What is the history of Ketamine?
Although ketamine has been around for nearly 50 years, depression wasn't its first indication. In the 1960s, psychiatrist John Lilly used it to treat migraines. He also used it in psychiatric research. Ketamine was one of three main drugs used in doctor-supervised "psychedelic psychotherapy," along with MMDA, LSD, and psilocybin (magic mushrooms). In the early 1970s, all of these drugs were outlawed except ketamine. In the late 1960s and 1970s, ketamine became the anesthetic of choice for American troops wounded in combat in Vietnam. It relieved pain and also gave soldiers a sense of being somewhere besides the battlefield. In the 1990s, Russian doctors started using ketamine to treat alcoholism. As many as 65 percent of patients receiving ketamine plus standard treatment achieved remission, compared to 25 percent of patients receiving standard treatment alone. Then, around 2000 and for the next 10 years, there was a flurry of reports of successful use of ketamine in treating OCD, anorexia, bulimia, and chronic pain. In 2014, Dr. Diogo Lara and colleagues at the Pontifical University of Rio Grande do Sul and the Spirit of Marília in Brazil discovered that low-dose ketamine brought relief to 77 percent of their patients suffering bipolar disorder. Then, in 2014, Dr. Delisa Guadarrama reported to the American Psychiatric Association that a single dose of IV ketamine had brought postpartum depression patients into remission. Dr. Jaskaran Singh of Janssen Pharmaceuticals then reported that IV ketamine had significant results in relieving treatment-resistant depression. The rush to investigate and use ketamine for treatment-resistant depression began. The FDA approved a close derivative of ketamine (called esketamine) treatment for depression on March 4, 2019. Director Joshua Gordon of the National Institute of Mental Health tweeted “Amazing news” and major news outlets referred to it as “the first truly novel drug for psychiatric illness” in many years.
How does ketamine work?
Unlike antidepressants that change the sensitivity of neurons in the brain to the neurotransmitters serotonin and norepinephrine, ketamine increases the production of a neurotransmitter called glutamate. But that isn’t all ketamine does.
At the same time it increases the amount of glutamate circulating in the brain, it blocks the effects of glutamate on inhibitory neurons. These are the neurons that keep transmissions from flowing to neurons around them.
Ketamine also increases the production of brain derived neurotrophic factor (BDNF). This compound helps the brain create new circuits in the course of learning. Some scientists believe BDNF helps the brain repair itself after circuits are damaged by stress. Experiments with mice show that ketamine reverses the damage done to the brain by prolonged exposure to the stress hormone cortisol. Ketamine may protect a tiny part of the brain that deals with motivation and emotion called the habenula.
Doctors pay special attention to giving the right dosage of ketamine to make a positive change in the way their patients feel. They tend to err on the side of not giving too much, so improvement for some patients may take longer than for others.
Just how well does ketamine work?
About 70 percent of patients with treatment-resistant depression respond after one, two, or three ketamine treatments. Up to 60 percent of patients with treatment-resistant depression go into remission for an extended period of time. For some people, the response to ketamine is almost miraculous. There is almost immediate relief from symptoms. For others, achieving relief from depression requires increasing dosage between sessions (always under medical supervision). There are some patients for whom ketamine “boosters” are necessary to stay in remission, and there is a small minority of patients who also become resistant to treatment with ketamine. It seems to be necessary to use enough ketamine to induce a “trance state” to make it work. Some doctors embrace the War on Drugs narrative and seek to find the lowest possible dosage of ketamine to relieve depression with a minimum of psychedelic experiences. Others seek to ensure that psychedelic experiences are safe and effective. About one-third of people with depression will not respond to any other medications. Ketamine is a tremendous boon for many of these people. Ketamine is also useful as an anesthetic for both people and pets—it is hard to overdose, and it does not depress breathing. It is prescribed off-label for controlling pain after surgery, lowering the required dosage of opiates such as oxycodone and morphine.
Are ketamine and PCP the same thing?
PCP and ketamine aren’t the same thing, but they share a common story.
About one hundred years ago, pharmaceutical companies started looking for new ways to treat depression. A scientist at Parke-Davis was trying to change a compound to create a pain reliever, and accidentally created an entirely new class of drugs that included phencyclidine, also known as PCP.
A scientist at the University of Michigan named Dr. Domino began testing the safety of PCP on animals. He found that monkeys given PCP seemed to achieve a state of tranquility and serenity. (Smaller animals became paralyzed.) Parke-Davis started selling PCP under the brand name Sernyl.
It occurred to scientists at the pharmaceutical company that Sernyl might also be very useful as an anesthetic. It had an unusually high safety margin. Even ten times the dose needed for anesthesia would not suppress breathing. Other pain relievers in the 1950s, such as phenobarbital and fentanyl, could much more easily cause death if they were overdosed. The problem with using PCP was that patients often experienced convulsions and hallucinations when they got out of surgery.
Parke-Davis then contracted with a Dr. Stevens, at Wayne State University, to develop a drug chemically similar to PCP that didn’t cause convulsions and hallucinations. The answer was ketamine. After Dr. Domino confirmed that ketamine was safe, the drug received FDA approval and became the preferred anesthetic for treating wounded American soldiers on the battlefield in Vietnam. It has become an important anesthetic for surgery on dogs and cats.
Like many drugs, the process of making ketamine creates molecules that are mirror images of each other. Some rotate light to the right, and some rotate light to the left. Molecules that rotate light to the right are designated R-for right or D- for dextro. Molecules that rotate light to the left are designated L- for left or S- for (based on an old term) sinister. Because of the way it binds to receptors in the brain, S-ketamine has a much stronger antidepressant effect. It has become the modern drug esketamine.
Are ketamine infusions FDA-approved?
Ketamine is a lawful drug. It’s not a violation of any drug laws for a doctor to administer it. There are clear standards for using it safely. The FDA approves the use of ketamine as an anesthetic for both people and small animals. (A veterinarian doing surgery on a cow or a horse would use ketamine to get the animal ready for a more potent anesthetic.)
However, the FDA has not approved ketamine for treatment-resistant depression. Treating depression with ketamine is an off-label use that often is not covered by insurance.
The reason no company has done the studies the FDA requires to approve ketamine for treating depression and other psychiatric issues is that it is a generic drug. No single company owns the patent for it. A drug company would have to spend tens or hundreds of millions of dollars over several years to get a patent for using the drug to treat depression, but many doctors are already doing exactly that. There is no profit for a company to do the testing to get FDA approval. That is not the case, however, with esketamine, which is FDA-approved.
Is ketamine only used to treat depression?
Ketamine is also used to treat:
- Bipolar disorder
- Chronic pain
- Complex Regional Pain Syndrome
- OCD (Obsessive-Compulsive Disorder)
- Post-Traumatic Stress Disorder (PTSD)
What is the clinical difference between ketamine and esketamine?
Ketamine is injected. Esketamine, which is sold under the trade name Spravato, is a nasal spray. It is useful for people with treatment-resistant depression who are skittish about being hooked up to an IV.
Some doctors are finding that three weeks of treatment with esketamine gives a kind of relief that allows other antidepressants to work. Esketamine also can help when patients are waiting for an SSRI like Prozac or an SSNI like Effexor to start taking effect. These patients aren’t treatment-resistant. Esketamine just helps them avoid several weeks of suffering.
The wholesale drug cost for the first month of treatment with Spravato is $4,720 to $6,785. The FDA requires it to be used under medical supervision. Patients spend at least two hours at the doctor’s office for each treatment, and have to get someone to drive them home. Follow-up treatment costs another $2,360 to $3,540. Drugmaker Jannsen Pharmaceuticals has a program that enables some commercially insured patients (not on Medicaid or relying on Part B of Medicare) to get their treatments for $10 each, with a benefit of up to $7,150 per year.
Are ketamine infusions safe?
There are risks with any psychoactive drug. Doctors C. E. Strong and Mohamed Kabbaj at Florida State University have collected reports that suggest that ketamine:
- Produces more “psychedelic” effects in men than in women.
- May be more addictive for women and teenagers of both sexes.
- Often produces hallucinations and feelings of being separate from the world (dissociation) during treatment sessions.
Ketamine infusions may also produce short-term side effects for up to four hours after the treatment session. These side effects include blurry vision, dizziness, headache, nausea, vomiting, difficulties concentrating, difficulties with muscle coordination, and restlessness.
All of these effects have to be weighed against the potential benefits of the drug. Especially when patients are suicidal, the potential benefits are usually considered to be worth the risks.
How addictive are ketamine infusions?
Neuroscientists have observed that the frontoparietal lobe of the brain “lights up” in people who get ketamine infusions the same way it becomes more noticeable in cocaine addicts. This does not mean that ketamine is addictive. The two case studies of ketamine addiction occurred in a teenager who gave himself ketamine infusions without medical supervision and another case in which the patient was poorly supervised. Doctor-supervised, low-dose ketamine infusions don’t seem to be addictive.
Can ketamine be taken orally?
It’s not unusual for patients to be given ketamine to be taken orally for pain relief. There are anesthesiologists who work with patients being treated for depression with oral ketamine, but only a specialist can calculate the right dose.
When you take ketamine or any other drug orally, it has to be broken down in the stomach, absorbed in the small intestine, and sent through the hepatic portal vein to be processed by the liver before it goes into general circulation and to the brain. This means that how long it has been since you last ate and what you last ate affect how your digestive tract handles the ketamine. Your liver processes ketamine with the help of several enzymes. One of these enzymes, CYP3A4, is affected by compounds found in fruit, especially grapefruit and apple peels. They make the drug more potent in your body. But taking ketamine on a full stomach can make it less potent. These problems are avoided with infusion.
Are ketamine infusions covered by Medicare?
No. Patients who have a Medicare supplement (Plan G or Plan N) may be able to get payment assistance for esketamine nasal spray.
Where is ketamine legal?
Ketamine is legal throughout the United States. Off-label use will probably not be paid by insurance. Ketamine is also approved by HealthCanada, but it may not be available through provincial insurance plans except for pain relief.
Can ketamine cause seizures?
Ketamine can cause seizures in patients who have a condition called colpocephaly. It is a congenital condition in which two ventricles in the brain are larger than normal. Your doctor will do a brain scan to check for this condition before giving you ketamine.
Can ketamine cause psychosis?
Ketamine has been known to cause short-term symptoms similar to schizophrenia in healthy people who were prescribed it for pain, according to a report in JAMA Open. However, psychotic symptoms occurred when ketamine was given in a single, large bolus by IV rather than in a slow infusion. The clinical trials for esketamine excluded people with substance abuse problems or bipolar disorder, but the FDA guidelines currently permit it to be given even to people who have psychotic disorders if they have failed to get results from eight different antidepressant drugs.
Can ketamine cause hallucinations?
Ketamine often causes hallucinations during the treatment session. If ketamine is given in a slow infusion, hallucinations end when the treatment session ends.
Will ketamine help my depression?
Ketamine has a good track record of helping people with depression when no other medication has worked. It is also used to help people who are getting no treatment at all bear their symptoms until a different drug becomes available. Not everyone gets relief from depression with ketamine, so this is a matter you will have to discuss with your doctor.
Where can I find ketamine near me?
Any psychiatrist can make a referral to a doctor who specializes in ketamine infusion treatment, if it is appropriate for you. Your doctor will run tests to make sure ketamine treatment will not have any unusual side effects. Start the process with a psychiatric evaluation.
Where can I find ketamine trials near me?
The American Society for Clinical Psychopharmacology (ASCP) maintains a website with a list of current clinical trials. If there is a clinical study of ketamine anywhere in the United States, it will probably be listed on their site.