Welcome to Strange Medicine — a series of nonfiction articles based on recent journal-published, peer-reviewed case studies, review articles, meta-studies, scientific studies, and primary literature. Each relates to events that made the medical community’s eyes widen and scratch their heads, though, please note that all are significant toward scientific and medical progress because they also forced us to consider the unknown. This week’s featured image is by Hiroshi Tsubono on Unsplash (Previous article: Ebola Loves Balls)
Disclaimer: This article is for educational purposes only. Please, for your own wellbeing and safety, put nothing in your body like our case study back in Injected Mushrooms. Always follow the advice of your doctor or trusted medical professional.
Depression is a global public health crisis. Imagine that you’ve tried every prescription and herbal drug on the market. Lifestyle changes are part of depression’s exhaustion now. You’ve been in therapy for years. Your life isn’t coming back together. You’ve been through so much neuroinflammatory trauma you need a reset button. You’re in a state that gets labeled “treatment-resistant depression” and your psychiatrist mentions a few options you haven’t tried yet. Like electroconvulsive therapy. Or ketamine. Or both. So, you decide to investigate the least scary of those three options: ketamine.
You’ve seen the billboards along the highway with a phone number and some doctor’s name. Now, it’s being recommended to you? Is it quack medicine? You’re thinking to yourself, What’s ketamine? I thought that was a party drug or, like, a tranquilizer?
Well, it’s both and neither of those things. Historically, Ketamine gained popularity in field hospitals during the Vietnam War. Developed as an anesthetic, it is most closely related to other anesthetics developed during the mid-twentieth century, such as phencyclidine (PCP). Ketamine’s chemical structure comes in two chiralities or forms that have different anesthetic dose-response curves based on electroencephalograph (EEG) studies. As an example of how misunderstood Ketamine was when it was first used as a field anesthetic in military hospitals, it was first thought to be an opiate. This hypothesis failed to be supported when Naloxone failed to reverse the effects of dosing with ketamine, demonstrating that is not an opiate. Outside of anesthetic uses, we know it under the pseudonyms “Special K” or “Vitamin K” as a party drug for its dissociative and hallucinogenic effects. Together, let’s examine the four groundbreaking case studies where its use treated depression and gained attention from the medical community.
When it comes to depression everyone has heard of serotonin receptors, but you might not have heard of NMDA receptors. Ketamine acts on a specific receptor in the brain called the NMDA receptor. This receptor interacts with calcium and glutamate and when ketamine binds it systemically results in changes to heart rhythm and a flood of exciting activity within the brain. The NMDA receptors interact with every part of normal function, from our perceptions of reality to our movement. Research connects its function and dysfunction with everything from schizophrenia to cataplexy, nightmares, mood regulation, anesthesia, learning, and memory. It’s a target of drugs used to treat delusional disorders, schizophrenia, migraines, concentration, mood regulation, agitation, and memory/dementia. Many anesthetics and dissociatives act on this receptor, including nitrous oxide and other similar surgical gaseous anesthesias, intravenous or oral anesthetics, and dissociative party drugs. The party drug cases are not surprising given NMDA receptor agonists make people trip balls in high enough doses. This group of compounds includes pharmaceuticals such as dextromethorphan, an ingredient found in cough syrup used for “robotripping”.
So how did we figure out that ketamine, an anesthetic, can treat depression? Completely by accident.
In 2006, patients with Complex Regional Pain Syndrome enrolled in pain management. They received an experimental low-dose ketamine infusion for chronic pain. How low of a dose? A sub-anesthetic threshold, so low that the patients experienced neither hallucinations nor sedation. They discharged patients from observation after five days and followed up with them for a full year. While the primary purpose of the study was to treat chronic pain, medical staff noted some peculiarities in the way two patients behaved while remaining under observation for the first five days post-infusion. Their two previously depressed patients… were different.
How much? Well, if you know the story of Lazarus, it was a little like raising the dead.
Patient A, a 39 years young woman with an 18-month history of depression, stopped working because of her debilitating depression. She tried three types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, and selective norepinephrine reuptake inhibitors (SNRIs). She experienced all the side effects with no improvement. Desperate, she voluntarily underwent electroconvulsive therapy without success. After receiving the experimental ketamine infusion treatment for her chronic pain condition, nursing staff and family members noted a change in the first couple of days. She cooked meals and snacks for fellow patients and staff. She showed interest in topics of discussion and activities that previously brought her joy. Her personality as they knew it changed. At a follow-up one month after her infusion, her nine-year-old son remarked, “I have got my mummy back.” These results persisted, and by her twelve-month follow-up, she joined a “return to work” program and maintained remission from treatment resistance on a low dose of an SSRI.
At 33, Patient B’s depression was all he’d known for approximately half his life. Well-documented to be constant for the previous four, he attempted treatments for his depression with multiple types of antidepressants and Lithium augmentation therapy (taking Lithium with an antidepressant), atypical antipsychotics, and voluntary electroconvulsive therapy. Also like Patient A, he had left the workforce because of his treatment-resistant depression. After 2 days, he said his mood “felt better.” He became spontaneous in his speech and expressions. After 3 days he talked about potential plans, interacted with staff, and started conversations. After 4 days, he smiled and visibly expressed positive emotions. His improvement continued. He mentioned to doctors that he socialized well. Later, he not only found employment at a local supermarket but attended college part-time for computer science. Unlike Patient A, around three months he noted that his depression returned. This coincided with depression scores as measured by the Beck Depression Inventory (BDI) and Hamilton Depression Rating Score (HRSD) tests.
Based on their previous observations of both Patients A and B, the doctors tested something: would a second course of ketamine infusion make a difference? Was this a fluke? So, science did what science does best — act like a “crazy” person and do the same thing expecting a potentially different result. However, that’s not what they found. Instead, nursing staff reported observing the same pattern of improvement, though the patient and his mother subjectively felt little change after the first five days, after ten days he claimed: “the fog has lifted.” He required a third course of treatment after another six months. At the twelve-month follow-up, he maintained full-time employment and started painting his parents’ house, as well as planned an international vacation. He maintained his remission on a low daily dose of Lithium.
That study caught the attention of many people, but the clinical studies didn’t catch on yet.
Up to 42 percent of hospice patients experience depression and up to 70 percent experience anxiety. They’re dying, and the process of accepting one’s own mortality is hard. Dying from a horrific illness, like cancer, is only going to make the process worse. Medical staff working in palliative care strive to improve the quality of life for those in hospice, including handling the psychiatric extremes that prevent people from comfortably enjoying the remainder of their lives with loved ones. One of the issues with the antidepressant options used in hospice patients is that they can take longer than the patient has to live to start working. Given this issue, in 2010 researchers tested ketamine as an option for palliative psychiatric care on hospice patients needing rapid treatment for depression and anxiety.
Well, based on the results, ketamine won’t stop death, but it may make it an easier experience to handle.
Divorced and 64 years old, S.B. entered hospice with respiratory failure and chronic obstructive pulmonary disease. Oxygen-dependent and limited on time, she developed severe symptoms of depression and anxiety associated with the preoccupation with death. She reported one to three panic attacks per day and anxious behaviors, such as picking and fidgeting (noticeable to medical staff during the interview). Her roommate, best friend, and caretaker became concerned for her wellbeing and reported these signs, besides irritability, to clinic staff, who confirmed these observations upon interview. To put it mildly, no one goes into hospice because they’re healthy, and these situations are common for those experiencing dying. By two hours after oral dosing with ketamine, her mood improved, as noted by almost halving her HRSD score compared to before the dose. By the fifteenth day after the dose, she maintained a 66 percent improvement. Based on the Hospital Anxiety and Depression Score (HADS), anxiety improved 83 percent in 120 minutes after dosing and maintained a 50 percent reduction by day 15. Researchers found no adverse effects in terms of cognitive function, and the patient reported fewer pain-related symptoms after dosing.
But what did S.B. and her roommate think? Her friends reported she seemed hopeful and improved. She engaged with her friends, resumed her interactions, and lived the rest of her life with enjoyment. While they gave her an additional dose of ketamine, no significant improvements were noted. Her mood and anxiety remained improved, though gradually tapering off as she reached the end of life.
At 70, K.H. had metastatic prostate cancer that had spread to his bone, lung, and liver, leaving him bedridden for over six months. Having no history of psychiatric illness, he found his severe depressive episode distressing with symptoms lasting for at least 3 months. These included ruminations on the desire for death, insomnia, early morning waking, low mood, unintentional weight loss, feelings of guilt about being a burden to his wife, and a “loss of his zest for life.” He no longer enjoyed activities he maintained the ability to do to bring himself joy while bedbound. Visits with friends and family, watching and discussing movies with his wife, reading, and eating food from his favorite restaurants failed to bring him joy. He experienced multiple panic attacks per day and constant worrying relating to his insomnia. By an hour after dosing, K.H.’s HRSD depression score dropped by a third. By day eight it dropped by 57 percent. Based on the HADS, at one hour anxiety improved by 15 percent, but 85 percent by day eight. He reported improvements in mood, pain, and could enjoy his favorite foods again. His wife, by day three, noted his humor returning. As his mood continued to improve, he returned to planning for friends and family members to visit him, and he could enjoy his remaining days. Unfortunately, by day 13 K.H.’s health deteriorated beyond his ability to continue participating in the study’s assessments and he died shortly after. His wife remarked that his focus on death shifted to acceptance, rather than wanting.
Based on this information, would I try ketamine? Absolutely! Under the guidance of licensed physicians that are practicing established protocols, individuals will not experience hallucinations, nor should they experience any sedation. While we discovered the benefits of ketamine for treating depression accidentally, some of the best discoveries in medicine are accidents. Researchers are still tearing apart the relationship between pain, inflammation, depression, and how ketamine interacts. Still, we now have over twenty years of evidence saying it works, and given depression is the most common mental illness worldwide, this may be an avenue to keep exploring.
[Update: 9/7/2021] Over Summer 2021 I had the opportunity to interview a patient receiving treatments at a clinic in the greater Puget Sound area of Washington state. To preserve anonymity I will refer to him as Patient D. After 6 years of treatment resistant depression and attempted treatment with three different classes of antidepressant and anxiolytic medications, he sought a professional consultation. Instead of the infusions describe in the studies above, the medication he was prescribed and was administered in office was Spravato. While he did not notice much of a difference after the first treatment, those around him began mentioning changes in behavior immediately. Those around him reported improved mood and saw benefit with each subsequent treatment. Unfortunately, issues with Cigna’s insurance prior authorization status being recalled for review resulted in the individual having to discontinue treatments since. The benefits and improvements have persisted for the following 6 weeks without additional treatments. I did not ask about the in office experience portion of treatment.
This article was originally published on April 5, 2021 on Coffeehousewriters.com and is linked here. The Update: 9/7/2021 to include the results of the interview with Patient D is marked as such at the end of the article.
