Could Party Drug Ketamine Be a Treatment for Depression?

Anne McNealis tried at least a dozen medications to manage her depression before turning to ketamine. Prozac, Paxil, Zoloft, Cymbalta – you name it, she’s used it. But McNealis couldn’t tolerate those conventional treatments, she says. She has struggled with severe depression for about 20 years and even on medication, she still woke up every morning wishing she hadn’t.

Two years ago, McNealis decided to enroll in a ketamine clinic at a Kaiser Permanente facility in San Francisco to see if the experimental treatment could achieve something conventional medicine could not. The national healthcare network launched one of the first pilot programs to use the street drug ketamine to help people with severe treatment-resistant depression. McNealis attributes ketamine with saving her life.

“It’s been a return to some normalcy,” she tells Rolling Stone. “I feel like a normal person again.”

Last Thursday, McNealis joined Dr. Mason Turner, Kaiser Permanente’s chief of the Department of Psychiatry, at the Mental Health America Conference in Washington, D.C., to discuss the organization’s success with ketamine treatment. According to Turner, data has shown that about 65 to 75 percent of the clinic’s patients with severe depression are improving on ketamine, which he says is “much higher than typical, traditional antidepressants” in the treatment-resistant population.

“We really believe that ketamine has saved lives because a lot of patients have had unrelenting, chronic suicidal thoughts for most of their lives,” Turner says.

But what does ketamine exactly mean for people diagnosed with depression? Here’s everything you need to know.

What is ketamine?
Ketamine, also known as Special K, is a popular party drug that creates a dissociative, dream-like state and cause hallucinations. People who use ketamine experience a rapid high that causes them to feel detached from their environment and their physical body, similar to an out-of-body experience. Ketamine also impairs motor function, which has led some assailants use the odorless, colorless substance in drug-facilitated sexual assault.

Ketamine can be snorted, taken orally, sprayed into the sinus cavities or injected. Many clinics, such as the one run by Kaiser Permanente, deliver a low-dose of ketamine through an intravenous infusion, a process that can last nearly an hour, according to the American Psychiatric Association (APA).

In 1970, the U.S. Food and Drug Administration approved ketamine for use as an anesthetic and sedative during the Vietnam War. But the FDA has yet to give ketamine the green light for treatment as an antidepressant, which means anyone using the substance is doing it off-label and footing the bill.

What are ketamine’s effects on the brain?
Ketamine limits production of glutamate, a neurotransmitter responsible for processing information and communications between the body and the conscious brain. Researchers believe this is what causes ketamine users to feel disconnected from their surroundings and less sensitive to physical pain – proving the substance to be an effective anesthetic.

Animal studies have also shown that ketamine causes nerve cells to produce more brain-derived neurotrophic factor (BDNF) – a protein important to brain function and development. It also brings about the fast outgrowth of dendritic spines, or small protrusions in the neuron that help carry electrical signals and store synaptic strength. According to Dr. Rupert McShane, new connections can occur at the synapses on the sprouting dendritic spine, which helps neuronal processing.

“Think of a neuron as a tree,” says McShane, a consultant psychiatrist who leads the ketamine treatment program at Oxford Health NHS Foundation Trust (OHFT) in the United Kingdom. “In the winter of depression, things retract and our thinking is less rich. When spring comes, the tree buds. Ketamine stimulates the production of a nourishing fertilizer and budding.”

How does ketamine help people with treatment-resistant depression?
Scientists don’t know how ketamine affects the brain as an antidepressant exactly, though some research gives them a rough idea. Studies have found that ketamine can reduce functional connectivity of the subgenual anterior cingulate cortex, a collar-like region near the front of the brain that’s connected to the prefrontal and frontal cortexes. The unique position of the anterior cingulate cortex allows it to control emotion, impulse control, decision-making and reward anticipation. Research suggests ketamine decreases “the ‘over-wiredness’ of the emotional regulation area,” McShane says. In other words: Severely depressed people on ketamine may feel relief from repetitive thoughts of worthless and inadequacy.

McNealis left Kaiser Permanente’s program in February, but says the effects of ketamine have been long lasting. She hasn’t felt the need for an infusion since ending treatment months ago.

“It has been life-changing for me,” she tells Rolling Stone.

But McNealis may be an exception and not the rule; according to McShane, many people with treatment-resistant severe depression only experience brief relief, meaning an increase in ketamine dosage is often needed for a longer-lasting effect. “It does not cure the ruminative ‘ruts.’ They are still there when the effect wears off,” he says.

Still, the rapid relief brought on by ketamine may also be useful in patients with suicidal ideation. According to Turner, about a third of patients who didn’t respond to ketamine treatment in the first cohort did notice a decrease in suicidal thinking. “So there’s an independent action with suicidal thoughts, which can be very important that we need to learn more about,” Turner says.

How is recreational use different from ketamine treatment?
The positive results so far doesn’t mean a person with severe depression should use ketamine as a treatment tool outside of a clinical setting. Ketamine has addictive properties, so there is some risk for long-term substance abuse, says Dr. Gerard Sanacora, professor of psychiatry at Yale University School of Medicine and director of the Yale Depression Research Program, which offers ketamine clinically. Sanacora also notes that ketamine can lead to some “unpleasant and odd experiences that can be troublesome to some patients,” so it’s necessary for people interested in treatment to be monitored by a doctor.

To that end, research has found that ketamine can induce hallucinations, delusions, social withdrawal and cognitive problems in drug abusers. The substance also may not be beneficial to all mental illnesses; according to Turner, the Kaiser Permanente clinic doesn’t administer ketamine to people with psychotic conditions such as schizophrenia because they may have a negative reaction to its dissociative effect. “Nor is there any evidence that it actually helps those patients,” he adds.

What are the side effects?
Side effects of ketamine vary by dose. The National Institute on Drug Abuse (NIDA) lists mood and behavior numbness, confusion, dizziness, disorientation, loss of coordination, nausea, vomiting, loss of appetite, and short-lived hallucinations among the short-term effects of low to moderate doses. According to Drugs.com, these common side effects are also associated with ketamine when its used as an anesthetic.

High doses, on the other hand, can trigger potentially life-threatening side effects. People who’ve taken a significant amount of ketamine may experience extreme panic, fear, anxiety, paranoia and aggression, as well as feeling that they’re immune to damage. Their heart beat, respiratory rate, blood pressure, and body temperature may also elevate or decrease to dangerous levels, according to the NIDA. Mixed with alcohol, and these side effects can prove deadly.

Where does research go from here?
The FDA granted intranasal esketamine a breakthrough therapy designation twice in the last four years – first in November 2013 for treatment-resistant depression, then again in August 2016 for severe depression with imminent risk of suicide. The designation helps speed up development of the ketamine-based drug, which is undergoing a phase III trial. According to the National Institutes of Health, more than 90 clinical trials studying ketamine’s antidepressant properties are either underway or have completed.

Although anecdotal evidence has shown that ketamine can benefit people with treatment-resistant severe depression, experts believe more research needs to be done to understands its full potential and risks. “We don’t know what the optimal dose is, how frequently we should be giving this. We don’t know how long to be giving it for,” Sanacora tells Rolling Stone. “Those are the type of questions that need to be addressed.”

Earlier this year, the APA task force released a consensus statement in JAMA Psychiatry that acknowledged ketamine’s effects on depression and other mood disorders, but also noted its limited data concerning its effectiveness and safety. The APA advised that doctors remain cognizant of the lack of information when weighing whether or not ketamine is the best treatment option for their patient. Sanacora, McShane and other psychiatrists have even suggested developing a registry of ketamine patients to capture relevant data about use, benefits and side effects.

“It’s potentially one of the most interesting new treatments to be developed in the treatment of depression in decades and it holds great promise,” says Sanacora, the lead author of the APA report. “But we have to keep our eyes open to the potential risk and the fact that we still really aren’t sure how to use this drug in the long-term.”