• Psychedelic Medicine

KETAMINE | +50 articles

mr peabody

Bluelight Crew
Aug 31, 2016
Frostbite Falls, MN

Ketamine: A legal, yet overlooked psychedelic

by Marlene Rupp | Sapien Soup |

Is ketamine going to be Psychedelic Therapy’s opening act? At medium to large doses, Ketamine evokes colorful visions and mystical type experiences that have been linked to positive treatment outcomes. And—unlike other psychedelics—Ketamine has been readily available at clinics worldwide for 50 years.


Psilocybin and MDMA have gotten much attention for their potential efficacy in treating some of the most prevalent psychiatric conditions of our time, such as depression, trauma and anxiety disorders. Phase-3-studies are well underway, effect sizes look promising and therapists around the globe are being trained to bring this new and potentially groundbreaking treatment to the masses. However, clinical approval of psilocybin and MDMA might still be a long way ahead of us. In the meantime, some within the psychedelic community are looking to see whether ketamine may be able to fill the gap.

What is ketamine?

Ketamine is a so-called dissociative anesthetic. Like all good anesthetics, it ensures patients have no body movements, no pain and no memory. What’s more, Ketamine has two important advantages over other anesthetics. First, it doesn’t cause significant drops in blood pressure. And second, it doesn’t cause respiratory depression. These additional features made ketamine the anesthetic of choice for operating under suboptimal conditions, like in the Vietnam War where anesthesiologists, who must monitor vital signs and adjust dosage to keep patients from dying, were rare in the field.

Is ketamine legal?

Yes. Ketamine is legal, dirt cheap and readily available in hospitals everywhere.

However, despite its advantages, clinicians have taken a step back from using ketamine as anesthetic due to its peculiar side effects. Namely, patients have reported bizarre visions and out-of-body experiences on coming out of their anesthesia. Hence the name dissociative anesthetic. These psychoactive properties of ketamine were considered undesirable and as a result, ketamine is used only infrequently as an anesthetic today.

From anesthesia to psychiatry

Starting around the year 2000, ketamine has had a revival in the field of psychiatry. It turns out that, in lower doses, ketamine has distinct antidepressant effects. Ever since, psychiatrists have administered ketamine to patients who suffered from severe depression. The clinical use confirmed what studies had previously shown: for many patients, ketamine could immediately relieve symptoms of depression—even with just one dose. This extremely fast onset closed an important gap in the clinical treatment of depression, because modern antidepressants like SSRIs and SNRIs take about two weeks to come into full effect. Acutely suicidal patients can’t wait that long, thus ketamine has gained popularity again, now as a so-called rapid-acting antidepressant.

Why hasn’t my doctor suggested ketamine to me?

Let’s discuss why ketamine is not without controversy.

- Short-lived duration

About 60-70% of depressed patients respond to ketamine. This is a great result, considering that these patients suffer from a treatment resistant form of depression, meaning that at least two prior treatments have failed. Unfortunately, these effects are short lived. About one week after a single administration of ketamine, the symptoms usually kick back in.

In clinical practice, patients are started off with a flight of ketamine to lift them out of their depression. At the same time, they are shifted from their old SSRI to a new SSRI. The rationale is that it’s the SSRI that does the long-term stabilization and ketamine is only an add-on to that therapy. Patients who respond to the initial ketamine flight but then relapse may receive a weekly dose of ketamine as maintenance therapy.

- Clinical approval

This is where it gets complicated: Ketamine is approved as anesthetic, but not as an antidepressant. And yet, it’s possible within medical practice to use pharmaceutical drugs for unapproved indications if there is no other treatment available. This is known as off-label use. Ketamine has widely been used off-label in treating treatment-resistant depression. But in order to be formally approved as an indicated treatment it takes a long, complicated and expensive procedure, which typically only pharmaceutical companies can afford. After 20 years of off-label use, the pharma company Johnson & Johnson changed the game. In 2019 they attained FDA approval for a variant of ketamine—Esketamine—which they patented and sell today as a nasal spray called Spravato. Now that there is an approved treatment available, doctors are compelled to use the proprietary nasal spray over regular ketamine. The catch: a single dose of Spravato is priced in the high 3-digits, whereas a dose of regular ketamine costs less than a cup of coffee.

There is little data comparing the efficacy of Esketamine to that of regular ketamine. A small study suggests that Esketamine is not inferior to regular ketamine in treating treatment-resistant depression. 6 However, it hasn’t been proven superior either. According to the clinicians that I’m in touch with, regular ketamine is just as good, if not better.

- Abuse potential

Ketamine is a derivative of PCP which some readers may know of as the street drug called Angel Dust. Chemical compounds escaping the lab and being used recreationally is a common theme throughout the history of pharmaceutical drug development. Heroine, cocaine, LSD and various types of methamphetamines were originally developed in pharmaceutical labs for therapeutic purposes. It is because they were so effective that they leaked into the party scene. By their nature, all psychoactive substances that are “fun” will be used recreationally and the same has been true for ketamine. Outside the lab ketamine is sold as Special-K or Vitamin-K in the form of a snortable powder. Ketamine has detrimental side effects if used frequently, it can lead to addiction and—under unfavorable und unsupervised circumstances—can be lethal. More on that later.

Thus, ketamine is not designed for home use, but rather being administered at clinics and by trained medical staff.

Three different ketamine models

What makes ketamine effective? The short answer is: we don’t know for sure. Amongst clinicians, researchers and practitioners we currently find three different hypotheses which—in turn—result in three different treatment models that will be laid out in this section. What’s effective is 1) the pharmaceutical substance, versus 2) the combination with psychotherapy, versus 3) the visions themselves.

Let’s explore what’s behind these three hypotheses and who provides the treatment that comes with them.

Ketamine treatment models - medical, therapeutic, psychedelic


The medical model

Dosage: 0.5mg/kg
Routes of administration: intravenous drip, nasal spray

The medical model operates with small doses, no visions and higher frequency. With low dosages, psychoactive effects can be kept at bay. On the other hand, low doses need to be administered more often in order to achieve a cumulative effect. As mentioned above, ketamine is used as an add-on treatment to conventional antidepressants. The medical model is the status quo in most larger clinics around the world.

Recently however, a new perspective has emerged amongst experts in the field: what if the psychoactive properties aren’t merely an irritating side effect, but are actually responsible for the efficacy of ketamine?

The therapeutic model

Dosage: 0.25-0.75mg/kg
Routes of administration: intravenous drip, intramuscular injection, lozenge

The idea of the therapeutic approach is to use the psychoactive properties of ketamine as lubrication for talk therapy. In other words, to help patients relax and talk about things that are too painful to talk about otherwise. During this approach, patients are fully conscious but feel a bit more disinhibited, which makes it easier for them to open up. 7 This approach has been named Ketamine-Assisted Psychotherapy (KAP) and is offered by smaller treatment centers and individual health care providers.

The psychedelic model

Dosage: 1-2mg/kg
Routes of administration: intravenous drip, intramuscular injection

In the psychedelic model, the patient is lying down and fully giving in to the psychedelic experience which can involve colorful dream-like visions, meaningful insights and full dissociation which manifests as out-of-body experiences. This is the state that recreational users refer to as being in a k-hole. Psilocybin and LSD Studies from the 1960s until today have shown a correlation between such mystical-type experiences and positive treatment outcomes. It stands to reason that the same principle could apply to ketamine as well, thus the psychedelic model. But little data has been gathered to confirm this assumption.

Typically it’s the same providers that offer the therapeutic model, that would also offer the psychedelic model. It’s widely agreed however, that this high-dose approach is not appropriate for many patients.

*From the article here :
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Ketamine-assisted Psychotherapy – Online?

by Veronika Gold, LMFT and Eric Sienknecht, PsyD | PSYCHEDELIC SUPPORT | 30 Nov 2020

Is the COVID pandemic presenting us with a new opportunity in the field of psychedelic-assisted psychotherapy? Can we collaborate with patients to offer virtual sessions safely and effectively? If so, what are the implications of this new way of providing treatment? Join Dr. Eric Sienknecht, PsyD and Veronika Gold, LMFT in an exploration of offering ketamine-assisted psychotherapy during social distancing.

In mid-March 2020, as the Shelter-In-Place order was put into effect in San Francisco, nearly all businesses and services ground to a halt. We stayed home, canceled all plans and appointments, foraged for the meager supplies remaining in stores, and waited. Our ketamine-assisted psychotherapy clinic, Polaris Insight Center, was closed for business, indefinitely. As fears of infection spread, along with the virus, we worried about our many patients, some of whom were suffering from Treatment-Resistant Depression and Anxiety while others reported newly emergent symptoms, exacerbated by the stress of the pandemic.

The question on hand became: How could we best respond to this potential healthcare crisis?

After several meetings, and as Telemedicine and HIPAA regulations were relaxed, we decided to begin offering virtual ketamine-assisted psychotherapy (KAP) sessions. Although our physicians regularly provide suitable patients with prescriptions for ketamine lozenges for at-home use during maintenance phases of treatments, we typically require in-office medical and psychological evaluations and several in-office KAP sessions before transitioning to at-home regimens. In this new COVID era, we would now be conducting evaluations, determining treatment plans, and facilitating the self-administration of ketamine lozenges at home via Zoom, all without ever meeting the patient in person.

Readers with an understanding of the powerful, often transformative, effects of psychedelic medicine may be skeptical and may wonder, “How is this possible?” and “Is this safe?” We also had similar questions, which informed the development of a new protocol for virtual services that included additional requirements to maximize safety and support.

Consider these three dimensions of virtual ketamine-assisted psychotherapy:​

1. Accessibility

Virtual KAP is more affordable compared to in-office treatment: Standard KAP treatment is a significant time investment. Typical treatments will include, at minimum, 1/2 hour with the physician, 1-hour intake with the therapist, 1 – 3 hours of preparation, several 2- to 3-hour experiential sessions, and 1 or more 1-hour integration therapy sessions. Because off-label use of ketamine is not usually reimbursed by insurance companies, the 10 – 20 hours or more of treatment are typically paid out of pocket. Virtual sessions allow for savings on rent in clinics and allow clinicians to see more patients, as there is less time spent between sessions (in the waiting room, in transition between session and transportation, changing sheets, and resetting the room).

Virtual KAP is more accessible compared to coming in person to the clinic: People who live in remote areas and places where there are no Ketamine-Assisted Psychotherapy clinics can now have access to this treatment.

KAP is most often used to target Treatment-Resistant Depression. One of the common challenges with depression for people is finding the motivation to engage in treatment, i.e. planning for sessions, leaving the house, and driving to and from appointments. With virtual sessions, these roadblocks are removed, facilitating access to, engagement in, and delivery of treatment.

The home setting can be more convenient for supporting the inner process and reducing side effects: Patients can stay with their process without interruption beyond the time of the session. Ketamine can elicit non-ordinary states of consciousness and, even when patients return to their normal state of consciousness, the physical effects of the medicine can continue beyond the time of the session. For this reason, many clinics, like ours, have “recovery areas” where patients wait, and patients are required to have arranged a ride home. When treatment is done at home, the patient can stay in their bed or on their sofa for as long as they need, and there is no pressing need to shift the state and commute home. One of the most common side effects of ketamine therapy is nausea, which is exacerbated by movement, and so this is greatly decreased during at home sessions where the patient can stay in a comfortable position as long as they need.

Due to limitations of the online format, there is a greater need to communicate instructions clearly. During in-office sessions, the therapist/physician team are responsible for creating the setting and co-creating the set of the sessions. During online sessions, the patient has to prepare the set and setting themselves. As such, additional communication around details of preparation – from interacting with the compounding pharmacy, to learning how to use the lozenges, to setting up the music, to navigating online platforms – are needed. Instructions need to be explicitly spelled out and often repeated. In short, more energy and effort are required by the provider on the front end to facilitate a smooth, safe, and supportive experience.​

2. Safety

Virtual sessions in the familiarity of the home environment are experienced as safer for some patients, allowing for the possibility of greater vulnerability and increased capacity to fully let go into the therapeutic process. As human beings, we are wired for relationships and in healthy individuals, personal contact and connection facilitates relaxation, feelings of joy, and openness. However, for many people who suffer with depression, anxiety, and PTSD, personal contact and/or being in clinical settings can increase their discomfort, thereby creating an obstacle to depth exploration.

Safety concerns for our patients and legal concerns for our clinic required us to spend more time and energy upfront anticipating risks and creating contingency plans. We developed new informed consents, including a telehealth consent and an at-home lozenge-use consent, describing in detail set and setting requirements, safety plans, and the importance of support systems. Additionally, since we would be expanding our services to people outside the Bay Area, we created new contact lists for local emergency services for various areas in California.​

3. Support System

Particularly since the pandemic, there has been a greater need for connection with others and as well with those who are familiar with KAP. . We have found ourselves sharing more community online resources with our patients and discussing the importance of Ketamine Integration groups. We have seen much more interest in virtual support groups such as the weekly Psychedelic Integration Circles with Tam Integration and Polaris Insight Center and the weekly Ketamine Integration Circles with Sage Integrative Health.

The patient’s support system is even more important if they are engaging in virtual sessions. Time and energy are needed to communicate with the patient’s support system. In cases involving extreme social isolation, inability to communicate with others and/or absence of a support system could be a major obstacle to this kind of treatment.

Compared to in-person sessions where the therapist/physician is physically present and can provide verbal and physical support, patients can sometimes find it harder to take in the support in a virtual session. As such, having a sitter present during the session, in the same or separate room, or at least someone who is aware that the patient is taking a journey and who can be on-call if needed, should be arranged.

The favorable outcomes we have witnessed thus far with this new method of collaboration between providers and patients have broader implications for our healthcare system. Patients treated at home might be less dependent on the system for their healthcare needs, resulting in greater self-empowerment and agency, and less strain on the healthcare system. Furthermore, with at-home sessions being significantly less expensive than in-office treatments, access to care would widen.

As at-home sessions are being provided by more clinics, it will be important to track safety and efficacy in an ongoing way, and protocols will need to be revised accordingly. Nevertheless, after successfully facilitating many at-home treatments, it is our belief that virtual KAP sessions can be provided safely and effectively when paired with sufficient screening, preparation, and support.

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From chaos to calm: A life changed by ketamine

by Jon Hamilton | NPR | June 4, 2018

For six years now, life has been really good for James. He has a great job as the creative director of an advertising firm in New York City. He enjoys spending time with his wife and kids.

And it has all been possible, he says, because for the past six years he has been taking a drug called ketamine.

Before ketamine, James was unable to work or focus his thoughts. His mind was filled with violent images. And his mood could go from ebullient to dark in a matter of minutes.

Ketamine "helped me get my life back," says James, who asked that we not use his last name to protect his career.

Ketamine was developed as a human and animal anesthetic in the 1960s. And almost from the time it reached the market it has also been used as a mind-bending party drug.

But ketamine's story took a surprising turn in 2006, when researchers at the National Institutes of Health showed that an intravenous dose could relieve severe depression in a matter of hours. Since then, doctors have prescribed ketamine "off label" to thousands of depressed patients who don't respond to other drugs.

And pharmaceutical companies are testing several new ketamine-related drugs to treat depression. Johnson & Johnson expects to seek approval for its nasal spray esketamine later this year, though the approval would be limited to use in a clinical setting.

Meanwhile, doctors have begun trying ketamine on patients with a wide range of psychiatric disorders other than depression. And there is now growing evidence it can help people with anxiety, bipolar disorder, post-traumatic stress disorder, and perhaps even obsessive-compulsive disorder.

"I think it's actually one of the biggest advances in psychiatry in a very long time," says Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and director of the Developmental Biopsychiatry Research Program at McLean Hospital.

Ketamine may also offer new hope for people like James who have symptoms of several different psychiatric disorders.

James had a happy childhood, he says. But his thoughts were out of control. "I always felt like I was crossing a freeway and my thoughts were just racing past me," he says.

He spent much of his childhood terrified of "an unknown, an ambiguous force out there." The fear was "overwhelming," he says. "I literally slept with the cover over my head with just room to breathe through my mouth until I went to college."

And there was something else about James: his body temperature.

"I overheated constantly," he says. "I would wear shorts all year long. In my 20s in my apartment I would sleep with the windows open in the middle of the winter."

In his late 20s, James saw a doctor who told him he had attention deficit hyperactivity disorder. So he started taking stimulants.

At first, the pills helped him focus. Then they didn't, no matter how many he took.

He'd done well as an idea guy in the advertising industry. But now James was trying to work at home, and it wasn't going well.

"ADHD pills will make you interested in anything," he says. "So I was putting the desk together and taking the desk apart. I was putting a laptop stand together and taking it apart. I was going in a massive downward spiral."

James had always suffered from mood swings. But now they were rapid and extreme. And he couldn't stop thinking about gruesome scenarios, like a murderer coming for his family.

"My wife took a summer off to be with me because she was scared of what was going to happen to me," he says. "She would go to work for a few hours, then rush home. There would be times I'd call her just screaming, 'Please come home. I can't get through another minute.' "

Eventually, James found his way to Dr. Demitri Papolos, an associate professor of clinical psychiatry at Albert Einstein College of Medicine.

"He was like a whirling dervish when he came into my office," Papolos says. "He was extremely fearful, scanning the environment all the time and he overheated at the drop of a hat."

Papolos diagnosed James with a variant of bipolar disorder he calls the "fear of harm phenotype." It typically appears in childhood and often doesn't respond to traditional psychiatric drugs.

But Papolos has found that the condition does respond to ketamine. "It's been transformational," he says.

In January, Papolos published a study of 45 children with the problem. They inhaled a nasal mist containing ketamine about twice a week. Nearly all got dramatically better.

Scientists still aren't sure why ketamine works, but there's evidence that it encourages the brain to rewire, to alter the connections between cells. That process has been linked to recovery from depression. And it may also explain why ketamine helps people who have symptoms associated with several different psychiatric disorders.

"I think it's having multiple effects, and that means it's probably useful for multiple different disorders," Teicher says.

One of those effects involves a part of the brain involved in temperature regulation. And that could explain why patients like James usually stop overheating once they are taking ketamine.

James started taking a ketamine nasal spray every other day. He says his response was dramatic.

"One day I turn to my wife and I'm like, 'I feel calm today. I don't know if it's the sun coming in, I don't know if it's just the way we're sitting here, but I feel like I could go and sit at the computer and work.' "

The next day, James did sit down at his computer. A month later, he was back at work.

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How to know if Ketamine Therapy is right for you

by Inna Lee | Santa Clarita Magazine | 25 Jan 2021

There are a lot of treatment options out there for mental health, and everyone is different, so finding the right treatment can take some trial and error. While it’s always best to talk to a medical professional about starting new medications or treatments, there are some ways to get an idea if ketamine therapy is a good fit for someone.
In case you need a refresher, ketamine therapy is a type of mental health treatment that uses ketamine (a psychedelic drug) to help relieve emotional pain + suffering.

Ketamine has been used in surgery as an anesthetic for a long time, and research has shown that the use of ketamine in low doses to treat mental illness can be extremely effective. However, it’s not a perfect wonder drug – there are some people who won’t do well on ketamine (just like there are people who won’t do well on any type of medication). With that being said though, research has shown that ketamine treatment can be effective for up to 70% of people (whereas traditional antidepressants are effective for around 20% of people).

Here are some reasons why ketamine might be a good option for you:

1. You have treatment-resistant depression
As mentioned above, there can be some trial and error when it comes to medications for mental health, and not all medications will work for everyone. Since traditional anti-depressants only work for around 20% of people, there are many people who try every option available to them to treat their depression only to find that nothing helps relieve the severe symptoms they experience. Ketamine has shown to be a helpful treatment for depression that other medications leave untouched, giving people options where they thought they had none.

2. You want to experience relief quickly with minimal side effects
Ketamine treatment is known for working fast. Sometimes folks notice a change in as little as an hour after treatment. Ketamine has long-lasting effects on mood disorders, even though the infusion only takes about an hour. Some patients report feeling better right after their first dose, and some report an immediate decrease in thoughts of self-harm or suicidal ideation. Since ketamine only stays in the body for a short time, any side effects felt from the treatment (like dizziness or nausea) will also only last a short time. It’s also rare to experience allergies to ketamine.

3. You are willing to come in for maintenance
While some people experience relief from a single infusion, most people have to come back in for maintenance to keep up the results. While this is less of a time commitment than, say, going to talk therapy and a physician regularly to be prescribed antidepressants, there is still a time commitment involved. If going in for multiple treatments doesn’t bother you, then ketamine might be a good choice.

4. You have chronic pain
Ketamine can also help folks with chronic pain. It is a pain-relieving medication (remember, it is used as an anesthetic). Chronic pain is a serious condition and ketamine can be a reliable way to decrease the pain that people experience. Some people have been on opioids for a long time and find them to be less effective, and of course, there is an opioid crisis in the United States right now, making many folks wary of relying on opioids.

5. You are experiencing suicidal ideation
Ketamine therapy can quickly relieve suicidal ideation, making it a life-saving medication for people who are experiencing thoughts of suicide. Some people report feeling an almost immediate decrease in suicidal ideation after a single injection, which can be useful if someone is in a crisis

6. You have severe anxiety
Similar to treatment-resistant depression, some anxiety disorders don’t respond to the traditional treatment methods used. Ketamine has been shown to lessen severe anxiety, even for folks who didn’t respond to other treatments. Severe anxiety can be incredibly limiting, so having an option to quickly treat it can be invaluable.

7. You’re willing to pay out of pocket
Since it is not an FDA approved treatment, ketamine is not likely to be the first line of treatment. It is not covered by insurance, unlike therapy and medications, which sometimes are. People who are treated with ketamine for mental health problems have often tried just about every treatment under the sun with little to no relief for their pain. Though there are studies underway to prove the efficacy of ketamine as a mental health treatment (and get it approved by the FDA), many folks can’t afford (emotionally, physically, or financially) to wait. For now, the use of ketamine to treat things like depression is off-label, which means it won’t be covered by insurance.
Who shouldn’t get ketamine therapy

If you’re on other medications, like benzodiazepines, make sure to talk to your provider before you go in for treatment. They will let you know what you should keep taking and what you should stop taking before treatment.

While ketamine therapy has the potential to help many people, there are still some folks who won’t benefit from it. People who are pregnant are usually not advised to receive ketamine therapy. Folks with schizophrenia are also not candidates for ketamine therapy, as there is concern that ketamine could make their condition worse.

Ketamine can be a useful treatment for a number of disorders – depression, anxiety, chronic pain, and more. If you think that ketamine is right for you, get in touch with our office to book your appointment.

*From the article here :
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The complete guide to ketamine therapy for depression, from someone who’s tried it

by Allegra Ringo | allure | Oct 30 2019

Ketamine is an anesthetic that's used off-label for depression, but does it work?

When I entered the ketamine clinic for the first time, I started crying almost immediately. This was for two reasons: First and foremost, I was scared. After watching a documentary that introduced me to the subject and reading several accounts of ketamine infusion therapy, I knew a fair amount about the process. But the experience sounded strange, disorienting, and mysterious. Despite having done my research, I still didn’t feel like I had a good idea of exactly what it would feel like.

I was also crying simply from sadness. I’d been trying for almost 10 years to manage my depression with medications and therapy but felt worse than ever. The many medications I’d been prescribed over the years would work for a little while, then inevitably stop being effective, sending me into a progressive spiral that would worsen every time. I felt like I'd tried everything, but that wasn’t quite true. I hadn’t tried ketamine.

Ketamine has been used as an anesthetic since the1960s. In the 1990s and 2000s, researchers began looking into trying it off-label as an antidepressant. Fairly recently, it has come into use for people with treatment-resistant depression, as well as people with other diagnoses, like bipolar disorder and post-traumatic stress disorder (PTSD). (It’s also used for treating pain.) Ketamine clinics have opened in select states throughout the U.S., including California, where I live.

Ketamine is available in a couple of different forms: It can be administered through an IV or ingested via a nasal spray called esketamine. Esketamine is approved by the FDA for the treatment of treatment-resistant depression. IV ketamine is not, and thus treating depression with ketamine is an off-label use. Ketamine lozenges are also available to some patients.

I was about to give IV ketamine a try, and although I was terrified, the unknown was preferential to continuing on the same path I was used to because it came with a massive potential benefit: finally finding relief from my depression.

What ketamine can do for depression

Ketamine has been shown to be effective in treating symptoms of depression and can be especially helpful for treatment-resistant depression (TRD), which is generally defined as “inadequate response to at least one antidepressant trial of adequate doses and duration,” according to a study published by Harvard Medical School. If you’ve tried multiple antidepressant medications (possibly in combination with other treatments) without success, you might have treatment-resistant depression.

In several studies at Yale, more than half of the participants who were given ketamine infusions showed a significant decrease in symptoms associated with depression after only 24 hours. These results are significant for two primary reasons: One, these participants were people who had experienced no “meaningful improvement” on other antidepressants. Two, the alleviation of depression symptoms after just 24 hours is extremely fast compared to other antidepressants, which can take weeks to kick in. To a severely depressed person who might be experiencing suicidal ideation, a fast-acting treatment could make all the difference in the world.

John Krystal, the Robert L. McNeil Professor of Translational Research and chair of the Yale department of psychiatry, believes that ketamine is a promising treatment for depression for several reasons. First, it can be effective for people whose depression symptoms have not responded to other treatments. Second, as noted above, the effects are rapid. “People who are severely depressed, suicidal, and might otherwise need hospitalization may get better as quickly as 24 hours after their first dose,” says Krystal.

A third reason is that ongoing ketamine therapy can protect a patient against a return of depression symptoms. “The reason that this is so important is that even after trying many different treatments, as many as 30 percent of patients will remain significantly depressed,” Krystal tells me.

How it works

Robert C. Meisner is the medical director of the McLean Ketamine Service in the psychiatric neurotherapeutics program at McLean Hospital, the major psychiatric hospital for Harvard Medical School. In an article for Harvard, he writes that experts aren’t exactly sure how ketamine works to combat depression, but that one likely target is N-methyl-D-aspartate (NMDA) receptors in the brain. “By binding to these receptors, ketamine appears to increase the amount of a neurotransmitter called glutamate in the spaces between neurons,” Meisner writes. Then it activates connections in another receptor, called the AMPA receptor.

“Together, the initial blockade of NMDA receptors and activation of AMPA receptors lead to the release of other molecules that help neurons communicate with each other along new pathways,” writes Meisner. This process likely affects mood, thought patterns, and cognition.

Ketamine may also reduce symptoms of depression in other ways, such as reducing signals involved in inflammation. Meisner and other experts theorize that ketamine likely works in several different ways at the same time.

Potential risks of ketamine therapy

I asked Meisner about the risks of ketamine therapy, including whether ketamine can be addictive. “All of us who specialize in this area remain concerned about the potential for physiologic and psychological dependence,” he tells me. At his clinic, for example, a previous history of substance use usually means a patient will not be treated with ketamine (though there are some rare exceptions).

“It’s important to understand that even though you may suffer from treatment-resistant depression, ketamine may not be the wisest choice,” he says.

That said, Meisner and his colleagues have not seen a high volume of patients who show signs of ketamine addiction. “To the best of my knowledge, we have received only one consultation request over the phone in which the caller was seeking treatment with ketamine for reasons consistent with addiction,” he tells Allure. “Moreover, to the best of my knowledge, not a single one of our patients has gone on to develop physiologic or psychologic dependence to ketamine after completing our protocol.”

However, experts remain alert about any potential for abuse. Currently, there is an epidemic of oral ketamine abuse in parts of Asia. Ketamine as a street drug is quite a different experience from ketamine as a treatment for depression (and street drugs carry the risk of being cut with other substances), but epidemics like this are always cause for concern.

In addition, there are some basic physiological changes that happen when ketamine is administered, such as a rise in blood pressure. For many patients, this isn’t a problem, but if you have some preexisting conditions, it may pose a health risk. That’s why it’s so important to find a ketamine clinic that prioritizes safety.

The financial cost

Ketamine therapy isn’t cheap. When I was determining where to go for my ketamine infusions, I asked about pricing at several clinics. The range I found in the Los Angeles area was $450 per infusion (the lowest price I could find) to $750 per infusion. Anecdotally, the highest price I’ve heard of is $1,000 per infusion. The clinic I ultimately went with charged $750 for the first two infusions and $600 for all subsequent infusions.

In other U.S. states, the price varies, but it’s never exactly an inexpensive option. (A map of “active clinics in good standing” from the website Ketamine Clinics Directory lists the price of ketamine infusions at clinics across the U.S. The lowest price listed is $250 per infusion, at a clinic in New Jersey.) Many clinics recommend six initial infusions, though of course, they can’t make you do any more than you want to.

The other big question associated with cost is whether health insurance will cover it. All of the clinics I spoke to in Los Angeles billed out of network, meaning that my insurance company might end up covering some of it, but either way, I would have to front the cost. (After many months, I am still waiting to hear back from my insurance company about whether I will be reimbursed for any of my treatments.)

If you have health insurance, you’re at the mercy of your insurance company to determine whether they’ll cover any of your ketamine therapy. To be fair, this is true of most medical procedures that are still considered experimental. I haven’t found a clinic that is an in-network provider for any health insurance plans, although that doesn’t mean they don’t exist. If you don’t have health insurance, of course, you’ll be paying the cost yourself. This can add up to many thousands of dollars, depending on the number of infusions you receive. On the bright side, some ketamine clinics offer payment plans.

If you are able to find an academic center in your area, the pricing may be different. At this time, it’s difficult to find any comprehensive list of prices throughout the U.S., so it’s important to call around and ask for pricing information when you’re doing your research.

What it feels like

This remains the most difficult part of the ketamine process to describe. Even after seven sessions, I never got very good at describing what it feels like to undergo a ketamine infusion.

I spoke to a writer, who I’ll call Rebecca for the purposes of anonymity, who was prescribed esketamine after suffering from treatment-resistant depression for many years. She described her first two experiences of esketamine (which were a higher dose than her subsequent doses) thusly: “There was a physical sensation of heaviness but at the same time I felt separated from my body. Or it might be more accurate to say, separated from my consciousness. I was able to view certain things more objectively. Things that were upsetting suddenly seemed less important.”

This description rang true for me. If you’ve ever done a hallucinogen, like LSD or mushrooms, this probably all sounds familiar to you. Ketamine felt similar to other hallucinogens but way more intense, and for me, it lacked any feeling of euphoria, though I did find myself laughing during several of the treatments.

Now, let's talk results

Like almost anything, the effects of ketamine therapy vary greatly from person to person. Studies show that ketamine is associated with a rapid reduction in depression symptoms, including suicidal ideation. Overall, ketamine is promising in terms of its general effectiveness, as well as its fast-acting properties.

However, that doesn’t mean it will be effective for every individual. Like any treatment for depression, there is, unfortunately, no way to test whether it will be effective for a given person. When intravenous ketamine does work, patients usually respond to it within one to three treatments. If a patient doesn’t respond at all to those initial treatments, further infusions are not likely to be effective.

In addition, most experts agree that ketamine works best as part of a larger treatment plan, which usually involves talk therapy and sometimes ongoing use of antidepressant medication. Meisner says "it’s important to remember that ketamine is not a magic bullet."

In my case, the first two treatments did not feel effective to me, although I experienced mild euphoria for short periods after each of them. After my third infusion, though, I began to feel significantly better. Many of my symptoms subsided, I felt “lighter,” and I laughed a lot more.

Between my third and sixth infusions, and for about a week afterward, I continued to feel relief from my previous symptoms. Unfortunately, that relief faded quickly. My symptoms returned about a week after I finished my sixth infusion. Ketamine’s effects are known to be relatively short-term; the staff at my ketamine clinic told me that most of their patients feel relief for about three months after completing six infusions. I was one of the people who experienced its effectiveness for a very short time. After trying a seventh infusion, I was prescribed ketamine lozenges, which are supposed to prolong the effects of the ketamine infusions. I do find the lozenges effective, though for very short periods. For me, their effects last about a day.

However, I spoke to other people who reported success with ketamine therapy. Rebecca, who takes esketamine for depression, has experienced a significant reduction in her symptoms.

Her first two doses were eight sprays each, taken under the doctor’s supervision, followed by a “maintenance dose” of two sprays a week, taken at home. Rebecca told me that she experienced immediate positive effects, that it boosted her energy levels and took the edge off her depressive symptoms. Before the ketamine treatment, her depression was causing her debilitating levels of “brain fog,” negatively affecting her memory and cognition. She feels that the esketamine, which she continues to take at home, is helping with that. She says that after about a month and a half of treatment, she’s cautiously optimistic.

How to seek out ketamine therapy

If you’ve been diagnosed with major depressive disorder (MDD), bipolar, or PTSD (or some other diagnoses, in some cases), and other treatments haven’t helped you, you might be a good candidate for ketamine therapy. However, it’s important to get an opinion from your psychiatrist first as to whether ketamine is a good option for you. “They may not be especially familiar with these emerging treatments, but they should understand your response to first-line antidepressants and be able to offer an opinion regarding the likelihood that further trials with more established medications will yield different results,” says Meisner.

Start by researching ketamine clinics in your area. Again, this map is a handy place to start, though it’s not comprehensive, and the quality of each clinic is not guaranteed. If you don’t feel up to doing this research, this is a great project to ask a non-depressed loved one to do for you. The person doing the research should determine a reasonable distance from where you live and call any ketamine clinics in that area. They should ask about price, insurance options, payment plans, and how many initial sessions the clinic recommends.

Many clinics recommend six infusions within a two- or three-week period, so if you do go ahead with treatment, be sure to schedule them when you can spare that time. My infusions lasted 55 minutes each, plus 15 to 20 minutes of recovery time afterward — you need some time before you are steady enough to walk again. You also can’t drive yourself home after an infusion, and you will feel fuzzy and possibly sleepy in the hours afterward, so schedule accordingly. Also worth noting: My clinic instructed me to fast for four hours before each infusion.

What to look for in a ketamine clinic

Additionally, many ketamine clinics will ask to be put in contact with a therapist, psychiatrist, or general practitioner who can confirm your diagnosis, so have that information ready. Meisner also stresses the importance of finding a ketamine clinic that’s evidence-based and data-driven, and that puts safety first. He has a few key recommendations for anyone considering ketamine treatment:

- Seek out a specialist who is “not only willing — but enthusiastically supports — close collaboration with your outpatient psychiatrist.” Collaboration of this kind can be time-consuming and is often not reimbursed but is extremely important with “emerging treatments” like ketamine.

- Find a specialist who is willing to be transparent about the uncertainties of ketamine treatment. “This is not a sub-field in which arrogance — of any kind — is a marker for competence,” says Meisner. “If you sense someone is overpromising, they probably are.”

- Be relentless about ensuring that the clinic has appropriate safety measures in place. “Don't be afraid to ask what specialists are on sight, and why they are qualified for a psychiatric use of a medication typically categorized as an anesthetic,” says Meisner. "For example: Are both a psychiatrist and an anesthesiologist present? What sort of training does staff have that qualifies them to administer ketamine? And crucially, what kind of monitoring is in place during treatment?"

In all honesty, I wanted ketamine to cure my depression instantly and forever. Deep down, though, I think I knew it couldn’t do that. Ketamine isn’t for everyone, and it isn’t a magic bullet. But it taught me that my brain, as hopelessly entrenched in sadness as it sometimes seems, has the potential to change, and that it’s possible for me to feel better. For those of us who have spent a long time suffering and who have been unable to find an effective treatment, ketamine therapy offers a ray of hope. For some of us, that hope can be life-saving.

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High doses of ketamine found to temporarily 'switch off' the brain

University of Cambridge | | Science Daily | 11 Jun 2020

Researchers have identified two brain phenomena that may explain some of the side-effects of ketamine. Their measurements of the brain waves of sheep sedated by the drug may explain the out-of-body experience and state of complete oblivion it can cause.

Researchers have identified two brain phenomena that may explain some of the side-effects of ketamine. Their measurements of the brain waves of sheep sedated by the drug may explain the out-of-body experience and state of complete oblivion it can cause.

In a study aimed at understanding the effect of therapeutic drugs on the brains of people living with Huntington's disease, researchers used electroencephalography (EEG) to measure immediate changes in the animals' brain waves once ketamine -- an anaesthetic and pain relief drug -- was administered. Low frequency activity dominated while the sheep were asleep. When the drug wore off and the sheep regained consciousness, the researchers were surprised to see the brain activity start switching between high and low frequency oscillations. The bursts of different frequency were irregular at first, but became regular within a few minutes.

"As the sheep came around from the ketamine, their brain activity was really unusual," said Professor Jenny Morton at the University of Cambridge's Department of Physiology, Development and Neuroscience, who led the research. "The timing of the unusual patterns of sheep brain activity corresponded to the time when human users report feeling their brain has disconnected from their body."

She added: "It's likely that the brain oscillations caused by the drug may prevent information from the outside world being processed normally."

The findings arose as part of a larger research project into Huntington's disease, a condition that stops the brain working properly. The team want to understand why human patients respond differently to various drugs if they carry the gene for this disease. Sheep were used because they are recognised as a suitable pre-clinical model of disorders of the human nervous system, including Huntington's disease.

Six of the sheep were given a single higher dose of ketamine, 24mg/kg. This is at the high end of the anaesthetic range. Initially, the same response was seen as with a lower dose. But within two minutes of administering the drug, the brain activity of five of these six sheep stopped completely, one of them for several minutes -- a phenomenon that has never been seen before.

"This wasn't just reduced brain activity. After the high dose of ketamine the brains of these sheep completely stopped. We've never seen that before," said Morton. Although the anaesthetised sheep looked as though they were asleep, their brains had switched off. "A few minutes later their brains were functioning normally again -- it was as though they had just been switched off and on."

The researchers think that this pause in brain activity may correspond to what ketamine abusers describe as the 'K-hole' -- a state of oblivion likened to a near-death experience, which is followed by a feeling of great serenity. The study was published in the journal Scientific Reports.

Ketamine abusers are known to take doses many times higher than those given to the sheep in this research. It is also likely that progressively higher doses have to be taken to get the same effect. The researchers say that such high doses can cause liver damage, may stop the heart, and be fatal.

To conduct the experiment sheep were put into veterinary slings, which are commonly used to keep animals safe during veterinary procedures. Different doses of ketamine were given to 12 sheep and their brain activity recorded with EEG.

Ketamine was chosen for the study because it is widely used as a safe anaesthetic and pain-relief drug for treating large animals including dogs, horses and sheep. It is also used medically, and is known as a 'dissociative anaesthetic' because patients can appear awake and move around, but they don't feel pain or process information normally -- many report feeling as though their mind has separated from their body.

At lower doses ketamine has a pain-relieving effect, and its use in adult humans is mainly restricted to field situations such as frontline pain-relief for injured soldiers or victims of road traffic accidents.

"Our purpose wasn't really to look at the effects of ketamine, but to use it as a tool to probe the brain activity in sheep with and without the Huntington's disease gene," said Morton. "But our surprising findings could help explain how ketamine works. If it disrupts the networks between different regions of the brain, this could make it a useful tool to study how brain networks function -- both in the healthy brain and in neurological diseases like Huntington's disease and schizophrenia."

Ketamine has recently been proposed as a new treatment for depression and post-traumatic stress disorder. Beyond its anaesthetic actions, however, very little is known about its effects on brain function.

"We think of anaesthetic drugs as just slowing everything down. That's what it looks like from the outside: the animals basically go to sleep and are unresponsive, and then they wake up very quickly. But when we looked at the brain activity, it seems to be a much more dynamic process," said Morton.

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Best ketamine clinics and therapists: What to look for, and how to find ketamine clinics near you

by Jennifer Boeder | DoubleBlind | 10 Mar 2021

Ketamine clinics are opening across the country—but they range in quality widely. Here’s what to look for.

Ketamine has been one of the most widely used anesthetics on the planet since the 1960s. So when Yale University School of Medicine researchers discovered in 2000 that ketamine could swiftly relieve symptoms of depression in some patients, numerous ketamine clinics sprang up offering treatments. Mental health experts and ketamine advocates, however, have warned against unscrupulous health centers that tout ketamine as a magic bullet for treatment-resistant depression, bipolar disorder, post-traumatic stress disorder (PTSD), and other diagnoses, without addressing integration, therapy or patient oversight.

Many people seeking ketamine therapy are enormously vulnerable, and have spent years struggling with serious mental health issues. Yet a 2019 investigation published in STAT revealed that “in many cases, clinics don’t have a psychiatrist or other mental health professional on staff, though they are working with challenging patients who haven’t responded to other treatments and may have suicidal thoughts.” Some clinics don’t even require that patients be under the care of a mental health professional. “When ketamine is wielded well, with appropriate guardrails and therapeutic alliances, it can be an incredible accelerator for healing,” says Lauren Taus, a clinical therapist who specializes in addiction and trauma treatment and offers ketamine-assisted therapy. “But ketamine is not a cure—it’s a tool, one that in my experience is most effective when it is wielded as part of a therapeutic process.”

Hallmarks of a good ketamine clinic: What to look for

Mental health professionals on staff. Because ketamine originated as an anesthetic, some ketamine clinics are run by anesthesiologists or nurse practitioners. But depression, bipolar, PTSD and other mood disorders are serious mental health issues, even more serious if they’ve been treatment-resistant. The experts we spoke to recommended that mental health experts be included in all ketamine therapy treatment plans. Phil Wolfson, author of The Ketamine Papers, Director of the Center for Transformational Psychotherapy, and a pioneer in the world of ketamine-assisted psychotherapy, always includes a trained therapist and a medical doctor as part of ketamine treatments. Wolfson’s website cautions against ketamine therapy clinics that take an overly medicalized approach. Knowing how to administer an IV does not mean you know how to properly monitor how a patient’s brain is responding to ketamine.

If a patient is already working with a psychiatrist or therapist, clinics should collaborate with them. Dr. Cristina Cusin, co-director of a ketamine clinic at Massachusetts General Hospital and psychiatry professor at Harvard Medical School, told STAT that her patients are required to have a primary mental health provider to receive ketamine.

Dr. Gerald Sanacora, Professor of Psychiatry at Yale University and the Director of the Yale Depression Research Program, emphasizes strongly that ketamine needs to be one aspect of a larger treatment plan for depression. “Patients will call me up and say they don’t want any other medication or psychotherapy, they just want ketamine,” he told Yale Medicine. “I have to explain to them that it is very unlikely that a single dose, or even several doses of ketamine alone, will cure their depression.”

A thorough screening process and patient assessment.

The American Psychiatric Association strongly recommends that ketamine clinics assess any patient’s physical and mental health status before, during, and after treatment. But as there is no regulated standard of care for ketamine clinics, it’s up to patients to find ketamine therapy practitioners who do thorough screening.

Ethical clinicians will do a thorough pre-treatment evaluation, and take into consideration any medical, psychological or social factors that could affect the treatment. Same-day appointments are another giant red flag.

Realistic projections of the potential for improvement.

Like any drug or therapeutic intervention, the efficacy of ketamine therapy varies greatly, and there are no guarantees of success. Prospective patients should be wary of any clinic that promises results or offers a “cure” for their issues. The authors of a 2016 study published by Neuropsychopharmacology expressed concern that unethical providers could prey upon the pain suffered by many with treatment-resistant depression or other serious mental health problems by guaranteeing relief: “While there is strong evidence that treatment with ketamine can provide significant short-term benefits to a large proportion of individuals suffering from serious, disabling and potentially fatal mood disorders, the treatment has not yet undergone the test of larger-scale clinical trials to demonstrate the durability and safety of long-term treatment.” Simply put, there’s not enough existing data for ketamine clinics to make promises that ketamine will offer relief, and any clinic that does so should be regarded skeptically.

Yale researchers who have been working with ketamine for nearly two decades reported “dramatic” results: In several studies, more than half of the participants showed a significant decrease in depression symptoms after just 24 hours. But it’s important to recognize that 50% of the study subjects did not experience that same rapid decrease. Some subjects felt relief after several days, or several rounds of ketamine infusions, but some patients simply do not respond to ketamine therapy. Responsible clinics will be honest with prospective patients about the potential for success and failure, particularly when dealing with vulnerable people who are struggling with treatment-resistant mental health problems.

After the ketamine clinic: a plan for integration.

Look for a clinic that includes some type of integration as part of the ketamine treatment plan. While psychedelic integration means different things to different people, it can be defined as taking the time to glean the insights gained from a drug experience, processing those insights through journaling, meditation, or talking with mental health professionals or other supportive people in your life, and figuring out how to incorporate those shifts of the experience into daily living. As Juliana Mulligan, ibogaine treatment and integration specialist and Psychedelic Program Coordinator for the Center for Optimal Living, told DoubleBlind, "integration is about processing all the underlying emotional stuff that gets brought up by the psychedelic experience.”

“When ketamine is wielded well, with appropriate guardrails and therapeutic alliances, it can be an incredible accelerator for healing.”

Psychedelic experts see integration as a crucial aspect of the healing these experiences can bring about, and many leading mental health experts who’ve worked with ketamine feel the same way. Dr. Sanacora tells patients that the benefits of ketamine therapy can be much more sustainable as part of a comprehensive treatment plan; Dr. Cusin also cautions against ketamine clinics that see depression as a problem with an easy solution, rather than an ongoing process: “You don’t treat an advanced disease with just an infusion and a ‘see you next time.’ If doctors replace your knee but don’t do physical therapy, you don’t walk again.”

Both Lauren Taus and Dr. Wolfson emphasize the importance of integration in ketamine-assisted psychotherapy. The Sage Institute, a well-regarded psychedelic therapy center that offers ketamine as part of its services, requires patients to undergo several integration sessions with a therapist after receiving ketamine. The Sage Institute defines integration as "a process that helps patients bridge the highly significant experiences you have in psychedelic states with changes in your behavior, ways of thinking and perceiving, personality style, emotional patterns, relationships, as well as your values and worldview.”

Whether they label it integration, therapy or follow-up, ask whether the ketamine clinic you are considering has a plan for managing any issues or roadblocks that arise after treatment.

Ketamine therapy costs

Ketamine is expensive and rarely covered by health insurance (in part because it has not been FDA-approved to treat mental health conditions). Clinics charge anywhere from $350 to close to $1,000 per infusion, and many patients receive at least six rounds of infusions. And while there are movements afoot to make ketamine therapy more affordable to those who need it, the high cost is not only a major barrier to entry, but makes the stakes astronomically higher for those who actually access it.

Some professionals in the ketamine space warn against clinics that require patients to purchase multiple ketamine infusions at once, and argue that reputable clinics should charge for only one ketamine infusion at a time. Some clinics do allow for payment plans.

Ketamine clinic locations: How to find a ketamine clinic near me

As Allegra Ringo noted in an Allure article about her experience with ketamine therapy, the process of locating a reliable ketamine clinic or therapist can be overwhelming—especially if you are dealing with other mental health problems. She advised readers to ask “non-depressed loved ones” for help with online research, emails, and calls.

DoubleBlind has compiled a non-exhaustive list of reputable clinics and practitioners, whose staff and patient care standards comply with the requirements we’ve listed above at the time of this writing.

Ketamine clinics and therapists, Bay Area

The Sage Institute
Oakland, California

Phil Wolfson
San Anselmo, California

Ketamine clinics, Denver

Integrative Psychiatry Centers
Boulder, Colorado

Ketamine clinics and therapists, Los Angeles

California Center for Psychedelic Therapy
Los Angeles, California

Lauren Taus, Inbodied Life
Venice Beach, California

Dr. Jeffrey Becker
Los Angeles and Santa Barbara, California

Ketamine clinics and therapists, Chicago

Dr. Phil Welches
Chicago, Illinois

Michelle Flowers
Deerfield, Illinois

Ketamine clinics and therapists, Portland

Rainfall Medicine

Ketamine clinics, Seattle

AIMS Institute
Seattle, Washington

Ketamine clinics, Michigan

Michigan Progressive Health
Royal Oak, Michigan
Ann Arbor, Michigan

Ketamine clinics, New York

Ember Health
Brooklyn, New York

Ketamine can offer hope for people whose mental health issues seem insurmountable—but it’s more important than ever to make sure the ketamine clinic or therapist you work with operates with transparency, employs mental health experts, views ketamine therapy as a part of a larger treatment process, and treats you as an individual whose therapeutic journey matters.

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Ketamine-induced brain rhythm causes dissociation*

by Lily Aleksandrova, MSc, PhD | Psychedelic Science Review | 21 Oct 2020

While ketamine produces a whole symphony of effects in the brain, surprisingly, a localized neural oscillation in a lesser-known area of the brain is enough to cause feelings of dissociation.

In the last decade, ketamine has received considerable research interest as a novel, rapid-acting antidepressant. Classically used as an anesthetic, it induces feelings of dissociation or disconnection between the mind, body, and outside world. This side effect is reported even at low sub-anesthetic doses. The neural mechanisms of how ketamine causes “out-of-body” experiences have remained elusive.

While monitoring the activity of cells throughout the brain of ketamine-treated mice, Vesuna et al. from Stanford University recently stumbled upon a specific neuronal rhythm deep in the cortex, which may hold the answer. The discovery reported in the journal Nature identified a new brain activity marker for dissociation in mice, and in a rare opportunity for scientists, also in a human. Their findings summarized below, shed more light on the neural mechanisms underlying the mysterious phenomenon of dissociation.

Unique brain wave in mice linked to dissociation following ketamine

According to Vesuna et al., when administered to mice, the dissociative drugs ketamine and phencyclidine (PCP) caused a specific population of brain cells found in layer 5 of the retrosplenial cortex, to fire at a rate of 1-3 times each second. The unique rhythm, which began within 2 minutes of drug injection and lasted 45 minutes, coincided with the mice experiencing a “dissociative-like” state.

The animal dissociative-like behavior was characterized by a disconnect between the perception of incoming aversive sensations, which remained intact, and more complex emotional responses to the threat, which were blunted. Namely, mice still reflexively withdrew their paw from a heat source but failed to lick the paw to cool it off as they normally would (they’re registering the sensation but don’t care about it as much).

Importantly, the ketamine-induced firing pattern caused this cortical region, which normally communicates with the rest of the brain, to become disconnected. Since the retrosplenial cortex plays a role in cognition, navigation, and episodic memories, this could explain why such functions may go “offline” during dissociation.

Next, Vesuna et al. used optogenetics, a cutting-edge technique that shines light onto a brain area of interest to control its activity. Importantly, artificially producing this brain rhythm in drug-naïve mice elicited them to act as if they were under the influence of ketamine. Going one step further, the authors identified a key protein found in retrosplenial neurons, a “pacemaker” ion channel called HCN1, which plays a crucial role in setting this unique rhythm. Specifically, in mice lacking the HCN1 channel, ketamine failed to induce the key oscillation and elicit a dissociation-like state.

Role of deep cortical rhythm in dissociation confirmed

Brain activity in humans can often be measured with electroencephalography (EEG) using sensors placed on the scalp. However, this brain rhythm was located deep in the cortex, requiring more invasive techniques for investigation. Luckily, Vesuna et al. gained access to a unique human volunteer. The patient, who had a form of epilepsy that caused dissociation, had electrodes implanted in the brain (for diagnostic and treatment purposes), allowing for several exciting observations.

First, self-reported pre-seizure dissociation correlated with a similar rhythm localized to the corresponding cortical region in the human brain. Below are excerpts from the patient report describing their pre-seizure dissociation experience.

I was listening to two parts of my brain speak to each other in a way that a third part of my brain, which I considered to be me, was able to listen.”

What would it feel like if someone else were to come into your head?… What I considered me shrank to this other part of me where the other parts of my brain that were talking, I stopped considering them me.”

“…where is this 3D space am I?…I took a blanket…threw it over my body, just to see, because I knew that when I don’t feel it, I don’t consider it me and immediately my legs were no longer a part of me.”

Further, the electrical stimulation of this brain area caused immediate feelings of dissociation in the patient. Even though it represents a single clinical observation, this experiment replicated what was observed in the mouse brain.

Putting these findings into context: Brain waves and the retrospinal cortex

Brain waves refer to rhythmic, synchronized patterns of neural activity. In humans, each of the dominant brain waves (from delta to gamma, 0.5-42Hz) is thought to correspond to a specific brain state (e.g., deep sleep, awake, deep thought, etc.). Such oscillations allow different regions to effectively communicate with each other, similar to tuning the radio frequency to increase the signal and reduce the noise.

Ketamine has been shown to cause global changes in cortical brain waves. In contrast, the dissociation oscillation identified by Vesuna et al. is localized to a very small cell population.6 In simple terms, while ketamine produces a whole symphony of effects in the brain, surprisingly, a single note played by a lesser-known instrument in the orchestra is enough to cause feelings of dissociation.

The retrosplenial cortex has been suggested to play a role in mediating the interaction between perception and memory, as well as in translating between self-centered and world-centered spatial information. While the exact functions of this brain region are still not well understood, it now appears crucial for keeping us tethered to reality.

The clinical significance of this new study

Recent research has primarily focused on identifying the key brain mechanisms responsible for ketamine’s therapeutic actions. Understanding how this drug causes its dissociative effects may facilitate the development of a new generation of safer, more selective antidepressants. However, dissociation may not just be a side effect but an integral component of ketamine’s therapeutic action.

Mammalian brains can temporarily decouple the mind and body, which may be an evolutionarily adaptive mechanism (e.g., during trauma). Ketamine not only hijacks this mechanism, but the level of dissociation reported predicts a more robust and sustained antidepressant response. It is not hard to imagine that being temporarily forced to dissociate from those rigid, negative, and maladaptive beliefs about oneself and the world would be beneficial for patients suffering from depression.

Whether the neural mechanisms identified by Vesuna et al. apply to the mind-altering/out-of-body effects of classical psychedelics (which act through a different brain receptor than ketamine) remains an open question.

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Listening to Ketamine

by Emily Underwood | Knowable Magazine | 19 Mar 2019

The fast-acting drug offers a new way to treat depression and fathom its origins. Recent approval of a nasal spray promises to expand access, but much remains unknown about long-term use and the potential for abuse.

At 32, Raquel Bennett was looking for a reason to live. She’d struggled with severe depression for more than a decade, trying multiple antidepressants and years of talk therapy. "The treatment helped, but not enough to make it seem worth living with a debilitating mental illness," she says. “I was desperate.”

In 2002, following a friend’s suggestion, Bennett received an injection of ketamine, an anesthetic and psychedelic party drug also known as Special K. During her first ketamine trip, Bennett hallucinated that God inserted a giant golden key into her ear, turning on her brain. “It was as if I was living in a dark house and suddenly the lights came on,” she says. “Suddenly everything seemed illuminated.”

The drug lifted Bennett’s depression and dispelled her thoughts of suicide within minutes. "The effect lasted for several months, and," she says, "the respite saved my life." She was fascinated by the drug’s rapid effects and went on to earn a doctoral degree in psychology, writing her dissertation about ketamine. Today, she works at a clinic in Berkeley, California, that specializes in using ketamine to treat depression. “This medicine works differently and better than any other medication I’ve tried,” she says.

When Bennett experimented with ketamine, the notion of using a psychedelic rave drug for depression was still decidedly fringe. Since the first clinical trials in the early 2000s, however, dozens of studies have shown that a low dose of ketamine delivered via IV can relieve the symptoms of depression, including thoughts of suicide, within hours.

Even a low dose can have intense side effects, such as the sensation of being outside one’s body, vivid hallucinations, confusion and nausea. The antidepressant effects of ketamine typically don’t last more than a week or two. But the drug appears to work where no others have — in the roughly 30 percent of people with major depression who, like Bennett, don’t respond to other treatments. It also works fast, a major advantage for suicidal patients who can’t wait weeks for traditional antidepressants to kick in.

“When you prescribe Prozac, you have to convince people that it’s worth taking a medication for several weeks,” says John Krystal, a psychiatrist and neuroscientist at Yale University in New Haven, Connecticut. “With ketamine, patients may feel better that day, or by the next morning.”

The buzz around ketamine can drown out just how little is known about the drug. In the April 2017 JAMA Psychiatry, the American Psychiatric Association published an analysis of the evidence for ketamine treatment noting that there are few published data on the safety of repeated use, although studies of ketamine abusers — who typically use much higher doses — show that the drug can cause memory loss and bladder damage. Most clinical trials of the low dose used for depression have looked at only a single dose, following up on patients for just a week or two, so scientists don’t know if it’s safe to take the drug repeatedly over long periods. But that’s exactly what might be necessary to keep depression at bay.

The analysis also warned about ketamine’s well-established potential for abuse. Used recreationally, large doses of the drug are known to be addictive — there’s some evidence that ketamine can bind to opioid receptors, raising alarms that even low doses could lead to dependence.

Bennett has now been receiving regular ketamine injections for 17 years, with few negative side effects, she says. She doesn’t consider herself addicted to ketamine because she feels no desire to take it between scheduled appointments. But she does feel dependent on the drug, in the same way that a person with high blood pressure takes medication for hypertension, she says.

Still, she acknowledges what most clinicians and researchers contend: There simply aren't enough data to know what the optimal dose for depression is, who is most likely to benefit from ketamine treatment and what long-term treatment should look like. “There’s a lot that we don’t know about how to use this tool,” Bennett says. “What’s the best dose? What’s the best route of administration? How frequently do you give ketamine treatment? What does maintenance look like? Is it OK to use this in an ongoing way?”

Despite the unknowns, pharmaceutical companies have been racing to bring the first ketamine-based antidepressant to market. In March, the US Food and Drug Administration approved a ketamine-derived nasal spray, esketamine, developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. Only two of Janssen’s five phase III trials had shown a benefit greater than taking a placebo. Still, in February an independent panel recommended FDA approval. That makes ketamine the first novel depression drug to hit the market in more than 50 years, notes Carlos Zarate Jr, a psychiatrist who studies mood disorder therapies at the National Institute of Mental Health.

Although clinicians are hopeful that Janssen Pharmaceutical’s newly approved esketamine nasal spray, Spravato, will expand access to treatment, many also worry about the drug’s potential for abuse.

Thousands of people are already flocking to private clinics like Bennett’s, which provide intravenous ketamine infusions. Because the drug was approved in the 1970s as an anesthetic, physicians can legally provide the drug as an “off-label” depression treatment. Many ketamine clinics have long waiting lists or are so swamped that they aren’t accepting new patients, and Janssen’s nasal spray could rapidly expand access to treatment.

But some researchers worry that the nasal spray won’t solve many of ketamine’s problems and could create new ones. Although the FDA is requiring that the nasal spray be administered only in a certified doctor’s office or clinic, esketamine is “every bit as habit forming as regular ketamine,” and will be difficult to keep out of the hands of abusers, says Scott Thompson, a neuroscientist at the University of Maryland and a coauthor with Zarate of a 2019 review on fast-acting antidepressants in the Annual Review of Pharmacology and Toxicology. A nasal spray can’t deliver as precise a dose as an IV infusion, Thompson notes. “If someone has got a cold, they’re not going to get the same dose.”

Scott Thompson (University of Maryland, School of Medicine) discusses the current evidence for ketamine as a psychiatric treatment for severe depression, the unknown risks of long-term use and both the promises and risks of the esketamine nasal spray.

In Thompson’s view, esketamine holds few advantages over generic ketamine, which costs less than a dollar per dose, although the IV infusions in private clinics often cost hundreds of dollars per visit. Janssen has indicated that each esketamine treatment will range from $590 to $885, not including the costs of administration and observation.

Zarate and others are still thrilled to see big pharma investing in ketamine, after decades of stalled efforts to find new psychiatric drugs. “As esketamine hits the market, venture capitalists will come up with better versions and move the field forward,” Zarate says. Several drug companies are now testing other ketamine-like compounds in hopes of developing drugs that have its potent antidepressant potential without its psychedelic and dissociative side effects.

Depression, fast and slow

In 2001, writer Andrew Solomon published a haunting description of the depression that derailed his early 30s: “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure,” he wrote.

When Solomon first fell ill, in the 1990s, many clinicians and researchers presumed that the pathological brain changes underlying depression were inherently slow to repair. This mind-set was rooted in the modest but controversial success of a class of slow-acting drugs that includes Prozac.

Developed in the 1950s, the drugs were first inspired by the chance observation that a hypertension drug called reserpine – an extract of the plant Rauwolfia serpentina, or devil pepper — made people intensely depressed. After discovering that reserpine depletes monoamine neurotransmitters in the brain, including serotonin and norepinephrine, scientists hypothesized that low neurotransmitter levels cause depression. They went on to develop monoaminergic antidepressants, drugs designed to increase circulating levels of these chemicals in the brain.

Today, monoaminergic antidepressants include selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Lexapro and Zoloft, as well as the older and less commonly prescribed monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic antidepressants. Scientists have long debated whether the drugs work at all, but the most comprehensive study to date — published in The Lancet in 2018 — suggests that they do lower depression symptoms in about 60 percent of depressed people, albeit only modestly more than taking a placebo.

The benefits start to show up only after several weeks of treatment, however, and roughly a third of people with major depression disorder – called treatment-resistant patients — don’t respond to at least two types of monoaminergic antidepressant.

By the early 2000s, the monoamine hypothesis had unraveled. This was partly due to the antidepressants’ mediocre performance in patients, and partly to experiments which showed that depleting neurotransmitter levels in healthy people does not make people depressed. Scientists now believe that drugs like Prozac do not directly treat depression’s root cause. Instead, they think the drugs work via an indirect mechanism to subtly boost the growth of synapses and the birth of new neurons, and that this somehow relieves symptoms.

Solomon’s bleak metaphor of corrosion was at least partly grounded in science. Many scientists now agree that depression slowly eats away at the neural pathways underlying our sense of worth and well-being, our desire to go to the movies or get out of bed. But research into ketamine holds out new hope that — unlike rusted iron — the depressed brain can be restored, by repairing and strengthening the neural circuits that regulate mood. — Emily Underwood

Some researchers are also testing whether ketamine works for conditions beyond depression, such as obsessive-compulsive disorder, as well as in specific subsets of patients, such as severely depressed teenagers. Other scientists are using ketamine to help untangle one of the biggest mysteries in neuroscience: What causes depression? (See sidebar.)

Seeking answers in neural wiring

Thirty years ago, the prevailing thought was that low levels of certain brain chemicals, such as serotonin, caused depression. Boosting those could remove symptoms.

“I felt that depression needed months or weeks of treatment — that the plastic changes involved in the healing process would require weeks to reset themselves,” says Todd Gould, a neuropharmacologist at the University of Maryland and a coauthor of the recent review paper. But ketamine’s speed of action casts doubt on that idea.

Newer evidence suggests that depression is caused by problems in the neural circuits that regulate mood, Gould notes. Much of the evidence for this faulty-wiring hypothesis comes from rodents. Starting in the 1990s, scientists began to discover intriguing abnormalities in the brains of mice and rats that had been exposed to certain stressors, such as bullying by a big, aggressive male.

Stress and trauma are strong predictors of depression in people, but scientists can’t ask rats or mice if they are depressed. "Instead, they use behavioral tests for classic depression symptoms such as anhedonia, the inability to take joy in pleasurable activities," Thompson says. Depressed animals “give up easily” in experiments that test their willingness to work for rewards like sugar water, or their interest in the intoxicating scent of a potential mate’s urine. “They can’t be bothered to cross the cage,” he says.

Thompson and others have found that there are fewer connections, or synapses, between neurons that communicate reward signals in the brain in depressed animals. Other labs have found shriveled connections in neuronal circuits key to decision-making, attention and memory. Brain imaging studies in people with depression have also revealed abnormal activity in neural circuits that regulate emotion, suggesting that the findings in rodents may also apply to humans.

If faulty neural connections are to blame for depression, the next question is, “How do we get atrophied neural pathways to regrow?” Krystal says.

Circuit training

The answer, many scientists now believe, is the brain’s most abundant neurotransmitter, glutamate.

Glutamate is the workhorse of the brain. It relays fleeting thoughts and feelings, and enables the formation of memories by strengthening synaptic connections. Glutamate is the reason you can still ride a bike years after you learned, even if you never practiced.

Not all glutamate activity is good. Too much can cause the equivalent of an electrical storm in the brain — a seizure — and chronically high levels may lead to dementia. Abnormalities in glutamate receptors — specialized proteins on the surface of brain cells where glutamate can dock and bind — are linked to a wide array of psychiatric diseases, including depression and schizophrenia.

To maintain balance, cells called inhibitory interneurons act like brakes, releasing a neurotransmitter called GABA that quiets brain activity. Most mind-altering drugs work by changing the balance between GABA and glutamate — amphetamines and PCP enhance glutamate signaling, for example, while alcohol inhibits glutamate and boosts GABA.

By the 1990s, scientists had discovered that ketamine triggers a gush of glutamate in the brain’s prefrontal cortex. This region governs attention and plays an important role in emotional regulation. The out-of-body sensations that some people experience when they take ketamine may occur because this rapid release of glutamate “excites the heck out of a whole bunch of neurons” in the prefrontal cortex, says Bita Moghaddam, a neuroscientist at Oregon Health & Science University who discovered the drug’s glutamate-revving effect on rats while studying schizophrenia.

Scientists aren’t sure yet how ketamine forms stronger neural circuits. But the hypothesis goes roughly like this: When ketamine enters the brain, it causes a short-term burst of neuronal activity that triggers a series of biochemical reactions that create stronger, more plentiful synaptic connections between brain cells.

At first, many researchers thought ketamine’s antidepressant effects relied on a structure located on the surface of neurons, called the NMDA receptor. Like a key that fits into different locks, ketamine can bind to several types of NMDA receptor, making neurons release the excitatory glutamate neurotransmitter.

This hypothesis suffered a blow, however, when several drugs designed to bind to the NMDA receptor (as ketamine does) failed in clinical trials for depression.

Central to the controversy over how ketamine works in the brain is the NMDA receptor (illustrated above), which binds to the neurotransmitter glutamate. Some scientists believe ketamine’s antidepressant effects hinge on its ability to block NMDA receptors, but others believe the drug works via other mechanisms. Resolving that mystery is key to developing similar drugs with fewer side effects, scientists say.

Esketamine also complicates the story. Ketamine is made up of two molecules that form mirror images of each other, R- and S-ketamine. Esketamine is made up of just the S form and binds roughly four times as effectively as R-ketamine to the NMDA receptor. Despite acting much more powerfully on the NMDA receptor, studies in rodents suggest that S-ketamine is a less potent antidepressant than R-ketamine, although it’s not yet clear whether or not R-ketamine could work better in humans.

Zarate and others now believe ketamine may work through a different receptor that binds glutamate, called AMPA. By pinpointing which receptor ketamine acts on, researchers hope to develop a similar drug with fewer side effects. One hot lead is a compound called hydroxynorketamine (HNK) — a metabolic byproduct of ketamine that does not affect NMDA receptors but still produces rapid antidepressant effects in rodents. The drug appears to lack ketamine’s disorienting side effects, and Zarate and Gould plan to launch the first small clinical trials to establish HNK’s safety in humans this year, likely in around 70 people. “I think we have a very good drug candidate,” Gould says.

Plastic synaptic remodelers

To alter how the brain processes mood, scientists believe ketamine must ultimately change synapses. In experiments in rodents, Ron Duman of Yale University has shown that both ketamine and HNK can harness one of the brain’s most important tools for synaptic remodeling: brain-derived neurotrophic factor, or BDNF.

BDNF is a protein intimately involved in shaping synapses during brain development and throughout the lifespan. Healthy brain function depends on having just the right amount of BDNF in the right place at the right time. Many mental illnesses, including depression, are associated with low or abnormal amounts of the protein. For example, samples of brain tissue from people who have died by suicide often contain abnormally low amounts of BDNF.

Duman and colleagues have found that both ketamine and HNK cause a sharp uptick in the amount of BDNF that is released from neurons. This increase is required for the drugs’ antidepressant effects, and for the increase in dendritic spines — the stubby protrusions that form synaptic connections with other neurons. Both ketamine and HNK also seem to reduce inflammation, which has been linked repeatedly to the stress-induced loss of synapses.

Ketamine strengthens connections between brain cells. Compared with a control, a rat neuron (red) treated with ketamine has grown more dendritic spines (shown by yellow arrows).

Ketamine is not the only compound that can induce rapid synaptic plasticity: Other psychedelics, such as ecstasy (MDMA), acid (LSD), and DMT also trigger similar structural changes in neurons and rapid antidepressant effects in rodents, researchers at the University of California at Davis recently found. The effects don’t hinge on getting high, the team reported in March in ACS Chemical Neuroscience. Even very small doses — too low to cause perceptual distortions — can increase synapse density and lift depression.

Traditional antidepressants such as Prozac also increase BDNF levels in the brain, but not nearly as fast as ketamine does, Duman says. That is why most antidepressants take so long to remodel synapses and relieve depression symptoms, he says.

Dissecting depression

Beyond promising new treatments, Zarate and other researchers see ketamine as a powerful tool for probing depression’s tangled neurobiology. Studies in mice and rats are a good start, but scientists need to study the drug in people to truly understand how ketamine affects the brain. Unlike traditional, slower-acting antidepressants, ketamine lends itself to short-term lab experiments.

Zarate is using neuroimaging tools such as fMRI to study the human brain on ketamine. Past studies have shown that in people with depression, communication among several key brain networks is disrupted. One network, called the default-mode network (DMN), is involved in self-referential thoughts such as ruminating about one’s problems or flaws. This network tends to be hyperactive in people with depression, and less connected to more outwardly attuned brain networks such as the salience network, which helps the brain notice and respond to its surroundings.

Ketamine appears to strengthen connections between neural networks in people with severe depression. In a study comparing neural activity prior to a ketamine infusion, and six to nine hours after an infusion, a single dose made the brain more responsive to a simple sensory stimulus, the light stroking of a finger.

In one recent study, Zarate and his colleagues found that after receiving an IV dose of ketamine, people with depression had more normal activity in the default mode network, and that it was better connected to the salience network. At least temporarily, the drug seems to help people get unstuck from patterns of brain activity associated with repetitive, negative thoughts. Zarate does caution that the study results need to be replicated.

The team has also used brain imaging to study how ketamine affects suicidal thoughts. About four hours after an infusion of ketamine, a chunk of the prefrontal cortex that is hyperactive in people with depression had calmed down, researchers found, which correlated with people reporting fewer thoughts of suicide.

Ketamine also seems to tune other brain regions that are key to effective treatment. Last year, scientists published a study in mice showing that ketamine quiets abnormal activity in the lateral habenula, a small nodule wedged deep under the cortex. Some researchers have described the lateral habenula as the brain’s “disappointment center.” The region is responsible for learning from negative experiences, and is hyperactive in people with depression, as if “broadcasting negative feelings and thoughts,” Thompson says.

Such studies remain exploratory. As to why ketamine works — and just as important, why its effects are transient — scientists are still speculating. “I think ketamine is resetting neural circuits in a way that improves the symptoms of depression, but the risk factors — whether genetic, environmental or other risk factors — are still present,” Gould says. “It seems to help reset things temporarily, but the underlying cause is not necessarily resolved.”

Helen Mayberg, a neurologist at Mount Sinai Hospital in New York who specializes in using an experimental procedure called deep brain stimulation to treat depression, suggests that ketamine may be like using a defibrillator on someone experiencing cardiac arrhythmia. “I am not addressing the fact that you have underlying heart disease, but now that your arrhythmia is gone, I can concentrate on other treatments.”

It’s important to put the potential risks of ketamine into perspective, particularly for people contemplating suicide, researchers emphasize. Most people are willing to tolerate severe side effects for other life-saving treatments, such as cancer drugs, Mayberg points out. “If you can interrupt an extreme suicidal plan and ideation, I’ll take that.”

Ketamine in teens?

For Krystal, weighing ketamine’s still largely uncharted risks and potential rewards ultimately comes down to a deeply personal question: “What would we want for ourselves? For our families? Do we want them to have to go through several failed trials over several months, or even a year, before taking a medication that might make their depression better in 24 hours?”

Some of the hardest decisions are likely to involve children and adolescents. Hospitalization for youth suicide attempts and ideation nearly doubled between 2008 and 2015, leaving many clinicians — and parents — desperate for more effective and rapid treatments. "Left untreated, depression is “really bad for the brain” and can cause serious, long-term cognitive and developmental problems when it starts young," Zarate says. “The question is, is that going to be better than the long-term side effects of ketamine?”

Untreated depression is really bad for the brain, especially in the young. The question is, is that going to be better than the long-term side effects of ketamine?

Scientists don’t yet know. Ketamine has been deemed safe to use as an anesthetic in children, but there aren't yet sufficient clinical data to show how low, repeated doses of ketamine used for depression could affect the developing brain.

On a more fundamental level, scientists don’t fully understand the neurobiology of adolescent depression, notes psychiatrist Kathryn Cullen of the University of Minnesota. "It may involve abnormalities in brain development, such as the way the prefrontal cortex connects to brain regions that process emotion, but we don’t know if the brain connection abnormalities emerge because of toxic stress induced by depression, or if these abnormalities predispose people to develop depression, or if depression itself reflects abnormal development,” Cullen says. “It’s critical to figure out how to alleviate the biological changes that are associated with [teen] depression so that the brain can get back on a healthy trajectory.”

Two recent clinical trials — one at Yale and another at Minnesota run by Cullen — have found that ketamine can lower symptoms in severely depressed teenagers, but neither study was set up to follow the teenagers long-term, says Cullen. Janssen is currently running a trial of its esketamine nasal spray with 145 youths who are suicidal, but the results of that study have not been published yet. Cullen thinks ketamine has potential for use in teens, particularly to avoid suicide, but “there are still a lot of unknowns.”

Not just a quick fix

Worldwide, depression afflicts more than 300 million people, making it the leading global cause of disability. When contemplating such overwhelming misery, the vision of a world in which depression can be cured with a single injection or squirt of nasal spray holds obvious appeal.

Thousands of private clinics in the United States, such as this outpatient clinic in Chicago, are offering repeated ketamine treatment off-label for depression and suicidal thoughts, but the drug's effects are temporary and scientists still don’t know whether taking the drug over long periods is safe.

"But — despite the hype — that is not what ketamine offers," Bennett says. Based on her own experience as a patient, and her clinical work, she is troubled by the framing of ketamine as a “rapid” depression treatment if that precludes the slower, more effortful process of psychotherapy. "Without psychotherapy," she says, “you’re not giving patients any tools to help themselves, just making them dependent on a molecule that has temporary effects. When the effect wears off, they have to go back for more medicine. This is going to be lucrative for the pharmaceutical company but probably not in the patient’s best interest.”

In Bennett’s clinic, ketamine is administered only alongside talk therapy, which she uses to prepare patients before they take ketamine, and afterward to help them process the experience. “I think this is the only ethical way” to administer a drug that can trigger disorienting psychedelic experiences," she says. “This isn’t a ‘take two and call me in the morning’ situation.”

There’s growing scientific interest in whether ketamine can enhance the effectiveness of therapy by increasing the brain’s ability to remodel circuits through experience, Krystal notes. And in 2017 a small Yale study found that providing cognitive behavioral therapy in tandem with ketamine can extend the drug’s antidepressant effects.

Unlike some researchers and pharmaceutical companies, which consider ketamine’s and esketamine’s psychedelic side effects inherently negative, Bennett thinks that for some people the visions can be positive — particularly in the context of therapy. There’s scant scientific evidence to support the idea that such hallucinations are therapeutic, and they can be deeply disturbing for some people. (If people who experience hallucinations do better, it may simply be because they have received a higher dose of ketamine, Krystal points out.)

Still, Bennett thinks researchers and clinicians need to stay open-minded about why ketamine is helping people — and be more attentive to the settings in which ketamine and esketamine are administered. “People consistently report that they experience the presence of God, or their own sacredness,” she says. “When someone comes to my office wanting to kill themselves, ready to die — and then they have a transformational moment where they believe their life is sacred — it’s indescribable how exciting that is as a clinician.”

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Ketamine found to normalize hyperactivity in a key brain region of depressed patients*

by Christian Rigg | PsyPost | 4 Apr 2021

There is no shortage of psychological and pharmacological therapies to combat the world’s most widespread mental health issue, major depressive disorder (MDD). However, a significant portion of the affected population fail to respond to many of these traditional therapies. For this reason, new drugs must be tested and validated. One promising candidate is ketamine –famously but somewhat improperly known as a horse tranquilizer.

However, the manner by which ketamine acts is not well known, meaning that clinicians are still circumspect regarding its use in treating MDD. Recently, researchers in New York look at how ketamine affects the subgenual anterior cingulate cortex (sgACC), a region of the brain whose hyperactivity has proven ties to MDD. The recent study, which appeared in Neuropsychopharmacology, helps bridge this gap in the literature.

In the study, 28 patients with MDD and 20 healthy controls underwent function MRI (fMRI) scans both at rest and while completing a monetary incentive-based task. The goal of the incentive task was to activate the sgACC, known to be implicated in reward anticipation.

The results of the study demonstrate a more complex relation between the sgACC and MDD than has been previously suspected. The authors evoke the existence of a “double dissociation whereby sgACC hyper-activation to positive feedback is associated with anhedonia [inability to feel happiness], whereas hyper-activation to negative feedback is associated with anxiety.”

This also enabled them to uncover what may be an important physiological distinction in the region, where the posterior region was more closely related to symptoms of anhedonia and the anterior region to anxiety.

In terms of a pharmacological treatment, ketamine was shown to operate by reducing sgACC hyperactivation to positive feedback. If this seems counterintuitive, it is important to remember that many brain centers are inhibitory by nature, meaning that the more active they are, the more strongly they inhibit other areas—thus producing, for example, a reduced response to positive feedback. Interestingly, the ketamine treatment blunted sgACC hyperactivation in response to positive feedback, but not negative feedback.

The neurological underpinnings of MDD are still not well understood. The same can be said for many of the drugs used in treating it. Rigorous clinical testing and exploratory studies like the present are thus essential in improving our understanding of both this disease and treatment options.

The study, “Ketamine normalizes subgenual cingulate cortex hyper-activity in depression,“ was authored by Laurel S. Morris, Sara Costi, Aaron Tan, Emily R. Stern, Dennis S. Charney, and James W. Murrough.

*From the article here :
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Laurie Higbed, Ben Sessa and Steve O’Brien at Awakn in Bristol, the UK’s first high-street provider of
psychedelic-assisted psychotherapy.
‘The ketamine blew my mind’: Can psychedelics cure addiction and depression?

by Alexandra Jones | The Guardian | 13 Mar 2021

This week sees the opening of the first UK high-street clinic offering psychedelic-assisted therapy. Could popping psilocybin be the future of mental healthcare?

In the summer of 1981, when he was 13, Grant crashed a trail motorbike into a wall at his parents’ house in Cambridgeshire. He’d been hiding it in the shed, but “it was far too powerful for me, and on my very first time starting it in the garden, I smashed it into a wall”. His mother came outside to find the skinny teenager in a heap next to the crumpled motorbike. “I was in a lot of trouble.”

Grant hadn’t given this childhood memory much thought in the intervening years, but one hot August day in 2019, it came back to him with such clarity that, at 53, now a stocky father of two, he suddenly understood it as a clue to his dangerously unhealthy relationship with alcohol.

The day before, a team of specialists at the Royal Devon and Exeter hospital had given him an intravenous infusion of ketamine, a dissociative hallucinogen, in common use as an anaesthetic since the 1970s, and more recently one of a group of psychedelic drugs being hailed as a silver bullet in the fight to save our ailing mental health. To date, more than 100 patients with conditions as diverse as depression, PTSD and addiction have been treated in research settings across the UK, using a radical new intervention that combines psychedelic drugs with talking therapy. What was once a fringe research interest has become the foundation of a new kind of healthcare, one that, for the first time in modern psychiatric history, purports to not only treat but actually cure mental ill health. And if advocates are to be believed, that cure will be available on the NHS within the next five years.

Thanks to its world-leading academic institutions, the UK has become a home to many of the biotech companies developing these treatments. But while investment money pours in and new experimental trials launch almost weekly, ketamine remains the only psychedelic drug that’s actually licensed for use as a medicine.

Under its influence, Grant had an out-of-body experience he struggles to put into words. “It was like I was sinking deeper and deeper into myself,” he says. “Then I became white… and I left my body. I was up on the ceiling, looking at myself, but I was just this white entity. I felt very serene and humbled; I finally understood my place in the universe, just a white speck of light, I wasn’t the centre of everything and that was fine.”

The next day, in a therapy session at the hospital, the motorbike story and other memories swirled up from his subconscious: being caught smoking at school and caned, and other instances of “playing up” as a child. Most vividly, he remembers the consequences: “I got my parents’ attention.”
"I realised feeling overlooked as a child drove my drinking. It hadn’t been on my radar – but with ketamine I got there."

His parents were evangelists; Grant’s father was a teacher and lay preacher, and his mother ran a nursery from home. They were also fosterers who, over the span of their marriage, gave a home to more than 200 children. “Growing up, love was never in short supply,” Grant says. What was in short supply was his parents’ attention. “They had a lot of commitments, they were very busy people,” he says. “I suppose what I realised in that therapy session was that I’d felt overlooked as a child and that had caused me pain.” Over the years, that pain crystallised, and alcohol became a crutch. “I could see it was the root of the negative emotions that drove my drinking, and a lot of other bad habits and behaviours.” He says it’s a realisation he might have taken years to come to with standard talking therapy. “It wasn’t even on my radar, so it blew my mind. To understand myself and my drinking, and why I behaved the way I did… With the ketamine therapy I got there in a few weeks. I feel free.”

In recent years, research into psychedelic-assisted mental healthcare has shed its outsider status. As far back as 2016, Robin Carhart-Harris and his team at Imperial College London published promising findings from the world’s first modern research trial investigating the impact of psilocybin (the active ingredient in magic mushrooms) alongside psychological support, on 19 patients with treatment-resistant depression (TRD). This is when a person doesn’t respond to two or more available therapies; it is particularly debilitating and, recent data shows, affects about a third of all people with depression. In the study, two doses of psilocybin (10mg and 25mg, seven days apart), plus therapy, resulted in “marked reductions in depressive symptoms” in the first five weeks, which “remained significant six months post-treatment”. This new treatment proved so promising that, in 2018, the US Food and Drug Administration (FDA) awarded breakthrough therapy status to psilocybin (given only to drugs that “demonstrate substantial improvement over available therapy”) as a treatment for TRD. In December 2019, a ketamine-like drug – esketamine – was licensed for use in the UK as a rapid-onset treatment for major depression: it starts working in hours, compared with weeks or months with traditional antidepressants. In April 2020, after running their own psilocybin-assisted psychotherapy study, with 24 participants who had depression, experts from Johns Hopkins University in the US issued a press release stating: “The magnitude of the effect we saw was about four times larger than what clinical trials have shown for traditional antidepressants on the market.”

All this, and other early-stage evidence, is fuelling larger, more ambitious investigations. The London life sciences company Compass Pathways, whose research led to the FDA award, is coordinating one of the biggest psilocybin for TRD studies in the world, involving 216 patients across Europe and North America. The aim is to develop a new style of therapy that harnesses the psychedelic experience, as well as to change these substances’ classification, so they can be licensed as medicines. This wouldn’t change the legal status of MDMA or psilocybin (banned for recreational use in the UK), but it would mean treatments using these compounds could be prescribed.

In the meantime, practitioners of this new kind of mental healthcare can use ketamine as their psychedelic agent; and some studies, such as the one Grant participated in, are even government funded. The Ketamine for Reduction of Alcoholic Relapse (Kare) study is a novel attempt to ease the huge burden on the NHS caused by alcohol-related illnesses. (Two years ago, a major review of inpatient records found that 10% of people in hospital beds in the UK were alcohol dependent, and one in five were doing themselves harm by drinking.) As the Kare study lead, Professor Celia Morgan, tells me, “Three-quarters of people who stop drinking and go through detox will be back drinking within 12 months: that’s not a good recovery rate.”

Patients aren’t merely given a dose and left to their own devices; a new style of therapy was developed for the study which, Morgan says, uses principles from cognitive behavioural therapy, mindfulness and relapse prevention. “We designed it to go with the ketamine effects. We wanted something evidence based, a therapy that has been shown to help people avoid alcoholic relapse. But also something that would work with what we know about the brain in the ketamine state.” The patient is primed for new learning, she says, and more able to view the self from an outsider’s perspective.

Until now, in the UK, therapy using psychedelics has remained the preserve of academic institutions – available only in research trials with highly specific criteria for inclusion. This week, though, with the opening of its clinic in Bristol, Awakn Life Sciences has become the UK’s first on-the-high-street provider of psychedelic-assisted psychotherapy. The clinical-biotech company is “researching, developing and delivering evidence-based psychedelic medicine to treat addiction and other mental health conditions.” This means it will be developing its own type of psychedelic-assisted psychotherapy (with a focus on MDMA to treat addiction) via experimental trials. And alongside it, delivering ketamine-assisted psychotherapy.

“Our USP is the clinics,” says Dr Ben Sessa, consultant psychiatrist, psychedelic therapist and chief medical officer at Awakn. “We’re aiming to open 15 to 20 across the UK and EU in the next 24 months. Patients will be able to self-refer or be referred by their GP (including NHS).” They will need a formal diagnosis and will most likely have to prove they have already tried a number of other therapies.
"See a psychiatrist at 20 and chances are you still will be at 60. We’ve come to accept we can’t cure patients. Why not?"

Sessa is scathing about the psychiatric profession as it currently operates: “We need innovation in this industry, desperately and now.” The problem, he argues, is that outcomes within psychiatric treatment fall far short of the gold standard set for the rest of the medical profession. “If you broke your leg and went to an orthopaedic specialist, you’d expect it to be fixed,” he says. “You wouldn’t expect to be prescribed painkillers for the rest of your life. But if you present to your psychiatrist in your early 20s with a severe mental illness, there’s a good chance you will still be seeing them when you’re 60. You’ll still be on the same daily drugs.” According to the most recent NHS figures, only half of talking therapy patients recovered from their condition. “What about the other 50%?” Sessa asks. “As an industry, we’ve come to accept that we can never cure our patients. But why not?”

Psychedelic-assisted psychotherapy, he says, may be “the holy grail – curative psychiatry”, arguing that these interventions offer relatively fast-acting alleviation of symptoms and don’t require the same level of maintenance (with drugs or talking therapy) as the treatments currently available.

Though alcoholism is a focus, Awakn will also offer psychedelic-assisted therapy to treat depression, anxiety, eating disorders and most addictions.

On a Monday in late February, the Bristol clinic is abuzz with builders and workmen. Formerly the site of an Indian restaurant, it sits in a 19th-century building on the corner of Regent Street and Hensmans Hill in Bristol’s chi-chi Clifton area. Its position, next to a barber shop and cocktail bar, and overlooking a small park, was picked for its ordinariness. As Awakn’s CEO Anthony Tennyson explains, “Our strategy is to normalise the industry; we want to integrate into the mainstream, so that popping in for mental health treatment is as normal as… ” he trails off. Getting your teeth whitened? “Something like that,” he laughs.

Inside, the clinic is painted a tasteful dove grey, with exposed brickwork and wooden floors. “It’s going to be sort of Scandinavian chic in design,” says Steve O’Brien, the operations manager. “That will be one of the treatment rooms.” He points up a flight of stairs to a room separated from reception by a reinforced glass partition. “We’re waiting for the beds to be delivered.” “Set and setting” (ie the mental state and physical environment) "have been shown to be vital to the psychedelic experience – and a bad setting can equal a bad trip."

This is something O’Brien has experience of. “Years ago I took [the powerful hallucinogen] ayahuasca in Iquitos, Peru. It was all a bit dodgy. I ended up in this dark little hut with breeze-block walls covered in sheets and 12 Peruvian ladies in deck chairs watching Friends really loudly next door. I thought I was going to be ritually sacrificed,” he says. The clinic’s attention to the furnishings and feel of the space isn’t just elegant window dressing: “It’s about preparing a client for their drug experience, allowing them to feel safe and warm. It’s about as far from that Peruvian hut as you can get.”

Patients will be assessed by Awakn’s team, including Sessa and Dr Laurie Higbed, a clinical psychologist who specialises in complex trauma and addictions, who has been part of research trials using both psilocybin and MDMA as adjuncts to psychotherapy. “I was the clinical psychologist, alongside Ben [Sessa as consultant psychiatrist], in an addiction service,” Higbed says. “We used to chat over coffee about how our caseload was full of clients who had experienced trauma in their lives, particularly in childhood. We were treating their heroin or alcohol use, but really that was just a symptom, rather than the cause.”

Her job was to help addicts uncover and work through those underlying traumas via talking therapy. But being forced to remember a trauma we may have spent a lifetime trying to suppress can be very daunting. “Often you get a little bit worse before you get better,” Higbed says, and this requires “a lot of faith that it’s worth the effort.”


Metaphors abound for exactly how psychedelics work on a neurological level but one of the most popular involves considering the brain as a snow globe, showing a pristine scene at birth. As we age, our experiences, habits and the traumas we live through create tracks in the snow for our thoughts to run along. The older we get, the more worn the tracks become, making it harder for us to escape established thought patterns. “So with things like depression,” Higbed says, “you might have this negative worldview which can be very difficult to break free from.” Psychedelic compounds shake up the snow globe. Old ruts are destabilised and thoughts are free to move in new ways.

“This is why therapy is an important part of the treatment,” says Morgan who, as well as running the research trial Grant was a part of, will be consulting on treatments for alcoholism at Awakn. “The drugs alone might prompt big epiphanies, but the therapy helps you to learn from them and create lasting change.” She has seen this process in action. “One patient had been drinking seven bottles of wine a day, and had seen his life crumble,” she says. “His wife left, his daughter stopped speaking to him.” The patient had been abused as a child, and over his lifetime had spent increasing amounts of energy trying to avoid the emotions thrown up by that early trauma. “He had a very strong reaction to the ketamine infusion,” Morgan says. “He said he felt a kind of love and safety that he hadn’t felt for a long time. At one point he felt like he was back in his mum’s tummy.”

As part of the psychedelic experience, he also encountered his abuser, his father. “He said he felt pity for him. This was a massive step because he was able to understand his experiences from the perspective of an observer; the pity also extended to himself, which alleviated a lot of the shame and guilt he’d been feeling because of his alcoholism.” Eighteen months later, the man was still sober – having previously only ever managed a month.

A treatment course at Awakn lasts six weeks, with four drug-assisted sessions in that time. “And a follow-up session at week nine, so it’s 11 in total,” Higbed says. “It’s intensive.” Though, ultimately, they hope to work primarily with MDMA, they’re hamstrung by the current global legislation, which says the drug can be used only in an experimental setting. In the meantime, they’ll offer ketamine injections, more fast-acting than the infusion Grant received, but likely to yield similar results. It will cost “around £6,000,” Tennyson says. “Though our ultimate aim is to make it available on the NHS, to help as many people as possible.”
"It’s not a magical cure. People should definitely try talking therapy first. It does work, and is much less invasive."

Tennyson comes from a corporate finance background (Merrill Lynch, Bank of Ireland and 10 years in the risk consulting arm of the insurer Aon). Like Sessa, he’s evangelical in his belief that the services offered by Awakn have never been more necessary. “Twenty per cent of the population have a mental health issue on an annual basis. The industry that is meant to be fixing this is significantly underperforming,” he says. In fact, according to figures from the mental health charity Mind, that figure is closer to 25%.

Tennyson’s job is to drive sales and generate investor interest. Financially, Awakn needs the clinics to be a success, but it’s also gearing up for a round of funding to help start its own research trials. Tennyson is coy about exactly how much this might cost (one academic confirms it runs to tens of millions) but says, “Ultimately, you can’t solve problems of this magnitude without capital.”

The capital, it seems, is following the science into a psychedelics gold rush. Peter Rands is the CEO of Small Pharma, a London-based life sciences company preparing to run the world’s first formal trial evaluating the combination of DMT (a short-acting but powerful hallucinogen) and psychotherapy to treat patients with major depressive disorder. “2020 was a relatively easy year to raise money into a psychedelics company,” he says, partly because investors understand the proposition now more than ever: “I don’t think this seems like a niche industry any more.” But it’s also because the pandemic proved drugs can suddenly have global demand. “Covid showed how much value there is in responding quickly to a major unmet medical need. Pre-pandemic, the biotech industry was worth a fraction of the price it is now. When drugs were suddenly being touted as a Covid cure, there was huge investor interest.”

A lot of investment, Rands says, is coming from Canada. Small Pharma plans to list on the Toronto stock exchange, and Awakn is incorporated in Toronto. “The Canadian investor community has a higher risk appetite to emerging industries,” Tennyson says. Rands agrees, pointing out that, “until recently, Canadian companies were pretty much all mining companies. And mining has a similar risk-return profile to drug development. In both industries," he says, "huge sums are invested upfront to excavate the necessary goods: “In drug development, that’s through clinical trials.”

In September 2020, Compass Pathways floated on the Nasdaq exchange. In October, it was valued at $1.3bn.

The company was founded in 2016 by Dr Ekaterina Malievskaia and her husband, George Goldsmith, after a years-long battle to find adequate mental healthcare for their son, who had OCD and depression. Goldsmith is quick to correct the narrative about his work. “We don’t see ourselves as part of a ‘psychedelics industry’ – we are a mental healthcare company.”

He is sanguine about how quickly these interventions could become more widely available, likening the process to climbing Everest. “A medicine is a drug plus the evidence that says it’s safe and effective to use for a certain type of patient. We’re about halfway through the process of collecting that evidence. But I think if everything works out well, by 2025 psilocybin-assisted therapy could be prescribed on the NHS for treatment-resistant depression.”

Sessa, whose focus is MDMA-assisted therapies to treat addiction, has a shorter timeline in mind. “MDMA is further along than psilocybin in the regulatory process,” he says. “It is thought it will be approved as a medicine by late 2022 or early 2023.” By that point, if Awakn has realised its ambitions, it will have a clinic in every major city in the UK.

Despite the widespread evangelism from within the psychedelic-assisted psychotherapy field, Higbed resists the idea that it is some kind of panacea. She points out that it doesn’t work for all people, and that many would be put off by the hallucinogenic experience. “It’s not a magical cure,” she insists. “People should definitely try talking therapy first. It does work, and is much less invasive.” She also points out that antidepressants and "other kinds of medications work incredibly well for many people. This is really only for the subset of sufferers who aren’t being helped by what’s currently out there. It’s an innovation in an industry that hasn’t innovated in a long time.”

Dr Andrea Cipriani, a professor at the department of psychiatry, University of Oxford, shares the enthusiasm about the potential for psychedelics, but cautions that there is still a long way to go before they are more widely used. “These are very potent medications which, from a public health policy point of view, means it’s not a straightforward path to delivering this in a wider clinical setting,” he says. “I don’t think ketamine will ever get into the NHS as a first-line treatment; you reach this option only if previous ones have failed. And for the other psychedelics, I think it’s more difficult.”

Meanwhile, Grant hasn’t picked up a drink once since his ketamine treatment. “I haven’t even thought about a drink,” he says. “Problem drinkers struggle so much to control this – they avoid aisles in the supermarket, they carry all this shame. If everyone who needed it had access to this, I truly believe it would change the world.”

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The treatment has helped Grant, 53, stop drinking after years of struggle.

How ketamine helped me kick my alcohol addiction

A new clinic believes that using psychedelic substances to aid psychotherapy can give hope to patients looking to change their lives

by Sharon Walker | The Telegraph | 15 March 2021

Psychedelic-assisted psychotherapy could transform the treatment of chronic mental health issues, offering new hope to patients suffering from the repercussions of childhood trauma or neglect, according to the leading psychiatrist behind a new mental health clinic which opens today.

The private Bristol clinic, run by Awakn Life Sciences, will offer ketamine-assisted psychotherapy for addiction and other mental health issues such as depression and anxiety.

“Many people are failed by the current treatments, especially when it comes to addictions,” says Dr Ben Sessa, psychiatrist and chief medical officer at Awakn.

“We have too many patients who are treatment-resistant and they remain with us (in and out of treatment) for life because there’s to much dependence on the biological model and SSRIs in psychiatry,” says Dr Sessa.

“What we’re offering with drug-assisted psychotherapy is hope, and often the chance to really tackle the rigid stuckness that many patients experience which is so often due to early trauma. When a child has been through this it sets up a blueprint for life and it’s very hard to treat because patients who have been traumatised become absolute experts at avoiding those memories. In ketamine-assisted therapy, we can help the patient get to the root cause of their problem and help them reflect and challenge those issues and move on. It’s going to be used in a number of applications but what underlies all of them is trauma.”

Though it is often branded as a horse tranquilliser, ketamine is far more commonly used in human medicine than in veterinary surgery. “It is the tranquilliser of choice when you don’t know a person’s medical history because it’s so safe,” says Dr Sessa. “As an anaesthetic it knocks the patient out but, 10 or 15 years ago, it was discovered that if you give a low dose that gives an altered state of consciousness and that’s how we are going to be using it in treatments.”

Although ketamine has been used by a small number of doctors to treat depression, this will be the first clinic to combine ketamine with psychotherapy.

Ketamine is also known as a party drug, popular at festivals for its euphoric trance-like effects, though more intense doses can lead to users falling into the “k-hole” with little control of their bodies and habitual long-term abuse has been linked with bladder issues. "Illegal street ketamine is often contaminated and bears little resemblance to the medical-grade ketamine used in therapy," says Dr Sessa.

The first clinical trial into ketamine-assisted psychotherapy, funded by the Medical Research Council, which is under review for publication, would seem to confirm that ketamine-assisted therapy could offer hope to those suffering from entrenched alcohol dependence.

While 75 per cent of patients who undergo alcohol detox generally relapse within a year, a randomised controlled trial of 96 patients with alcohol misuse disorder found that ketamine-assisted psychotherapy was associated with a 50 per cent reduction in relapse at six months, as well as a greater reduction in drinking compared to trial participants who received ketamine alone.

“Though there’s been lots of research on ketamine as an antidepressant, we were missing a trick by not harnessing the ‘ketamine experience,’” explains Prof Celia Morgan, who conducted the research. “How we think it works is by kickstarting the process of growing connections in your brain. In the hours and days following ketamine, we see an explosion of growth in the synapses between neurones in the prefrontal cortex. This manifests psychologically in a sense of awe and wonder. This is what we see in patients given ketamine; they’re much more awake and excited by life. This means that patients start therapy with the right mindset to make therapy most effective. We can give a few isolated doses of the drug but produce long-term change.”

Grant, 53, an events organiser from Glastonbury, was one of the patients randomly assigned to the ketamine-assisted psychotherapy group in the summer of 2019.

“I’d always been a fairly normal party drinker but, after my divorce five years ago, it escalated,” says Grant. “I was binge drinking two bottles of wine a night. Then getting up and doing a 16-mile run to try to offset the effects. But I was still putting on weight and not feeling great. It got to the point where I’d pour the booze down the sink, but then go out and buy some more.”

In the summer of 2018 Grant managed to give up alcohol for three months, but as soon as he drank again he was back to square one. “It was like a piece of elastic,” he says, “I just snapped straight back to it. I was desperate to be that person who can have a glass of wine with a meal, but that just isn’t me. I’m not that person.”

Grant experienced seven sessions of cognitive behaviour therapy, three of which were accompanied by ketamine infusions, over three weeks. “It’s been absolutely life-changing,” he says. “The ketamine was such a profound experience. It was as if my ego dropped away and I felt I was able to access a part of my unconscious where I hadn’t gone before. The therapy allowed me to look at issues from my youth. I wasn’t abused, but I had some issues that were damaging my relationships. I just came away thinking, ‘You’ve got to look after yourself,’ and haven’t drunk since. I don’t even think about it. There’s none of that nagging temptation. It’s given me a path back to how I was before I started drinking,“ he says. Grant has been sober for two years.

While ketamine is currently the only psychedelic drug that can legally be used in therapy, Awakn are researching the use of other psychedelics, such as MDMA-assisted therapy, which also reduced alcohol dependence.

Although currently only available privately, at the cost of £6000 for a nine week course of 11 therapy sessions, including four ketamine infusions, Dr Sessa hopes that psychedelic-assisted psychotherapy will eventually become available on the NHS and through private medical insurance.

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Columbia University Medical Center

Ketamine 'rapid and effective' for reducing suicidal thoughts

by Honor Whitema | Medical News Today

According to a new study by researchers from Columbia University Medical Center, Ketamine — a medication primarily used as an anesthetic — may offer a fast and effective way to reduce suicidal thoughts among individuals with depression.

Depression is by far the most common disorder underlying a suicide attempt; around 30–70 percent of those who attempt suicide have major depression or bipolar disorder.

But how can you tell if a friend or loved one with depression is having suicidal thoughts? Verbal threats of suicide or being a burden to others, an increase in the use of drugs or alcohol, and changes in mood can all be warning signs.

Of course, it is not possible to predict whether a person will attempt suicide, which highlights the need for speedy treatments that can reduce suicidal thoughts.

"There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm," explains study leader Dr. Michael Grunebaum, a research psychiatrist at Columbia University Medical Center.

"Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression," he adds, "but they can take weeks to have an effect."

Dr. Grunebaum explains, "Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients."

Previous research, however, has pointed to ketamine as a potential candidate, after finding that low doses of the drug may help to reduce suicidal ideation in people with depression.

Dr. Grunebaum and colleagues set out to investigate this association further with their new study. Specifically, they investigated whether or not ketamine could reduce suicidal thoughts within 24 hours of administration.

The findings were recently published in The American Journal of Psychiatry.

Ketamine quickly halved suicidal thoughts

The research included 80 adults who had major depression. All participants had suicidal thoughts, as determined by their scores on the Scale for Suicidal Ideation (SSI).

The participants were randomized to one of two treatment groups. One group received a low-dose of ketamine, while the other group received a low-dose of midazolam, a sedative.

Using the SSI, the researchers assessed the presence of suicidal thoughts at 24 hours after each drug was administered.

While both groups saw a clinically significant reduction in suicidal thoughts, this reduction was greater for subjects who received ketamine: 55 percent of the ketamine group experienced a 50 percent or higher reduction in suicidal thoughts, compared with 30 percent of the midazolam group.

Ketamine's effects on suicidal thoughts remained for up to 6 weeks, the team reports. Furthermore, those who received ketamine experienced greater improvements in mood, depression, and fatigue, compared with those who received midazolam.

The team notes the effects of ketamine on depression accounted for around a third of the drug's effects on SSI scores, which suggests that ketamine can directly target suicidal thoughts.

The most common side effects of ketamine were dissociation and an increase in blood pressure upon administration. However, the team notes that these side effects soon subsided.

Overall, the researchers say that their findings show that "ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression."

"Additional research to evaluate ketamine's antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster-acting and have the potential to help individuals who do not respond to currently available treatments."
- Dr. Michael Grunebaum


Ketamine found to rapidly reduce suicidal ideation

Ketamine infusions eliminate suicidal ideation in more than two-thirds of patients

by M. Alexander Otto | Clinical Psychiatry News | May 31 2019

Report of 235 cases is the largest series to date on the impact of the infusions.

Serial ketamine infusions eliminated suicidal ideation in more than two-thirds of patients at a psychiatry office in Connecticut but at significantly higher doses than those recently approved for Janssen’s new esketamine nasal spray (Spravato).

The patients were treated by Lori V. Calabrese, MD, at Innovative Psychiatry, her private outpatient practice in South Windsor. She presented her first 235 IV ketamine cases at the American Psychiatric Association annual meeting. It was likely the largest real-world series to date of ketamine infusions for treatment-resistant depression and suicidality.

The patients, 14-84 years old but mostly middle-aged, received six infusions over 2-3 weeks, starting at 0.5 mg/kg over 40-50 minutes, then titrated upward for dissociative effect to a maximum of 1.7 mg/kg. Subjects filled out the nine-item Patient Health Questionnaire (PHQ-9) at baseline and before each infusion. Item nine – “thoughts that you would be better off dead or of hurting yourself in some way” – was used to gauge suicidality. That item has been validated as a predictor of suicide risk.

Among 144 patients (62 percent) who were markedly suicidal, ketamine infusions were tied to diminished ideation in 118 (82 percent) and eliminated ideation in 98 (68 percent). They were severely depressed at baseline; PHQ-9 scores fell in 127 (89 percent), and depression went into remission in 89 (62 percent). There were no suicide attempts, ED visits, or hospitalizations during treatment and at 4-week follow-up.

“Even if they had been suicidal for a long time, been hospitalized, and made suicide attempts, 68% had full remission of suicidality. This is a life-saving treatment, a breakthrough option for psychiatrists,” Dr. Calabrese said.

The results are “fabulous,” said Jaskaran Singh, MD, who said he was clinical leader of the esketamine program at Janssen.

“You prevented hospitalizations and saved lives,” Dr. Singh said. “This is a marvelous study that we should have done.”

Dr. Calabrese’s report, however, raises the question of whether the nasal spray will be potent enough to achieve the same results. She found that cessation of suicidal thoughts required an average dose of 0.75 mg/kg IV ketamine, which is higher than the 0.5 mg/kg used by many ketamine infusion programs in the United States. It’s also significantly higher than Spravato dosing. The spray was cleared by the Food and Drug Administration in March for use with an oral antidepressant for treatment-resistant depression. It was the subject of much buzz at the APA meeting.

Esketamine is approved in doses of 56 mg, which works out to almost 0.2 mg/kg, and 84 mg, which works out to less than 4 mg/kg. Dosing is twice weekly at first, then weekly or biweekly for maintenance.

When asked whether he thought those doses would be enough to prevent suicide, Dr. Singh said his company has finished two trials in suicidal patients and would present results later in 2019.

Dr. Calabrese, meanwhile, plans to incorporate intranasal esketamine into her practice, but will continue to offer ketamine infusions. “How can I not? I’ve seen how effective they are,” she said.

She charges $500 per session, $2 for the ketamine plus nursing and other costs. Insurance companies have sometimes covered it for patients with a history of psychiatric ED visits and hospitalizations, on the grounds that infusions will prevent future admissions. But patients have to fight for coverage – and feel well enough to do so.

That’s the main reason Dr. Calabrese plans to start offering Spravato; coverage will likely be less of a hassle for patients once Janssen works out the insurance issues. Spravato has been reported to cost about $600-$900 per treatment session.

She noted that response among her infusion patients was bimodal, with suicidal ideation eliminated in some patients after one infusion, but most of the rest needed three or more. “Don’t give up,” she said.

Infusion response correlated with suicidality and depression severity, with the sickest patients having the most benefit. Among 91 moderately depressed, nonsuicidal patients, just over half responded to the infusions, and depression went into remission in about a third.

Side effects were minimal, transient, and easily handled in the office. A little bit of IV midazolam calmed patients who got too anxious, and IV ondansetron (Zofran) helped those who got nauseous. Blood pressure can bump up a bit with ketamine, so Dr. Calabrese follows it closely.


What I wish I’d known before Ketamine Therapy

by Olivia Clear, APCC | psychedelic.support | 5 Mar 2021

Ketamine therapy is incredibly promising for the treatment of depression, but what should you know before a session? Join Olivia Clear, APCC as she shares insights to help you prepare for your ketamine therapy session.

Although I am a therapist, the thought of being a client participating in a type of therapy that involves non-ordinary states felt vulnerable and anxiety-provoking. Planning and researching are some of my favorite ways to manage my nerves about the unknown, so I tried to learn everything I could for my first experience as a Ketamine Therapy client.

But treatment with Ketamine can be a big experience, so I couldn’t plan for it all. As someone who’s sat on both sides of the couch as a trained and practicing therapist and as a client with experience receiving Ketamine Therapy, I’d love to share with you what I wish I’d known before my first session:

1. It may feel incredibly disorienting.

Ketamine is a dissociative anesthetic which means you will likely feel a sense of disconnection from your body and/or mind. You’re departing from the default neural networks your brain uses to other less frequently used networks.

You may want to start your journey with an intention or an “ask” for the general experience, but also know that it may be out of your control what comes up. Opening to the unknown can be ungrounding so it’s important to be gentle with yourself after the experience.

It’s ideal to take it slow and easy afterward and allow yourself to return to ordinary consciousness. My favorite method is drinking miso soup and tea when the journey is over and relaxing in a dimly lit room while listening to music. Time away from work or life duties can be challenging, but if it’s an option, plan to step back from the day-to-day.

The only work to be done is to mindfully notice what feels present in your body through somatic sensations, emotions, or in your energy field. There’s no need to feel like you need to rush to make meaning of the experience.

2. Good boundaries are (almost) everything.

I think this is true in life, but when you’re inviting – in an experience that feels expansive (sometimes beyond space, time, and the planes of this reality) extra containment is needed. If you’re not familiar with the concepts of set and setting, I recommend reading about these guidelines to prepare for the experience.

If you’re receiving treatment via telehealth, make sure your space is protected from noise and outside intrusions. Have a TRUSTED and supportive person available in case you need them. Emphasis on the quality of trust because you will likely be dissociated, and this is a vulnerable state. Be sure to let them know you’ll be under the influence of a mind-altering substance.

You might want to discuss any anticipated needs, and how you’d prefer they help you if you want to be supported. Communication is key, even when it feels scary. This may sound like: stating a preference for firm touch, low lighting, or requesting that there are no guests in the house later in the day. Be clear about what works or doesn’t work. Now is a great time to practice vulnerability with your person because things might become more vulnerable from here on out.
Now is a great time to practice vulnerability with your person because things might become more vulnerable from here on out.

You can also set boundaries around how much of the substance you take, so speak with your provider about any anxieties you have surrounding the dosing. Your provider may be able to support your first experience by providing a low dose of Ketamine so you can explore how it feels before potentially entering a state of heightened dissociation at a higher dose. Work with someone who hears you and can address your concerns.

3. Your playlist matters…even more than for road trips.

With Ketamine, music is a tool that takes you through the journey. It sets the pace and invites you along. Your provider may have multiple playlists they use, and feel free to try them out, but don’t sit with music that you dislike. I recommend listening to music without words, or with words in a language that you don’t understand.

Consider including a mix of genres, if possible, to invite more depth into the journey. If you use a streaming service for your music, now is a good time to get a paid subscription because the commercials can bring you out of your exploration and into another sort of space.

I’ve learned from experience that it’s not fun trying to sort this out while you are sitting with Ketamine (see below). If you have access, I’d also recommend noise-canceling headphones to block out the exterior world and help you go inward.

4. Your inner vision may become clearer, but your eyes might get wonky.

I somehow missed the warning about the impact Ketamine can have on your vision. It might not happen to you, but it feels like my eyeballs are vibrating and unable to focus. If you have sight and would like to avoid this, an eyeshade or sleeping mask helps you focus on your inner experience instead of fighting with your eyes to return to their typical functioning.

I also recommend going to the bathroom before taking Ketamine because it does change your perception, and navigating your space might be difficult or even dangerous. Ketamine also has diuretic properties, so if you didn’t think you needed to go earlier, you probably will.

5. This work isn’t done alone.

You’ll need a prescribing doctor, but many clinics or practices do not offer much support regarding the integration of these experiences. The material that arises can span many different emotions and can be complex or contradictory.

Ketamine can invite in some big ideas/emotions/memories and more. And as I said earlier, the experience can be disorienting. It is normal to need support. As a therapist myself, I recommend talking with a therapist trained in integration.

If that’s not an option for you, consider attending a community-based integration circle or working with a coach or someone supportive from your spiritual community. If there’s someone within your COVID bubble, I’d also recommend having another human with whom to co-regulate your nervous system (breathing together can be lovely).

These are just a few considerations I am offering for your Ketamine journey. Use your discernment and know there is always more to learn!

Remember that your journey will be different from mine and everyone else’s. In my experience, the only thing predictable about working with Ketamine is its lack of predictability. Having experienced multiple Ketamine sessions at this point, I know it is not possible or desirable to plan for everything.

There’s an element of surrender to the experience once you’ve created a safe and supportive space for yourself. Now that you know more about Ketamine treatment, what will you add to your preparation plans for Ketamine Therapy?

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I was paralyzed by severe depression. Then came Ketamine

by Zoe Boyer | New York Times | 30 May 2021

The summer I was 26 years old, I moved into my parents’ home in the Chicago suburbs because I could no longer care for myself.

I had been severely depressed for most of my life, but that summer five years ago, even the most mundane tasks became insurmountable. I spent days on the couch where I rarely spoke, my mind so dull I struggled to form words. I lay awake at night thinking, I can’t go on like this.

Some people experience episodic depression, but since the onset of my illness in early childhood, I sank far and fast and never truly surfaced. By age 10, I found myself overcome with inexplicable dread, so ill at ease I could hardly sit through a television show. By the time I was a teenager, I awoke every morning to an immutable sadness and sobbed on my bedroom floor. Though I was once an excellent student, I struggled to make it through class. Finally, at age 16, I dropped out of high school.

Over the years I tried every available treatment. I stayed in psychiatric hospitals, underwent years of therapy and tried a pharmacy’s worth of antidepressants, but my condition never improved.

One day, I stumbled across an article on the use of ketamine as a promising treatment for severe, unresponsive depression. It was still relatively new at the time and, at $500 per infusion, expensive. After consulting the therapist I was seeing at the time, who was supportive, I found a nearby clinic offering the therapy and made the call.


Ketamine has a reputation as a party drug, but it was originally developed as an anesthetic. When administered properly, doctors say it’s safe and shown to treat major depression and severe PTSD. While other drugs like psilocybin and MDMA are also studied by scientists as a depression treatment, ketamine can be prescribed and administered outside a clinical trial. Traditional antidepressants may take weeks or months to take effect, but ketamine can be fast acting.

Cost, though, presents a major obstacle. Ketamine by infusion for mental illness is not usually covered by insurance — it wasn’t for me — which means it’s financially out of reach for many.

Days after making the call and completing a screening process that confirmed I was a good candidate, given I had unsuccessfully tried several other options, I arrived at the ketamine treatment center. I was put on a treatment plan of six initial infusions over two weeks, after which I would return for maintenance doses as needed, usually every one to six months.

During my infusion, I sat in a recliner while the nurse took my blood pressure, attached a heart rate monitor and inserted an IV line. Once the ketamine was administered and the lights dimmed, I lowered the recliner and took deep breaths as the playlist I’d made poured through my headphones.

For a few minutes I felt nothing, then the picture on the wall across from me began to cleave in two. Though my vision swam, I felt no motion sickness. At the low dose I’d been given to acclimate my body to the drug, I experienced only a mild, pleasant alteration.

With each subsequent visit my dose was increased, until the room dissolved around me in a transcendent swirl of lucid dreaming. I traveled backward in time, inhabiting memories in a pleasantly detached manner. I traveled forward, too, and visited places I’d never been. It felt as though I’d shed my corporeal form and was melding into the fabric of the universe.

But even though I felt at peace during the treatment, my depression didn’t subside right away. After three treatments, the doctor suggested it might not be worth the cost of continuing. Between infusions three and four I agonized over whether to keep going. Since I had already tried everything else, giving up on this meant giving up entirely.

Thankfully everything changed after my fourth infusion. It was as though a switch had been flipped and my brain lit up. I noticed color creeping back into the world, and the hard knot of dread and dispassion in my chest melted away.

My productivity skyrocketed. Within a couple weeks I had cleaned and organized my apartment, applied to and been hired at two jobs, started a meditation practice and begun learning a new language.


Though my jobs were poorly paid, ketamine allowed me to utilize the skills I’d learned in therapy to reframe experiences in a positive light. Bleaching gym mats in a martial arts studio and washing buckets in a flower shop became meditative practices, rather than drudgery. I hardly recognized the buoyant person I’d become.

When my brother got his first pair of glasses, he marveled that he could see individual leaves on trees. Ketamine felt a lot like that. To be in awe of simple pleasures felt like reason enough to live, and I was overcome with a quiet revelation: this is what it means to be content. I began contemplating a return to school. In May 2021, 15 years after dropping out of high school, five years after beginning ketamine treatment, I graduated from college.

I know how fortunate I am. Ketamine doesn’t work for everyone, and for many, the treatment is financially prohibitive. As more stories like mine emerge, I hope to see that change, and that others will not have to give up on finding relief.

Zoe Boyer is a writer who began ketamine treatment for depression in 2016.


High doses of ketamine found to temporarily 'switch off' the brain

University of Cambridge | 11 Jun 2020

Researchers have identified two brain phenomena that may explain some of the side-effects of ketamine. Their measurements of the brain waves of sheep sedated by the drug may explain the out-of-body experience and state of complete oblivion it can cause.

Researchers have identified two brain phenomena that may explain some of the side-effects of ketamine. Their measurements of the brain waves of sheep sedated by the drug may explain the out-of-body experience and state of complete oblivion it can cause.

In a study aimed at understanding the effect of therapeutic drugs on the brains of people living with Huntington's disease, researchers used electroencephalography (EEG) to measure immediate changes in the animals' brain waves once ketamine -- an anaesthetic and pain relief drug -- was administered. Low frequency activity dominated while the sheep were asleep. When the drug wore off and the sheep regained consciousness, the researchers were surprised to see the brain activity start switching between high and low frequency oscillations. The bursts of different frequency were irregular at first, but became regular within a few minutes.

"As the sheep came around from the ketamine, their brain activity was really unusual," said Professor Jenny Morton at the University of Cambridge's Department of Physiology, Development and Neuroscience, who led the research. "The timing of the unusual patterns of sheep brain activity corresponded to the time when human users report feeling their brain has disconnected from their body."

She added: "It's likely that the brain oscillations caused by the drug may prevent information from the outside world being processed normally."

The findings arose as part of a larger research project into Huntington's disease, a condition that stops the brain working properly. The team want to understand why human patients respond differently to various drugs if they carry the gene for this disease. Sheep were used because they are recognised as a suitable pre-clinical model of disorders of the human nervous system, including Huntington's disease.

Six of the sheep were given a single higher dose of ketamine, 24mg/kg. This is at the high end of the anaesthetic range. Initially, the same response was seen as with a lower dose. But within two minutes of administering the drug, the brain activity of five of these six sheep stopped completely, one of them for several minutes -- a phenomenon that has never been seen before.

"This wasn't just reduced brain activity. After the high dose of ketamine the brains of these sheep completely stopped. We've never seen that before," said Morton. Although the anaesthetised sheep looked as though they were asleep, their brains had switched off. "A few minutes later their brains were functioning normally again -- it was as though they had just been switched off and on."

The researchers think that this pause in brain activity may correspond to what ketamine abusers describe as the 'K-hole' -- a state of oblivion likened to a near-death experience, which is followed by a feeling of great serenity. The study was published in the journal Scientific Reports.

Ketamine abusers are known to take doses many times higher than those given to the sheep in this research. It is also likely that progressively higher doses have to be taken to get the same effect. The researchers say that such high doses can cause liver damage, may stop the heart, and be fatal.

To conduct the experiment sheep were put into veterinary slings, which are commonly used to keep animals safe during veterinary procedures. Different doses of ketamine were given to 12 sheep and their brain activity recorded with EEG.

Ketamine was chosen for the study because it is widely used as a safe anaesthetic and pain-relief drug for treating large animals including dogs, horses and sheep. It is also used medically, and is known as a 'dissociative anaesthetic' because patients can appear awake and move around, but they don't feel pain or process information normally -- many report feeling as though their mind has separated from their body.

At lower doses ketamine has a pain-relieving effect, and its use in adult humans is mainly restricted to field situations such as frontline pain-relief for injured soldiers or victims of road traffic accidents.

"Our purpose wasn't really to look at the effects of ketamine, but to use it as a tool to probe the brain activity in sheep with and without the Huntington's disease gene," said Morton. "But our surprising findings could help explain how ketamine works. If it disrupts the networks between different regions of the brain, this could make it a useful tool to study how brain networks function -- both in the healthy brain and in neurological diseases like Huntington's disease and schizophrenia."

Ketamine has recently been proposed as a new treatment for depression and post-traumatic stress disorder. Beyond its anaesthetic actions, however, very little is known about its effects on brain function.

"We think of anaesthetic drugs as just slowing everything down. That's what it looks like from the outside: the animals basically go to sleep and are unresponsive, and then they wake up very quickly. But when we looked at the brain activity, it seems to be a much more dynamic process," said Morton.


Ketamine may help alcohol addiction by rewiring the brain*

Ketamine may help change drinking habits by promoting neuroplasticity. But questions linger over the treatment's ethics and safety.

by Rebecca Tidy | Discovery Magazine | 20 Jun 2021

Alcohol misuse is a huge issue across the world, accounting for 4 percent of deaths and 5 percent of the burden of disease globally. It’s well-known that staying sober is the key to reducing alcohol-related harm, but unfortunately, treatments for alcoholism are limited in their effectiveness, and people often relapse after only a short time.

Over the last decade, there has been growing interest in the use of the dissociative anesthetic and scheduled drug, ketamine, to treat alcohol addiction. It’s traditionally used to induce and maintain surgical anaesthesia, but can legally be used off-label —sometimes in conjunction with psychotherapy — in the hope of sustaining abstinence for longer.

Clinics across the globe are offering ketamine infusions designed to help patients overcome addiction, and reduce the symptoms of psychiatric disorders. It’s making a controversial treatment choice, partly because this drug is commonly abused by recreational users — it holds the ability to make people feel dreamlike and detached, as well as relaxed and euphoric.

The UK’s first publicly accessible ketamine-assisted psychotherapy clinic — Awakn — opened in Bristol recently. Grounded in medicine, it’s run by trained professionals including a doctor, psychiatrist, psychologist and several research scientists. For a charge of around $8,300, patients participate in a course of nine psychotherapy sessions, with three incorporating low-dose ketamine infusions to boost the healing power of the therapy.

Discover spoke to the team at Awakn to find out more about ethics and safety in this emerging industry.

Firstly, is it safe to use a dissociative anesthetic during a therapy session?

Celia Morgan is the head of ketamine-assisted psychotherapy for alcohol use disorder at Awakn and a scientific researcher at the University of Exeter. She says, “When used correctly, ketamine is very safe — it’s administered daily in casualty departments across the world during minor surgical procedures. We use ketamine at much lower doses than it’s used as an anesthetic. And all patients are carefully screened and fully monitored throughout, as safety is a priority.”

Can it ever be ethical to treat alcohol addiction with a dissociative drug, such as ketamine? Surely you’re just replacing one addiction with another, even with small doses?

According to Professor Morgan, ketamine-assisted psychotherapy is a short-term treatment that leads to sustained behavior change and significantly improved abstinence rates. None of the existing studies saw people go on to ketamine dependence, possibly because the drug was not used on an ongoing basis.

She says, “This is why we think the therapy plus ketamine package is so important — it provides a safe container for these experiences, and patients understand the drug to be working with the therapy. After all, the drug is a catalyst but the therapy is where the healing truly takes place.”

“Interestingly, Bill Wilson — the co-founder of Alcoholics Anonymous — actually considered including LSD in the program to help people struggling with the spirituality aspect, but he was dissuaded. Since then, they've been very anti-drugs, though members can take antidepressants. If we can see ketamine as medicine, as we should, then perhaps its use wouldn’t be considered so problematic for organizations like AA,”
she explained.

Experts were unsure whether ketamine is definitely effective in treating alcoholism until recently. In fact, the American Society of Ketamine Physicians, Psychotherapists and Practitioners still notes that ketamine therapy isn’t a panacea for the general public experiencing stress or pain, and even argues that mainstream advertising for quick and easy access to an instant mood boost is harmful.

Until 2020, only two large studies suggested that ketamine could successfully reduce alcoholic relapse. They were carried out in Russia during the 1980s, but were limited in scope as participants chose whether they were assigned to the ketamine or control group. Those electing to receive the drug had three intravenous ketamine treatments combined with psychotherapy, while the other simply had psychotherapy — the results showed that 66 percent of patients who received ketamine were abstinent one year later, in comparison to 24 percent of the control group.

Since then, it’s been hypothesized that the increased level of abstinence among ketamine patients was the result of the drug’s acute antidepressant effect, and ability to improve the learning of new information.

Several studies have suggested that people struggling with addiction are more likely to have low levels of neuron and synapse growth — also known as neurogenesis and synaptogenesis — in the nervous system. This means they’re more likely to struggle to learn new information, such as alternative ways of conceptualizing situations.

It’s been hypothesized that ketamine is especially beneficial for people struggling with addiction, as it stimulates the growth of neurons and synapses in the nervous system, in turn boosting the efficacy of psychological therapy.

Morgan explains “From 2016 to 2020, the University of Exeter KARE study tested the impact of ketamine on alcohol use disorder (AUD). It measured 96 participants’ percentage of days abstinent and relapsed at six months, along with depressive symptoms, craving, and quality of life. The Medical Research Council-funded trial showed that a combination of ketamine and therapy demonstrated a clear capacity to improve the lives of people struggling with alcohol problems, and reduced drinking over a six-month period.”

So what’s the future of psychedelic-assisted psychotherapy in treating alcohol addiction?

Morgan says, “With drinking habits increasing during lockdown, we are now facing a significant increase in mental disorders and addictions to all substances, of which AUD is by far the most concerning.”

“Given the results we've seen from the KARE study and other psychedelics, we think this will be a real growth area — these drugs when combined with therapy are safe and have really long lasting effects so bring new hope for patients where previous treatments have failed.”

As we all know there’s no quick-fix cure or magic wand capable of reducing the symptoms of alcoholism or the underlying mental health problems, but perhaps psychedelic-enabled psychotherapy offers our best hope for the future — only time will tell.

*From the article here :

University of Illinois at Chicago College of Medicine

Breakthrough study finds new mechanism explaining Ketamine's antidepressant effects

by Rich Haridy | New Atlas | 21 Jun 2018

A team at the University of Illinois at Chicago has uncovered a new mechanism that helps explain the remarkably rapid, and long-lasting, antidepressant effects of the controversial drug ketamine. The exciting research reveals the drug operates in a similar way to conventional SSRI antidepressants, except is it significantly more effective.

For decades, there has been a growing body of anecdotal evidence suggesting ketamine has extraordinarily rapid antidepressant effects. Originally developed as an anesthetic, before moving into recreational circles due to its psychedelic and dissociative qualities, the drug is now being seriously investigated for its uniquely novel effects on the brain.

Research over recent years has generally focused on ketamine's effect in blocking a protein receptor in the brain called N-methyl-D-aspartate (NMDA). This action, unique to ketamine, is what has generally been thought to be the primary mechanism behind the drug's rapid antidepressant effects.

Mark Rasenick and his team at the University of Illinois at Chicago College of Medicine initially started their research by investigating the neurological mechanisms behind SSRI drugs, the most common antidepressant medication. The research revealed that patients with depression have larger volumes of G proteins held inactive in "lipid rafts" on cell membranes in the brain. These G proteins are vital in helping nerve cells signal effectively and suppressing their activity could lead to many hallmark symptoms of depression.

Traditional antidepressant drugs such as SSRIs were found to release these locked up G proteins, effectively resulting in their antidepressant effects. A mouse study found that this SSRI activity, releasing these G proteins out of the lipid rafts, took several days to manifest, which possibly explains why antidepressants are so slow to take effect.

Rasenick subsequently set out to investigate whether ketamine resulted in a similar effect on the brain, and the results were compelling. Ketamine did indeed result in a similar mechanism to SSRIs, releasing the G proteins from the cell membrane, except with this drug it occurred at an incredibly rapid rate.

Within 15 minutes of administration, the researchers identified the G proteins being redistributed out of the lipid rafts. And not only that, but the administration of ketamine seemed to result in the G proteins moving back to their inactive state much more slowly. This compelling observation could offer an insight into the observation of ketamine's long-lasting effects, weeks after the drug has left a person's system.

"When G proteins move out of the lipid rafts, it allows for better communication among brain cells, which is known to help alleviate some of the symptoms of depression," says Rasenick. "Whether they are moved out by traditional antidepressants or ketamine, it doesn't matter, although with ketamine, the G proteins are very slow to move back into the lipid rafts, which would explain the drugs long-term effects on depressive symptoms."

Another interesting discovery from the research was that when the team directly knocked out the NMDA receptor, classically thought to be the primary mechanism by which ketamine works, the effect on G protein activity was still prominent. This suggests ketamine's rapid antidepressant qualities aren't solely mediated through the mechanism of NMDA blocking.

The study offers a fascinating direct correlation between the way SSRIs work and the antidepressant qualities of ketamine. It is not only further proof that ketamine is an incredibly effective antidepressant compound, but it offers researchers new insights into neurological mechanisms that can be better exploited for future treatments.

The new research was published in the journal Molecular Psychiatry.

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Centers for Disease Control and Prevention

Ketamine's effects on depression identified in new study

by Timothy Huzar | Medical News Today | 9 June 2020

A new study has identified how ketamine combats difficult-to-treat depression.

New research has revealed the specific parts of the brain that ketamine affects when doctors use it to treat people with difficult-to-treat depression.

The study, which appears in the journal Translational Psychiatry, may open the door to new therapies in the treatment of depression.

According to the CDC, in the United States, about 8% of people over the age of 12 have depression during any 2-week period. The CDC describe depression as a sad mood that extends for a long period and affects a person’s ability to live a normal life.

When severe, depression can have a serious negative effect on a person’s life, sometimes leading to suicidal thoughts.

Experts do not fully understand why some people experience depression, although the National Institute of Mental Health suggest that genetic, environmental, biological, and psychological factors may play a role. It is treatable with medication, psychological therapy, or a combination of the two.

Previous research has made it clear that the drug ketamine can be an effective antidepressant, and some scientists have proposed it as a treatment in cases of depression that do not respond to conventional treatments.

However, precisely how and why ketamine functions as an antidepressant is less clear. As a consequence, the authors of the present study wanted to identify precisely what effects ketamine has on the brain of a person who is not responding to conventional treatments. They hope that this research may lead to better treatment options for these individuals.

Suicide prevention

If you know someone who is at immediate risk of self-harm, suicide, or hurting another person:

1. Ask the tough question: “Are you considering suicide?”

2. Listen to the person without judgment.

3. Call 911 or the local emergency number, or text TALK to 741741 to communicate with a trained crisis counselor.

4. Stay with the person until professional help arrives.

5. Try to remove any weapons, medications, or other potentially harmful objects.

If you or someone you know is having thoughts of suicide, a prevention hotline can help. The National Suicide Prevention Lifeline is available 24 hours per day at 800-273-8255. During a crisis, people who are hard of hearing can call 800-799-4889.

Click here for more links and local resources.


Looking at ketamine’s effects in the brain

To do this, the researchers gave participants doses of ketamine that were low enough not to have an anesthetic effect and then took images of their brains using a positron emission tomography (PET) camera.

According to the study’s first author, Dr. Mikael Tiger, a researcher at the Department of Clinical Neuroscience at the Karolinska Institutet in Solna, Sweden, “In this, the largest PET study of its kind in the world, we wanted to look at not only the magnitude of the effect but also if ketamine acts via serotonin 1B receptors.”

“We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”

By using a radioactive marker that binds to a person’s serotonin receptors, the PET images could highlight what effects ketamine was having on these receptors, which play a crucial role in depression by modulating the amount of serotonin that a person receives. Experts believe that low levels of serotonin correlate to more severe experiences of depression.

The authors of the study recruited people through internet advertising. After receiving 832 volunteers, the authors reduced this number to 30 to make sure that the participants were as relevant to the study as possible.

Other than having major depressive disorder (MDD), the participants were healthy. They had not responded to previous treatment for MDD.

The researchers split the participants into two groups, treating 20 people with ketamine and the other 10 with a placebo.

The study was a randomized, double-blind, placebo-controlled study, meaning that neither the doctors nor the participants initially knew to which group each participant belonged.

Prior to the treatment, the researchers took a baseline scan of the participants’ brains. They took a second scan in the days following the treatment.

For the second phase of the study, 29 of the participants agreed to take ketamine twice a week for 2 weeks.

Serotonin reduced, dopamine increased

Using a rating scale for depression, the researchers found that 70% of the participants in the second phase of the study responded to the ketamine.

Furthermore, after analyzing the PET images, the authors found that the ketamine was affecting the participants’ brains in a previously unidentified manner, reducing the output of serotonin but increasing the output of dopamine, which is also important for mood regulation.

According to the last author of the study, Dr. Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet, “We show for the first time that ketamine treatment increases the number of serotonin 1B receptors.”

“Ketamine has the advantage of being very rapid-acting, but at the same time, it is a narcotic-classed drug that can lead to addiction. So it’ll be interesting to examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.”
- Dr. Johan Lundberg