There is tremendous confusion and controversy surrounding a very old drug called ketamine (Ketalar). The FDA first approved Ketalar in 1970 as an injectable anesthetic. It had advantages over existing anesthetics. It was fast acting. Excellent pain relieving properties made it ideal for badly burned patients who needed skin grafts. It was also a good choice for accident victims who required prompt orthopedic surgery. This anesthetic doesn’t lower blood pressure, an important benefit if someone is in shock. Despite its pluses, there were some surprising ketamine side effects.
Surprising Ketamine Side Effects:
When drug companies test medications on animals they can measure lots of bodily functions. One thing they cannot do, however, is ask the animal how it is feeling. It came as a surprise to investigators to discover that Ketalar caused a “dissociative” brain reaction during recovery.
I (Joe G.) have long had a personal interest in this drug because my advisor and professor of neuropharmacology at the Univeristy of Michigan was Edward Domino, MD. He was the lead author on the first published paper about ketamine in humans.
In 1965 Dr. Domino and his colleagues published a paper about an exciting new drug labeled CI-581 (Clinical Pharmacology and Therapeutics, May-June, 1965). It was, as far as I can tell, the first use of the term “dissociative anesthetic.” They described what they observed this way:
“The syndrome immediately following the administration of the drug was of interest. Usually the subject was asked to keep his eyes closed during the procedure. Within a minute after drug injection, the subject reported numbness of the entire body, although sensation to touch remained intact. After 1.0 mg. per kilogram or more of CI-581, the subject would open his eyes and at the same time lose contact with the environment…
Recovery: Odd Ketamine Side Effects:
Dr. Domino, et al, went on to describe surprising ketamine side effects during the return to consciousness:
“During the recovery period the subjects showed considerable variability in psychic reaction. Some were completely oriented in time and place and showed no significant changes. Others showed marked alteration in mood and affect, some becoming apprehensive and aggressive and others markedly withdrawn. Almost all the subjects felt entirely numb, and in extreme instances stated that they had no arms or legs, or that they were dead. If they were touched, however, or moved, such stimuli were perceived….Other reactions noted included feelings of estrangement or isolation, negativism, hostility, apathy, drowsiness, inebriation, hypnogenic states, and repetitive motor behavior.
“At times some of the subjects had vivid dreamlike experiences or frank hallucinations. Some of these involved the recall of television programs or motion pictures seen a few days before, or they were at home with their relatives, or were in outer space, and so on. Some of these phenomena were so real that the subjects could not be certain they had not actually occurred.
“Usually these psychological aberrations subsided completely within a half hour after awakening. The subjects gradually became well oriented and frequently expressed amazement at the experience; most found the experience pleasant and were willing to undergo a second experiment, although 2 refused to continue.”
The Pros of Ketamine:
Dr. Domino explained to me and the other grad students in the department of pharmacology at the Univeristy of Michigan that ketamine was remarkable because it produced “profound analgesia.” The unusual pain-relieving properties of the drug made it highly desirable for procedures that were terribly uncomfortable.
Dr. Domino noted that the experimental subjects who received the drug reported “changes in mood, body image, and affect, and some reported vivid dreams/or hallucinations.” These surprising ketamine side effects were of concern to clinicians and no doubt to the drug company developing ketamine.
We were told that if patients were put in special recovery rooms after surgery with the lights dimmed and with no physical stimulation from nurses, they would often reorient to their bodies more gradually. This allowed for the dissociative state to wear off without some of the complications initially reported after the coma of anesthesia began to wear off.
Other Ketamine Side Effects:
In his original paper in 1965 Dr. Domino reported that subjects experienced watery eyes and profuse sweating. Nystagmus (uncontrollable eye movements) was common along with visual disturbances. Other ketamine side effects include excessive salivation, indigestion, nausea and vomiting. Blood pressure can go up along with heart rate. Some people also note muscle twitching.
Although anesthesiologists still use ketamine in certain circumstances, it has lost favor over the decades. Part of the reason may be that the recovery process can be challenging for busy hospital routine. We suspect that the strange psychological side effects, including hallucinations, also worry some anesthesiologists.
Unexpected Benefits of Ketamine:
When a person feels suicidal, seconds count. Delays could mean a life lost. But what do health professionals have to offer in an emergency?
Until recently, there hasn’t been an effective, fast-acting medication to ease severe depression or counteract thoughts of suicide. Traditional antidepressants can take six weeks or longer to act. That’s why there is growing excitement about the use of ketamine to treat suicidal ideation.
Interrupting Suicidal Thoughts:
A study published in The American Journal of Psychiatry (online, Dec. 5, 2017) demonstrated that a ketamine infusion can banish suicidal thoughts within hours for some people. That’s remarkable.
In this trial, 80 people were randomized to receive either ketamine or a benzodiazepine called midazolam. In this double-blind research, both groups got their medicine by intravenous infusion. Not only did ketamine help ease major depression, it also reduced suicidal thoughts directly.
Longer Lasting Benefits:
One of the unexpected results of this single-infusion clinical trial was the persistence of the benefit. Most other research has suggested that ketamine loses its antidepressant activity after a week or two. In this study, the improvement lasted for at least six weeks.
The implications of this research are profound. Emergency rooms are overwhelmed with severely depressed patients. Hospitals frequently do not have enough beds to care for suicidal patients. They may be left in the waiting room or in the hallway for days until a room becomes available. Even then, treatments are slow to kick in.
Now that intravenous ketamine infusions have been shown to control suicidal thoughts, emergency physicians may feel justified in administering the drug to desperate patients on the spot. There is a downside, however. You cannot just give a suicidal patient ketamine and walk away. Such patients require intense supervision and continued care. Once the ketamine wears off, they could end up back where they started or worse if there is not monitoring and further treatment.
Ketamine: Not FDA Approved for Depression!
Ketamine is not approved by the FDA for treating depression or easing suicidal thoughts. As a result, many clinicians may be uncomfortable administering it. Only those who are experienced with such treatment should consider prescribing this off-label use.
This is not the first study of ketamine to show promise. A meta-analysis of five trials found that ketamine “showed a large and consistent decrease of suicidal ideation” (Neuroscience and Biobehavioral Reviews, June, 2017). Other reviews also report that ketamine has a significant effect on suicidal thoughts (American Journal of Psychiatry, online Oct. 3, 2017).
We heard this from one reader who has received ketamine infusions:
“I feel frantically discouraged when I am too depressed to feel in control of my mind, body and ability to re-join life. So often, depressed people like me are shunted from hospital to hospital and given drugs that just don’t work. Ketamine is the only medicine that keeps me steady so I don’t want to jump off the nearest bridge.”
Lyn in Phoenix got ketamine during a colonoscopy:
“I was given ketamine by an anesthesiologist when he could not get into my veins for a colonoscopy. I did not come to afterwards. They sent me home anyway.
“My husband managed to get me in the house where I laid on the floor for twelve hours, throwing up occasionally. For the next three days I seemed to have Alzheimers. I kept asking the same questions over and over, I was told later. I could hardly get out of bed. My husband was concerned my brain was gone. This is a very dangerous drug. Stay away from it.”
Ketamine for Suicide vs. Surgery:
Lyn either got a very high dose by mistake or was super susceptible to ketamine. It was being used as an anesthetic during the colonoscopy procedure.
When the drug is used to treat suicidal thoughts and depression, the dose is much lower than that used for anesthesia. Still, study volunteers in the most recent study had some mild adverse reactions, especially elevated blood pressure and a spacey feeling during the infusion.
The scientists hope that further research on ketamine will lead to the development of new and better drugs that will act more quickly than current antidepressants to treat seriously suicidal people.
Want to Learn More?
If you would like to get the straight and skinny on the history of ketamine from the horse’s mouth, so to speak, check out this wonderful article by my old mentor, Edward Domino, MD (Anesthesiology, Sept. 2010). In it you will learn the back story on ketamine from a brilliant neuropharmacologist!
Share your own ketamine story below in the comment section.