Until the death of actor Matthew Perry many people had never even heard of ketamine. As a recreational drug, known as “Special K”, it can be extremely addictive and dangerous. But, when used under supervision, this powerful drug can help people with depression and various other mental health issues.
Dr. John Krystal, a leading expert on the neurobiology and treatment of psychiatric disorders, offers insights into why and how a drug once used as a horse tranquilizer and anesthetic has become a lifeline for those suffering from clinical depression.
Phil Stieg
With the recent death of actor Matthew Perry, people have become aware of Ketamine, also known as Special K, a popular but very dangerous party drug. But few people know about the other side of the story, that Ketamine, when used properly, is one of the most effective tools in treating severe depression and PTSD.
Today, we are here with Dr. John Crystal, a leading expert on the uses of Ketamine for psychiatric disorders, to discuss both its transformative and sometimes life-saving effects, as well as the many risks associated with its misuse. Is it really the miracle drug that it seems to be?
John, thank you so much for being with us today.
John Krystal
Phil, great to be here.
Phil Stieg
Before we start talking about Ketamine can you lay out what is the magnitude of depression? How common is it and how often is it resistant to standard therapy?
John Krystal
Remarkably, about one in five people will have a depression-like condition at some point in their lifetime. And the standard forms of treatment available, can be extremely helpful for many, many people. But as many as half of people with major depression, which is a subgroup of that one in five people, will not respond to their current medications, and sometimes they won’t even respond to various combinations of medication treatments. The numbers of people who have inadequate responses to standard treatments is extremely high in this country and is a major threat to health and a major burden on our communities.
Phil Stieg
Okay, so let’s now tell people, what is Ketamine and why are people so interested that is in it?
John Krystal
Sure. Well, Ketamine is an old drug. It’s been available since the 1960s in the United States. It was originally developed as an anesthetic drug and used before people really had any idea how it worked.
It wasn’t until the early 1980s when neuroscientists figured out that it worked by blocking a particular receptor subtype for the neurotransmitter glutamate. People know monosodium glutamate, but they don’t really appreciate that glutamate is the most important, common, chemical messenger in the brain, and it’s responsible for most of the excitation in the brain. And so Ketamine is an anesthetic because it blocks this excitatory receptor.
What’s kind of interesting about Ketamine is that we don’t use it at anesthetic doses to treat depression, because at anesthetic doses, it actually doesn’t work to treat depression. We use it at a very low dose, right at the level where people have alterations in perception, and other side effects, if you will, transient side effects of Ketamine that signal that enough Ketamine is getting in the brain to trigger the beneficial effects of the drug.
Phil Stieg
You’re considered a pioneer in the use of Ketamine for depression. How did that come about? And what led you to believe that it could be a such a miracle drug?
John Krystal
Around 1990, I started studying Ketamine effects, just trying to understand its effects on cognition and behavior, because at that time, my focus was trying to understand why Ketamine produced some cognitive effects and behavioral symptoms that might resemble aspects of schizophrenia.
Schizophrenia, at the time, was a disorder that people thought was explained by hyperactivity of a different chemical system called dopamine. Using Ketamine, we were able to begin to try to understand the biology of the cerebral cortex and to view Schizophrenia as a disorder of the cerebral cortex.
And so then we thought that perhaps depression in some ways like schizophrenia earlier, should be thought of as a disorder of the cortex and the limbic system. In order to study that question, we went back to Ketamine and using that as a probe of mood and cognition in depression. And in the process of that, we saw something that completely shocked us.
You know, up until that time, every treatment for depression took weeks, if not months, to produce clinical improvement. And what we saw in that study was that patients started to get remarkable recovery within 24 hours. And they often would show signs of that improvement, beginning improvement at about, say, 4 to 6 hours after the dosing o o f Ketamine.
Our whole idea about the biology of depression at that point and how depression could be treated was changing radically in the context of that study.
Phil Stieg
I’m one of your patients that’s refractory or unresponsive to all the standard medications, and I come to you and I say, “I’m really desperate. I want to try Ketamine”. Tell me, what am I going to feel?
John Krystal
So Ketamine can be administered in a variety of ways. One of the critical issues with Ketamine is it’s really important to get the Ketamine blood level into a specific target range. Too low, you don’t get effectiveness. Too high, you may still get effectiveness, but you’ll have more side effects, unnecessary side effects. And so intravenous gives you very precise control, perhaps the most control over the exposure.
S-Ketamine was developed, though, with intranasal administration. When we say S-Ketamine, that is one of two molecules that are mirror images of each other that make up standard Ketamine, R-Ketamine, S-Ketamine. And S-Ketamine is administered intranasally in order to avoid having to take it orally, because the oral absorption of Ketamine is very variable, and people are at risk of having either too low, meaning no efficacy, or too high, meaning unnecessary side effects. And so it turns out that a very good place to absorb Ketamine is in the nasal sinus, the nasal passages. Johnson & Johnson, the company that makes S-Ketamine, developed a specific device to promote the delivery of S-Ketamine in a way that it could be absorbed relatively well.
Ketamine can also be administered intramuscularly, right into the muscle – sort of a shot. And then it can be administered even subcutaneously, just under the skin.
It also can be administered orally, but it’s something like 30 times… You get something like 30 fold less exposure for the same amount of Ketamine if you take it orally than if you take it, say, intravenously. So you have to take a lot of Ketamine if you’re taking it orally, and you get this… You get two risks with oral Ketamine. One is the risk of suboptimal dosing, and then the other one is diversion, misuse, recreational use.
Phil Stieg
One of the side effects or one of the acute behavioral effects, as I understand it, is euphoria. Is that probably the reason for, as you said, the diversion/misuse category for patients?
John Krystal
Yes. One of the things that’s striking about the euphoria of Ketamine is that subjectively, if you give a low dose of Ketamine, you can give a dose that is experienced by many people as similar to, say, a glass of wine. And the similarity between the subjective effects of Ketamine and the subjective effects of alcohol grow as you give higher and higher doses of Ketamine. And when you get to the effects of a therapeutic dose of Ketamine, experienced drinkers, experienced very heavy drinkers, say that it’s somewhere between the standard antidepressant dose is somewhere between 6 and 12 alcohol drinks. Yeah, so pretty high.
Phil Stieg
I’d be asleep.
John Krystal
Yeah. And that’s no accident because alcohol, among it’s a very small molecule and has many different kinds of actions in the brain. But one of its more potent actions happens to be blockade of NMDA glutamate receptors. So people who are alcohol dependent are very tolerant to the effects of Ketamine, whereas, and may not experience some of the negative effects. And that, too, the propensity to develop tolerance is one of the things that sometimes drives compulsive use of Ketamine.
Phil Stieg
In regard to the negative effects, do many patients experience the nausea you of vomiting, and perhaps you could explain to our listeners what dissociative symptoms mean as it relates to Ketamine.
John Krystal
Yeah. So a few of your listeners probably no people who have consumed enough alcohol to get the spins. And where that comes from is that alcohol can affect a part of the brain called the vestibular nucleus that governs balance. So people, when they’re drunk, stagger. They have trouble maintaining their balance. Well, Ketamine does that, too. They get a little bit of that nausea – alcohol-like nausea. And I’d say more like 20 %, 10-, 20 % of people will have, at some point in their treatment, an episode of vomiting.
And I would say, by the way, out of all the side effects of Ketamine, all the potential ones, the one that bothers people the most is nausea. And the way that we manage it when we see that that’s an issue for somebody is that we can give people anti-nausea medications before we give them the Ketamine and they don’t interfere with the beneficial effects of Ketamine. So we can manage that nausea pretty well. But it is something that we always pay attention to during Ketamine treatment.
The dissociative effects are a little It’s a little bit like sensory changes. When you give Ketamine, time slows down. When you give Ketamine, your perception of your body may alter. You may feel like your limbs are changing their shape or proportion, that your body organs are altered in some way, that you, as a person, are relating to the world in a different way. The world may seem odd. It may seem unreal. You as a person, may feel like your identity or your sense of yourself may be changed.
And one of the reasons that you may have this feeling of unreality is because colors and shapes around you may be distorted. The walls may seem to breathe in and out. Sounds that are close may seem like they’re coming from far away. People talking in the next room may feel like they’re talking right into your ear. So the coherence of your experience of the world may be altered for about 20 minutes during the Ketamine treatment session.
Some people find those experiences curious, interesting, fascinating. Other people find them scary. I guess the way some people like going on roller coasters and other people really don’t like that. And what we do to help people manage those symptoms, first and foremost, is we help them to understand what might happen before they get the Ketamine treatment. Second, we don’t leave them alone. So we’re with them. And if they become frightened, we can be right there with them and help them through it. And once people go through it the first time, it loses a bit of its surprise, and people are more with it.
Phil Stieg
Can you give an example of one of your patients where it really changed their life after they came to you and you provided Ketamine therapy?
John Krystal
People reach out to me and tell me their stories, which is incredibly meaningful and gratifying, and to realize that this treatment is really changing people’s lives. So people tell me about how they felt completely devoid of emotion, no pleasure, no anxiety, just completely dull, just going through the emotions in their life, and then getting Ketamine and having an awakening experience where now they could see things, enjoy things, react to things, and really resume their lives.
We treated people who really couldn’t manage at all, couldn’t take care of themselves, couldn’t really stay connected with people and activities in their life, resuming those activities. We’ve had people who were very suicidal, who managed, had a different perspective. And one of the things that’s interesting to me about the relationship of the anti-suicide effect and the anti-depressant effect is they don’t always go together.
Often is that for some people, the depression will come back maybe before their next dose or after a gap. But having that one positive experience of recovery or improvement seems like it protects people from having the return of the suicide urges. So that in literally every domain where depression can be so crippling, so distressing, Ketamine seems to produce meaningful change that make a difference to patients. And their families and their employers and everybody around them.
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Ketamine was originally synthesized in the 1950’s in an effort to find a safer alternative to a drug called phencyclidine, (better known today as “Angel Dust”) which was found to have the unfortunate side effect of inducing severe psychotic episodes in some patients.
Ketamine was originally marketed in Europe as an anesthetic for veterinarians to use on horses and other large mammals.
During some of the first tests on humans in the early 1960’s, test subjects described a feeling of floating in outer space, disconnected from their body and having no feelings in their limbs. Researcher Edward Domino at the University of Michigan considered calling this unusual anesthetic state “dreaming” but his wife Antonia observed that since patients seemed to be ‘disconnected’, she suggested the term ‘dissociative anesthetic’.
In heavier doses, this dissociative effect can result in a phenomena that recreational users describe as the “K-hole”, where they seem to be floating above their body and their vision narrows down a tiny circle in the center of their visual field. Some users even consider this apparent “out of body” sensation to be some form of spiritual enlightenment.
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Ketamine was approved for use in 1965 and was quickly adopted by the US Military as a fast-acting battlefield anesthetic in the Vietnam War. Unlike other anesthetics, Ketamine does not lower blood pressure or stop a patient’s breathing, making it safer to use for emergency surgeries in the field without a ventilator or intubation, and saving many lives.
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With proper and cautions application, Ketamine continues to be vital drug in military field hospitals to this day.
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Phil Stieg
I want to talk a little bit about the outcome of Matthew Perry and the addictive and dangerous things associated with Ketamine usage. Given the potential downside of this drug, it’s a little bit frightening. Can you cover that for us?
John Krystal
Sure. Ketamine is a drug that has to be treated with tremendous respect. We talked about the behavioral symptoms of Ketamine intoxication, the dissociation, the nausea and vomiting that you can get. And out of all the risks of Ketamine, far and away, the greatest risk is developing a compulsive Ketamine habit. The propensity is there when people particularly use it at home. When people use it at home, they’re often not taking enough of the Ketamine to get the benefits of the Ketamine. So they’re exposing themselves to risks, and they’re not getting any of the benefits. That doesn’t-
Phil Stieg
Are they getting the side effects, the bad side effects?
John Krystal
They get some of the side effects. They get the euphoria. They get the… Along with the euphoria is an anti-anxiety effect. So they get a little bit of anti-anxiety. They get euphoria. They an interesting experience a little bit, but they’re often not taking enough to get the full antidepressant effect. So their depression is persisting. They feel better when they take the Ketamine for a little bit of time. And so the incentive is there for them to take the drug more and more frequently.
When we treat someone long term on Ketamine, maybe they’re taking a dose every two weeks. When you develop compulsive Ketamine use, I saw someone, for example, very knowledgeable person, and yet he was taking it six times every day. So —
Phil Stieg
Microdosing?
John Krystal
It wasn’t so micro! But so you have this situation where there are these – there are two kinds of ways that you can use the drug. One is intermittent, very controlled, directly related to the treatment of depression at these effective doses. And the alternative, which is to take these doses which are not effective, but which people use a little bit like Valium. But that can promote some people to become addicted to it.
Not everybody, Obviously. Some people can use just a little bit of Ketamine and get whatever benefit they get. But the fact that some people will develop these addictions, pretty bad addictions, when they have ready access to Ketamine all the time. That’s very concerning. And that led to Matthew Perry, his death. But we don’t know how many people were in car accidents because they were on Ketamine. We don’t know how many people exerted bad judgment in some important aspects of their life because they were on Ketamine. And one thing that’s often not appreciated is that when you use Ketamine frequently, it doesn’t treat depression. It increases your vulnerability to depression. So they may be worsening their own depression by using Ketamine so frequently for some people.
Phil Stieg
Maybe I’m reading into this, but as I listened to you, it would seem to me that you would not agree with these clinics that are out there that just willingly give out the Ketamine. It sounds to me like a drug that needs to be regulated more carefully so that the patient derives the benefit, but not necessarily the downside risks associated with frequent dosing at home.
John Krystal
I think Ketamine is still an in-clinic procedure. S-Ketamine is only approved by the FDA for administration in the clinic. I view the Ketamine treatment as an in-clinic procedure for all the reasons that we’ve talked about. I’m aware that many people disagree with me about that, but I’m a stickler about data, and I want to see long term safety data of at home Ketamine. And If those exist, then I’m open to being convinced.
My feeling about Ketamine is I view it as an intervention, but not the whole treatment. In other words, it’s very important for mental health practitioners, psychiatrists, to oversee the overall care of patients undergoing treatment. And you would not want to have, for example, you wouldn’t want to have bypass surgery and have that be the only treatment you get. No statin, no cardiac rehab. You wouldn’t think of treating cardiac disease that way. And I view depression treatment exactly the same way.
So for some people, many people, it’s really critically important for them to have psychotherapy along with the Ketamine. With Ketamine, when you open up these windows of enhanced neuroplasticity in the brain, that period may be an opportunity to get maximal impact from the cognitive behavioral therapy. And so I think that there may be synergy. I think of increasing neuroplasticity in the brain. It’s like making a horseshoe. We’ve made the metal red hot, and now psychotherapy can pound that metal into shape.
Phil Stieg
The one thing I wanted you to touch a little bit on just the unwillingness, the stigma in society to admit to some form of psychiatric disease. Is that changing in your mind?
John Krystal
It’s changing, but it’s still there.
Phil Stieg
Still too dominant?
John Krystal
Well, as you can imagine, it’s probably a worse problem among men than among women, that men not to be so open about their vulnerabilities or help-seeking. I think that’s changing and getting better. And women – again, this is a gross over generalization – tend to be a little bit more aware also about their feelings and have a better sense of when they need some help for their feelings.
Men may not always be as even aware that what they’re going through is depression. People, in general, don’t always have the right words to describe what they’re going through. And that’s why getting help sometimes starts with this initial discussion. “It’s not going right. Things aren’t going well. I’m not that happy with how things are in my life. I can’t sleep well. I have no appetite. I have no energy…”
When people just begin that process, just that step alone is really helpful for many people and gets them going down a good path. More effective treatments like Ketamine increase the idea that it’s really important.
In our society, we talk about depression like it’s having a bad day. We don’t talk about depression like it’s shortening your life expectancy by 10 years. And that’s the way we talk about cancer. That’s the way we talk about heart disease. And yet depression does this as well. So we really do need to find the words as a society and create a culture where getting help is supported.
People think about that getting help makes them weak. That’s their worry sometimes. But getting help makes them strong, makes them resilient, makes them effective. That’s really the story we should be telling.
Phil Stieg
What do you want the take home message for a person who is depressed to be regarding Ketamine? When should they start thinking about it? Who can they go to? What’s easy access?
John Krystal
When you were asking me, I was thinking about saying something silly, like when it comes to depression, just say yes. Remember Nancy Reagan? Just do it. Yeah, right. Just do it.
Literally, that’s true, though. When it comes, if you’re not feeling well, if things aren’t going right, just do it. Talk to someone. Talk to your family doctor, talk to your clergy, talk to your friends, find out how they dealt with these problems, who was helpful for them to get treatment.
The thing that ultimately holds people back is not getting help. We have so many ways to provide help for depression these days that each person who suffers in silences is just so sad.
Phil Stieg
Dr. John Crystal, thank you so much for spending this time with us. Ketamine is an important drug, whether it’s the magic drug that we want it to be, we have to determine. But I think you’ve made it clear for us the understanding about how to provide it safely so that we don’t have the likes of Matthew Perry.
Thank you so much for spending time with us.
John Krystal
Phil, it’s been a pleasure. Thanks.
