Ketamine was initially developed as an anesthetic for the battlefield, operating rooms, and veterinary practices. In rave culture, it is a popular recreational drug. But, somewhat recently, scientists have found that it can be used as a very potent therapeutic drug for treating depression — often easing symptoms when no other therapy works.

Ketamine: our secret weapon against depression?

Though ketamine users may actually incur depression if abused, in the right dosage and taken in moderation the drug is a proven remedy for depression. It’s so effective that the positive effects can be felt in a matter of hours and can last weeks, whereas conventional antidepressants take weeks to start working.

For the chronically depressed pondering suicide, those weeks of waiting could mean the difference between life and death. “It blew the doors off what we thought we knew about depression treatment,” says psychiatrist James Murrough at Mount Sinai Hospital in New York City.

Colleen Loo, a professor at the University of New South Wales in Australia, led a team that studied the drug’s effect on people over 60, concluding that depression symptoms were relieved in 43% of the patients. These effects lingered for six months after therapy, the authors reported in the American Journal of Geriatric Psychiatry.

The largest trial on ketamine’s antidepressant effects was conducted in 2013 with 73 participants. Mere 24 hours after the first treatment, ketamine proved to reduce depression symptoms in 64% of patients who had tried three or more other medications with unsuccessful results. Oth\er studies have confirmed the findings. “Feeling better faster, getting the mood to improve faster — that’s why ketamine is very promising,” said Alan Manevitz, MD.

Ketamine is considered by many psychiatrists as the only treatment for rapid relief of suicidal thoughts in depressed patients. In 2017, Michael Grunebaum, a psychiatrist at Columbia University Medical Center, performed a study involving 80 patients who were diagnosed with “clinically significant suicidal thoughts.”

The researchers administered the patients either a low dose of ketamine or a sedative called midazolam. Compared to the midazolam group, the patients who were given the ketamine showed a marked reduction in suicidal thoughts only 24 hours after the drug was administered — and this effect lingered on for six weeks after the single low-dose treatment. The ketamine group also reported an improvement in mood, as well as depression and fatigue symptoms, indicating that ketamine has a broad effect on psychiatric well-being.

How ketamine works to treat depression

There are two main types of ketamine used to treat depression in a clinical setting. One is racemic ketamine, which is a mixture of two mirror ketamine molecules (“R” and “S” ketamine). Most studies that investigate the therapeutic effects of ketamine for depression use the racemic variety, which is usually administered intravenously. The other type is esketamine, also known as Spravato — it was recently approved by the FDA in the United States and is given as a nasal spray. Esketamine only employs the “S” molecule.

The two forms of ketamine interact slightly differently with receptors in the brain and may cause different side effects. The rest of this article will focus on the effects of racemic ketamine, since it is more widely established in research.

Scientists are still figuring out how ketamine molecules interact with receptors in the brain to ease clinical depression symptoms. Studies suggest that ketamine binds to NMDA receptors in the brain, thereby increasing the amount of the neurotransmitter glutamate in between neurons. Glutamate increases the connections in another receptor, known as the AMPA receptor. This cascade effect ultimately causes the brain to release other molecules that help neurons communicate with each other along new pathways, affecting mood and cognition.

Dr. Conor Liston, a neuroscientist and psychiatrist at Weill Cornell Medicine in New York, published a 2019 study that showed ketamine triggers brain circuitry repair in a two-step process. In the study, the researchers used a virus activated by a laser microscope to destroy synapses in the brains of mice, mimicking the effect of chronic stress. The findings showed that in only six hours after a dose of ketamine, brain circuits damaged by depression started firing together again in sync. The mice also started exhibiting normal behavior in this time period. 

This study might also explain why ketamine’s antidepressant effects wear off eventually — if the synaptic changes cannot be maintained, there will be a relapse.

A study led by Hailan Hu, a neuroscientist at Zhejiang University School of Medicine in Hangzhou, China, found that ketamine may interact with the lateral habenula, a small region of the brain known as the “anti-reward center.” Neurons in the lateral habenula are activated by stimuli associated with unpleasant events, like the absence of the reward or punishment, especially when these are unpredictable.

In rodents with depression, neurons in the lateral habenula fire several times in quick bursts, rather than firing once at regular intervals in the case of healthy rats. An analysis of brain slices of healthy rats showed that they only had about 7% of these bursting type of neurons, in comparison to the depressed rodents that had almost 23% bursting neurons. But after the mice and rats were given ketamine, the number of bursting neurons became similar to those found in healthy animals. Even when the scientists directed the neurons to fire in bursts, animals that had been administered ketamine no longer exhibited symptoms of depression.

Daniel Lodge, Ph.D., of The University of Texas Health Science Center at San Antonio, found that ketamine activates the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in rats. Artificially stimulating this pathway mimics the anti-depressant effects of ketamine, whereas preventing activation of the circuit eliminates the antidepressant-like effects of ketamine.

Ketamine side effects

Whether administered orally, intravenously or nasally, ketamine produces several side effects. Some include headache, dizziness, dissociation, elevated blood pressure and blurred vision.

Previously, studies have linked the long-term use of ketamine to bladder inflammation, liver damage, cognitive changes like memory loss, and craving or addiction.

Regarding addiction to ketamine, only 15 cases have been officially described in the scientific literature over the last 20 years. Does this mean that ketamine isn’t addictive? That’s the problem: we don’t know that much yet, which is why researchers in the field claim that more studies specifically geared towards assessing the safety of dosing regimes for ketamine are urgently needed. Scientists can’t seem to cause ketamine addiction in rodents, which is one of the other reasons why it’s so challenging to study.

But by understanding how ketamine interacts with the brain — which we are only beginning to comprehend — is that it’s possible to design a new molecule that only has ketamine’s antidepressive effects without its potentially addictive side effects. Some researchers, like Lodge’s group at the University of Texas Health Science Center at San Antonio, are already working on finding a drug that interacts selectively with the ketamine-brain pathways.

“The idea is, if one part of the brain contributes to the beneficial effects of ketamine, and another part contributes to its abuse and effects such as hallucinations, now we can come up with medications to target the good part and not the bad,” Flavia R. Carreno, an assistant professor at University of Texas San Antonio, said in a statement.

“We’re working on testing compounds that more selectively target the hippocampus and we and others actually found and published that such compounds recapitulate the beneficial effects of ketamine without the abuse liability, without the psychotomimetic effects,” Carreno told ZME Science.

Is ketamine a miracle drug that can promise to ease even the worst depression? It’s difficult to draw any conclusion at this point, and research still has a long way to go. And while results so far are promising, ketamine’s side effects and its potential for abuse are poorly understood — and this is very problematic considering that there are now many people who are seeking ketamine treatments on their own.

In the United States, particularly in California, a number of clinics are already offering ketamine infusions. Anecdotal reports suggest they succeed in reducing depression symptoms among hard-case patients, who pay top dollar for an otherwise generic and cheaply sourced substance. For depression, the price per infusion ranges from $400 to $1000.

A number of clinicians and medical organizations, however, have raised serious concerns about the lack of regulatory or legislative oversight. “It scares the hell out of me that this is still unregulated,” said Steve Levine, MD, a psychiatrist who also is the founder of a clinic that offers ketamine infusions.

In an article published online in Lancet Psychiatry, researchers called for better oversight.

“We find that, based on current evidence, ketamine use for severe, treatment-resistant depression does not violate ethical principles,” they write.

“However, clinicians and professional bodies must take steps to ensure that guidelines for good practice are enacted, that all experimental and trial data are made available through national registries, and that the risk potential of ketamine treatment continues to be monitored and modeled.”