Ketamine is the only FDA-approved “psychedelic.” Research suggests it’s an effective medication for treatment-resistant depression, which doesn’t respond to traditional therapies like SSRIs. But the applications for ketamine could go beyond depression — it might even save lives.

What’s new — A fresh analysis, published Thursday in the British Journal of Psychiatry Open, uncovers the unique potential for ketamine as a treatment for other mental health issues than solely depression, including suicidality.

“People have reviewed the effects on depression and bipolar disorder, but ketamine is beginning to be used for a wider range of psychiatric disorders, so we thought this would be an important time to review the current picture of the evidence so that we can inform treatment providers,” Celia Morgan, a professor of Pharmacology at the University of Exeter and one of the authors of the review, tells Inverse.

Altogether, the data included in this review suggest ketamine is an effective treatment for depression and bipolar disorder. And ketamine reduced suicidal thoughts to a significant degree in some people, independent of its antidepressant effects.

What ketamine does to the brain

Ketamine affects the neurotransmitter glutamate. Neurotransmitters do precisely what the name suggests — they communicate signals between brain cells called neurons. Glutamate is abundant in the brain — some estimates suggest it is the transmitter stationed at 40 percent of all the connections — called synapses — between neurons.

Glutamate is also associated with neuroplasticity — the brain’s ability to forge new networks and communication highways. One way it does this is by helping to develop new connections between neurons when you learn something or form a memory.

Studies suggest ketamine stimulates glutamate production and may help repair the broken connections in the brain, especially broken connections running between neurons in the prefrontal cortex and the hippocampus. The prefrontal cortex controls cognitive skills like attention, focus, and flexible thinking, while the hippocampus governs learning and memory.

When a person is chronically stressed or depressed, it can affect critical connective points between neurons in these regions, called dendrites — these are like spines stemming from brain cells. Research indicates ketamine facilitates the growth of dendrites — at least in mice. The same may be true in humans, and it is part of the theory backing ketamine as a treatment for brain conditions like depression.

“A drug that works across different mental health problems would be really useful.”

How they did it — In the new review, the scientists analyzed the results of 83 peer-reviewed, published research papers on ketamine as a treatment for various mental health problems. The analysis includes 33 systematic reviews, 29 randomized control trials, and 21 observational studies.

From these papers, the most robust evidence for ketamine’s therapeutic potential is for people with depression or bipolar disorder. But ketamine also appears to produce a stark reduction in suicidal ideation. Interestingly, it seems ketamine tamps down suicidal thoughts independently of its antidepressant effects.

They also found evidence that ketamine can lead to short-term reductions in cravings and withdrawal symptoms for individuals with substance use disorders.

Many of the studies in this review are small — larger, randomized controlled trials need to be done to draw firm conclusions about ketamine’s potential beyond depression, bipolar disorder, and suicidality. But the early evidence suggests it may be an effective treatment for post-traumatic stress disorders, anxiety disorders, and obsessive-compulsive disorders, too.

Why it matters — What all this tells us is that ketamine may work where other treatments don’t, and it works fast.

Traditional SSRIs can take four to six weeks to work, and it can take months to feel the drug’s full effect — the differences with ketamine were much more rapid. The researchers found that symptoms associated with depression and bipolar reduced as quickly as one to four hours after a single dose. Even more encouragingly, the reductions lasted up to two weeks. In the case of suicidality, a drop was seen four hours post-treatment and lasted up to a week.

That ketamine reduces suicidal thought across various conditions is especially interesting, Morgan says, and could have some critical clinical applications.

“It is a really interesting effect that when we parse out effects on depressive symptoms, there is still evidence of a reduction in suicide,” Morgan says.

“This is important because suicide is not just seen in depression but across mental health diagnoses, particularly for example in schizophrenia and substance use disorders,” she adds.

She believes a drug that can reduce suicidal thoughts regardless of diagnosis would be a boon for emergency settings.

“Typically, when people come to emergency rooms following suicide attempts we often don’t know what their diagnosis is, so a drug that works across different mental health problems would be really useful,” Morgan says.

What’s next — For her part, Morgan was surprised by the lack of research into ketamine as a treatment for another mental health issue — eating disorders. But a few studies are currently underway that might provide some insight, she says.

“I think giving ketamine for eating disorders holds a lot of promise, so in some ways, it is surprising that there is little research here,” she explains.

“But it is very difficult to run trials in people with eating disorders — particularly restricting type anorexia where we see the highest mortality rate of any mental health problem — recruitment of volunteers is challenging,” she says.

In the future, Morgan says we need a better idea of who responds well to ketamine treatments and who doesn’t — that will give doctors a better understanding of when to prescribe such treatments.

“It doesn’t work for everyone,” Morgan says. “Because of the strong promise of this new treatment approach, not responding [to the drug] can leave people feeling even more hopeless. So if we can tell who it will and won’t work for, that will be really useful.”

If you are in crisis, please call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255), or contact the Crisis Text Line by texting TALK to 741741

Abstract:

Background: In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine’s therapeutic effects for a range of psychiatric conditions.

Aims: In light of these findings surrounding ketamine’s psychotherapeutic potential, we systematically review the extant evidence on ketamine’s effects in treating mental health disorders.

Method: The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist.

Results: We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis.

Conclusions: Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.