Researcher investigates hallucinogen as potential OCD treatment

The first time psychiatrist Carolyn Rodriguez gave an infusion of ketamine to a patient with obsessive-compulsive disorder, she was nervous. After all, while ketamine is approved by the Federal Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse.

“As a physician, you take an oath to do no harm,” said Rodriguez, MD, PhD, an assistant professor of psychiatry and behavioral sciences at the School of Medicine. “There are caveats with ketamine. People can feel disassociated, like they are floating; some feel nauseated.”

But the results simply astonished her.

The patient was a 24-year-old woman who had for years spent eight hours a day checking and rechecking that objects were precisely in place, due to her obsessions with symmetry and exactness. Midway through the 40-minute ketamine infusion, the patient said all obsessive thoughts and urges had suddenly disappeared.

“She was a lovely student who was very debilitated by her OCD,” said Rodriguez, who was an assistant professor at Columbia University at the time of this study of an individual patient, in 2009. “When I gave her the infusion, she was describing what she was feeling. About 20 minutes into the infusion, she just looked at me, eyes wide open, and said, ‘I feel like this weight has been lifted. Like I’m having a vacation from my OCD.’

“It was a very surreal moment. I thought, ‘Is she really saying that?’ I remember my heart was racing. I went back to my lab and said, ‘You will not believe this: It works.’”

Fresh hope

Ketamine has brought fresh hope to a field desperate to find new treatments for hard-to-treat disorders such as severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.

“Severe OCD takes such a toll on patients,” Rodriguez said. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”

Severe OCD takes such a toll on patients.

Over the past 10 years, dozens of small studies have reported remarkable results in the use of ketamine to treat a variety of mood and anxiety disorders. Findings include the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It can cause dissociative side effects — hallucinations and other psychotic-like symptoms — and has been used as a recreational drug. If used regularly, it can lead to dependence. It remains a mystery just how the drug works in the brain, and there are safety concerns about its current off-label use to treat patients. But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.

“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez said. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”

‘Right out of a movie’

Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia University. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.

Rodriguez, intent on searching for better, faster treatment for her patients with OCD, took note. There was an emerging scientific theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she said. Perhaps ketamine could help regulate OCD symptoms as well as depression.

About three years after Rodriguez’s pilot study on the 24-year-old student with OCD, she and colleagues at Columbia published their results from the first clinical trial of ketamine in OCD patients. This trial randomized 15 patients with OCD to ketamine or placebo.

Once again, the effect of ketamine was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. ... This is amazing, unbelievable. This is right out of a movie.”

“Carolyn’s study was quite exciting,” Zarate said, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and PTSD.

“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he said.

Search for a safer drug

Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. But exactly what it does remains unclear.

Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they've been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects from use of the drug.

Ultimately, Rodriguez said, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.

I just don’t like the idea of people being in pain.

Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.

“Ketamine is a complicated drug that works on many different receptor sites,” she said. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”

In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depression-like symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate said.

“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez said.

Rodriguez is also interested in using ketamine as a way to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome their OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.

Relaxation and other techniques also help patients begin to tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.

“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez said. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she said.

Almost a decade after her first ketamine pilot study, Rodriguez remains inspired by the magic of seeing the 24-year-old student’s eyes light up as the drug alleviated OCD symptoms that had caused her years of daily suffering.

“After the study, I was walking her to her taxi to go home,” Rodriguez said. “The side effects of the drug had worn off; she was back to her baseline. I asked what it was like not to have OCD. She said it was the strangest feeling. She could do normal things but without the OCD symptoms. So just the fact that in a matter of hours you can disconnect from OCD makes me a believer.

“I just don’t like the idea of people being in pain,” Rodriguez said. “I want to see science translated into treatments now.”