'Nothing less than transformational:' Ketamine brings relief to people with severe depression

Ketamine gave Rachel Morgan her life back.

The 33 year old has struggled to beat back severe depression and post-traumatic stress disorder for much of her life. She's tried more than 30 psychiatric medications, none of which helped. Her inner pain reached a level so unbearable that she retreated from the world. She stayed in bed. She stopped doing the dishes and taking out the trash, which piled up in her San Francisco apartment. She stopped socializing.

She lost the will to live.

"I had gotten to a point where I disappeared, mentally and physically," Morgan said. "My psychiatrist kind of put his hands up in the air and said, 'There's nothing else I can do for you.'"

But he did suggest something different she could try, albeit not through him: ketamine. The only legally available psychedelic in the U.S., the drug is widely used as an anesthetic in hospitals and medical settings. But it has been found to give people with severe mood disorders, including treatment-resistant depression and suicidal ideation, almost unbelievably fast-acting relief from their symptoms — some with a single dose, though more commonly it takes several treatments.

Morgan received her first ketamine infusion in a Palo Alto psychiatry clinic in June. By her second treatment, she took out the trash for the first time in months. After several infusions, friends told her she was talking more than she had in a year.

For the first time in her life, "I felt like there is a future for me," Morgan said. "It's left me a different person than I was a year ago."

Ketamine is starting to shed its reputation as a psychedelic club drug and experimental mental health treatment as more patients like Morgan see results and more research is conducted on the drug's impact on the brain. A watershed moment came in March when the U.S. Food and Drug Administration (FDA) approved Spravato, or esketamine, a ketamine nasal spray for adults with treatment-resistant major depression. One short-term clinical trial showed the spray had a statistically significant effect on depression compared to a placebo, and patients saw some effect within two days, according to the FDA.

A handful of local private psychiatry clinics, including in Palo Alto, Menlo Park and Woodside, have in recent years started offering ketamine. They are working at the forefront of a promising new treatment in psychiatry, a field that has seen little medication innovation for decades.

Many of the psychiatrists who run these clinics said they were initially skeptical of the drug's potential, with little still known about how exactly ketamine works as an antidepressant and its long-term effects, but became believers when they saw life-changing improvements in patients for whom nothing else had worked.

"I think we're on the brink of an amazing revolution in psychiatry," said Alex Dimitriu, who offers ketamine treatments at his Menlo Park private psychiatry clinic. "We're on the brink of understanding that a lot of drugs that previously we thought were drugs of abuse are actually turning out to be some very powerful agents."

Exploring ketamine's potential

Ketamine was developed in 1962 as a fast-acting anesthetic and continues to be widely used as such today, particularly for surgery and pain relief, including with children and in veterinary medicine. The drug is a schedule III controlled substance, meaning its medical use is accepted and it has moderate to low potential for abuse. The World Health Organization has included ketamine on its list of essential medicines since 1985 and calls it "possibly the most widely used anesthetic in the world." As an anesthetic, it is incredibly safe (it does not depress breathing or blood pressure) and is easy to administer, according to the World Health Organization.

In higher doses, ketamine produces a "dissociative" state that can include hallucinations and out-of-body experiences. The drug's conscious-altering potential led to its recreational use in the psychedelic era of the 1960s and 1970s.

Reports of ketamine use to treat psychological or psychiatric disorders first emerged in the 1970s, including in Argentina, Mexico and Russia, according to a study co-authored by Jennifer Dore, who offers ketamine at her private Helios Psychiatry practice in Woodside.

In 2000, a group of Yale University researchers published a seminal but small-scale study that found seven patients with major depression who received ketamine showed significant improvement in their symptoms within 72 hours, suggesting the drug could be used as an antidepressant.

Six years later, a National Institute of Mental Health study showed that ketamine reduced depression symptoms more quickly than a placebo.

Dore, who trained as a resident at the Stanford University Department of Psychiatry, became curious about ketamine several years ago while treating patients with severe PTSD and treatment-resistant depression. They simply weren't getting better.

Dore dug into the available research on the drug's antidepressant effects, which suggested that ketamine inhibits the action of the brain's NMDA receptors and triggers glutamate production, which causes the brain to form new neural connections. She reached out to Phil Wolfson, director of the Center for Transformational Psychotherapy in San Anselmo, who pioneered ketamine-assisted psychotherapy, in which ketamine is administered while simultaneously patients receive therapy. She was compelled by taking this approach rather than the more medical model of providing the drug in isolation.

The results with her early patients in 2016 were like nothing she had ever seen.

"They had immediate relief," she said.

Dore said her clinic was the first on the Peninsula to offer ketamine-assisted psychotherapy. She now offers trainings for other providers and sits on the board of the Ketamine Research Foundation.

In March, Dore published a five-year study with two other psychiatry practices that found patients who received ketamine saw clinically significant improvements in depression and anxiety, particularly so for people who came in with more severe symptoms like suicidality and a history of psychiatric hospitalization. At their clinics, they saw the drug help people suffering from obsessive compulsive disorder, bipolar disorder, personality disorders, substance abuse, psychological reactions to physical illness and even relationship issues and social anxiety.

"Ketamine promotes a time-out from (the) ordinary, usual mind, relief from negativity, and an openness to the expansiveness of mind with access to self in the larger sense," Dore's study states. "These effects enhance a patient's ability to engage in meaningful psychotherapy during and after administration."

Dore is a staunch champion of combining ketamine with psychotherapy, which she believes is necessary to harness the full potential of the drug. She doesn't see ketamine as a magic bullet, but rather one tool she can use in concert with others — talk therapy, medication, nutrition — to treat people in serious psychological pain.

Before patients start ketamine, Dore carefully evaluates them to determine if it's an appropriate next step in their treatment, as recommended by the American Psychiatric Association, including through therapy sessions, psychological tests and a review of their medical history. If they choose to proceed, Dore requires patients to sign a lengthy consent form that explains how ketamine works and its potential benefits and risks.

During a patient's initial treatment, Dore monitors their physical and emotional responses, including blood pressure and heart rate, to decide on an appropriate dose going forward. The highest doses can produce the dissociative state, or the dream-like sensation of disconnecting from reality, Dore said. (Some people believe they have died and are in a new reality, she said. One patient described it as being in a lucid dream.) At lower doses, it can feel more like having a glass of wine, she said. The peak effects last about 15 to 30 minutes, according to Dore.

Patients can take the ketamine via a small lozenge that dissolves under their tongues, intravenously or an intra-muscular injection.

They receive the ketamine in a large second-floor space at Dore's practice. It resembles a homey living room more than a psychiatric setting — a reflection of the importance of creating "set and setting" for a psychedelic experience, including a comforting physical environment. A large, soft corner couch is strewn with pillows, including one that says "anger" and another, "love." During treatments, Dore pulls down the blinds on the windows, adjusts the temperature and offers patients weighted blankets, eyeshades and quiet music. The sessions last two to three hours.

Gaining a new perspective

Andy Mathis was at the end of his mental rope when he found Dore. A father, husband and successful tech industry executive, he had quietly suffered from self-doubt and insomnia since he was a young child. By the time he reached his mid-40s, it had escalated to depression. He felt his well-being and very brain chemistry was at risk.

A friend of a friend referred him to Dore, who prescribed him antidepressant and anti-anxiety medications that finally helped him sleep. But she suspected there was more to understand about the root causes of his symptoms, he said, and suggested ketamine as a means for exploring that.

A former professional tennis player, Mathis said he had never taken any drugs before. He did his own research on ketamine and thought it sounded "groundbreaking." He was more curious than fearful about embarking on a psychedelic experience.

He received his first infusion two and a half years ago and continues to get ketamine every four to eight weeks today.

"It was indeed transformational," Mathis said. "Nothing less than transformational."

Mathis described the experience as taking him out of his own ego, a "tilt(ing) of the prism on how I see things."

"It allowed me to have a detached, philosophical view on all things — me, my place in the world, my relationships," he said.

This helps him make sense of his emotions "in a way that can be extremely difficult and sometimes even impossible to do when I am inside of myself," referring to his default, day-to-day mental state.

Over the course of the infusions, Mathis started feeling more comfortable in his own skin, which he said improved his relationships and even his work performance. He realized he has a love for music and at age 47, started to learn how to play the saxophone. He came to a better understanding of his relationship to food and how he had used it as a coping mechanism.

Combining the ketamine-induced realizations with therapy was crucial, Mathis said.

"It was the post-experience discussions that we would have that would also unravel and unwind some of the unhealthy habits," he said. "I'm 47 now, almost 48. I am healthier now than I was probably, maybe, ever."

Dore likened ketamine's power as a catalyst for psychological change to "a year of psychotherapy in three hours."

Unlike antidepressants, patients don't have to take ketamine every day and do not experience significant side effects; they can become nauseous or slur their words during the treatment, psychiatrists said. They require patients to have someone to drive them home after the treatment.

Mathis, for his part, did not experience any negative side effects. A patient at another local psychiatry clinic, Lisa Ward, however, said her mind feels "foggy" if she has two infusions in a single week. According to the FDA, the most common side effects experienced by patients treated with Spravato, the esketamine nasal spray, in clinical trials including disassociation, dizziness, nausea, lethargy and increased blood pressure.

"It would be inhumane," Dore said, to not offer ketamine to people in intractable mental anguish. "We need things that are transformative, that aren't putting a Band-Aid on a problem."

Psychiatrist calls it 'life-changing'

When Rameen Ghorieshi first looked into ketamine as an option for a patient with treatment-resistant depression about five years ago, it was still "very much fringe," he said. His colleagues at Stanford, where he completed his psychiatric training, knew about the drug but had no idea how to actually use it as a treatment.

He decided to offer ketamine at his small private practice in downtown Palo Alto, Palo Alto Mind Body. He trained with an anesthesiologist and started with two patients. One suicidal young woman who had dealt with a chronic illness since childhood and didn't intend to live past 30 years old, he said, got to the point where she was working four days a week, socializing and planning to go back to school.

"That just blew my mind," Ghorieshi said. "I knew it would help just reading the studies but seeing it firsthand was pretty incredible."

He has done more than 1,000 ketamine infusions at his downtown Palo Alto practice. Eighty-seven percent of patients rated their improvements as significant and 35% of those described it as "life-changing." It particularly helped suicidal patients, he said. About 13% of patients said the improvement in their symptoms was not worth the time and effort of the infusions.

"This is a bit of a departure for me. I'm a very conservative prescriber," Ghorieshi said. "My patients tend to be on one, two, maybe three medications. ... But it was so remarkable that it seemed hard not to offer it to people."

Ghorieshi said his was the first clinic in the Bay Area to treat someone with the tightly controlled, FDA-approved nasal spray. A handful of his patients have since received it, with good results, he said.

Esketamine is attached to a federal Risk Evaluation and Mitigation Strategy, which the FDA "can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks." Providers and patients must register and the drug must be administered in a certified medical office under the supervision of a health care professional.

At Palo Alto Mind Body, patients receive eight ketamine infusions over several weeks. They are strongly encouraged to also pursue therapy but it's not part of the treatment itself, Ghorieshi said.

He or a nurse supervises patients over the course of the 90-minute appointments. Morgan likes to sit upright on the couch in Ghorieshi's office, covered by a blanket that keeps her warm and gives her a sense of emotional security. She listens to relaxing elevator music. After, she goes home and naps off the residual effects.

Years ago, she was given much higher doses of ketamine as a pain treatment for chronic physical illnesses and had horrible hallucinations, which she described as "having my head slammed against a wall repeatedly by a slime monster from a deep black bog."

At the dose Ghorieshi gives her, she feels like the floor and ceiling switch. Her inhibitions dissolve. Afterwards, she feels more open to trying new experiences, from coping mechanisms for her depression to new foods. She feels her perfectionism, which for a long time had prevented her from being vulnerable with others, soften.

"To me, that's the magic of ketamine," Menlo Park psychiatrist Dimitriu said of the drug's tendency to destabilize entrenched behaviors. "I think that speaks to the magic of future psychedelic research, which is down the pipeline, in that it increases our openness to new experience. The general belief here is if you're depressed severely, you get stuck in maladaptive patterns."

Lisa Ward didn't see immediate relief from her life-long depression after her first ketamine infusion with Ghorieshi in March.

Then, a week later as the drug continued to work in her system, "the whole cloud just lifted," she said. (It takes most patients several treatments to see results, according to Ghorieshi.)

She had more energy. She felt more productive. The benefits extended to her loved ones, as she's engaged more with her two young children, husband, her parents and her sister.

"It's enough for me to have more fun with my kids. It's enough for me to spend more time with my husband instead of going to bed because I just can't deal with the day anymore," she said. "Being in depression you don't realize it but it takes a big toll on other people."

For Ward, a photographer, the effects of ketamine last about five weeks before she feels the cloud returning. There was one period where the ketamine seemed to stop working all together. Because she lives in Hollister — a three-hour round trip drive from Palo Alto, not including the time of the session itself — and pays out of pocket for the expensive treatment, gaps between her appointments stretch longer than she'd like.

She actually doesn't enjoy the experience of being on ketamine, which she described as mind-bending and often intense. But she said the disruption of her depression allows her to focus on shifting the underpinning behavior and thought patterns.

Ketamine "doesn't magically lift all ... your problems away," Ward said. "You're more apt to make changes when you're thinking clearly and you're not so focused on the depression."

While esketamine, the nasal spray, is covered by insurance because of the FDA approval, most other ketamine administrations are not. Morgan pays almost $1,000 out of pocket for each infusion, though Ghorieshi said some of his patients have been reimbursed for their treatments. Dore charges patients for her time as a provider, about $1,000 for a several-hour session, rather than for the drug itself.

Morgan felt strongly about using her full name in this article to dispel stigma around ketamine in the hopes it will be more widely accepted — and thus available to more people in need.

"Just because you hear something in one context, like ketamine being used as an illicit drug, doesn't mean it doesn't exist in another," she said. "I think that's what scares insurance companies away from covering it for patients. And that's what makes me angry because I wish this treatment was out there for everybody to see. I'm lucky enough to be able to handle the financial portion, but the average person might not be."

The as-yet-unknown risks

Despite the success stories, ketamine has not yet been fully accepted by the broader psychiatric community. The unanswered questions and possible risks that surround ketamine — how it works as an antidepressant, the long-term effects, the potential for abuse — are cause for caution, said Alan Schatzberg, a Stanford School of Medicine psychiatry professor and former president of the American Psychiatric Association.

"Rarely has there been so much anticipation for a new antidepressant as has been seen for intranasal esketamine," he wrote in the American Journal of Psychiatry in May about the newly FDA-approved ketamine nasal spray.

"Do we have clear evidence of efficacy? Maybe. How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It's not entirely clear.

"Taken together," he wrote, "there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice."

In an interview, Schatzberg said he's concerned about repetitive, extended use of any form of ketamine and the drug's potential for dependence. The American Psychiatric Association has said that the literature on ketamine's longer-term effectiveness and safety is so limited that the organization cannot "make a meaningful statement" on such use.

"The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment," an American Psychiatric Association task force wrote in a consensus statement on ketamine in 2017.

Schatzberg co-authored a 2018 study that suggests ketamine's antidepressant effects are tied to the brain's opioid system and said the implications of this for dependency should be studied further.

"This is the same as any potential drug of abuse, any kind of opioid type drug. Serial use is less the issue. It's when you get into repetitive use that one needs to be careful," Schatzberg said. "That's the clarion call that we've been sounding."

One of his study co-authors, Carolyn Rodriguez, a Stanford associate professor of psychiatry and behavioral sciences, has been blown away by the rapid benefits of ketamine in studies she's conducted with patients with obsessive compulsive order, or OCD. In the first-ever randomized clinical trial of ketamine compared to placebo in OCD, she found that a single low dose of ketamine prompted a decrease in OCD symptoms within hours for all participants.

Yet she remains cautious and said more research is needed to fully understand the powerful drug. She's currently studying the mechanisms of how ketamine works so quickly on OCD patients, with funding from the National Institute of Mental Health.

"I believe that the state of the field of ketamine and how it works on OCD is not at the point yet where I would recommend it clinically because I always like to see science, (including) my own science, replicated," Rodriguez said.

With pause about the long-term effects, she and other researchers have suggested a national registry be created to monitor side effects.

Ghorieshi said he is frank with his patients about the unknowns and potential downsides of ketamine, which must be weighed against other risks.

"We do know the immediate mortality and morbidity of things like suicide and depression.

I think that's, as with anything, the risk-benefit. What are the risks of suicide, but also depression and anxiety in general?" he said. "You have to balance that versus these unknown risks of ketamine."

Mathis, for his part, said he's not concerned about the long-term effects of taking ketamine.

"What I worry about," Mathis said, "is what my health would have done without it."