeared to increase in size over the trial period, effectively mirroring what a healthier brain looks like.

Let us back up a bit before we go on – the brain is made up of white and grey matter. White matter is all the connective parts of the brain, responsible for communicating between brain regions and the rest of the body. Grey matter is the brain tissue – or cell bodies – responsible for the actual processing of information, including emotion regulation, memory, and motor movement.

In people experiencing chronic suicidality, grey matter in certain brain regions tends to be shrunken or atrophied. Areas such as the striatum, nucleus accumbens, thalamus and periaqueductal grey, have been associated with suicidality and depression.

But our analyses showed that after six-weeks of low-dose ketamine treatment, these atrophied grey matter regions had actually grown – regardless of whether or not participants had reported a reduction in suicidality.

What’s unique about our findings, is the suggestion that ketamine can promote neurogenesis (or the creation of new neurons), in the striatum – an area associated with goal-directed behaviours and reward processing in depression.

This type of finding – where ketamine is able to help create new cells in the striatum – has only been discovered once in animal models, but not yet in humans.

Besides that, there is not a lot of research on low-dose oral ketamine treatment. Most relates to administering it intravenously or intranasally, making this research novel.

This whole field of research is still growing, which makes it an exciting space to work in – especially for early career researchers. We’re looking forward to playing a part in that journey.