Reprinted with the kind permission of Cort Johnson and Health Rising .
For years, ketamine was known for its use as an anesthetic or as a recreational drug. Its ability to provide quick and safe sedation saved many lives during the Vietnam war and is still the preferred anesthetic in battlefield situations . It can be used to induce a kind of trance-like state which wipes away pain, and it’s been used, in higher doses when taken orally, as a party drug (“Special K”) and hallucinogen. (It has structural similarities to PCP .)
Ketamine may turn out to be more than an anesthesia drug or an illegal means of getting high. While more research needs to be done, recent studies point to its ability to relieve treatment-resistant depression, act as an anti-suicide drug, possibly reduce pain, and even assist in PTSD.
New Approach to Depression
“In slightly more than a decade, the emergence of ketamine’s rapid antidepressant effects has been viewed by some experts in the field as arguably the most important psychiatric discovery in half a century.“ Niciu et al. 
The FDA panel’s recent overwhelmingly positive (14-2) vote and the subsequent approval  of a ketamine drug nasal spray called Spravato to treat treatment-resistant depression brought to market the first fundamentally new approach to depression in decades. Spravato was tested in people with severe depression who have not been amenable to other treatments. (Only people who have tried and failed two other depression drugs are eligible for Spravato.)
The need for more effective antidepressants is large. About a third of depressed patients  do not get relief, and about 50% more stop their drugs because of side effects or other issues. Plus, the current crop of antidepressant drugs typically take weeks to months to take effect, and withdrawing from the drugs can produce major problems in some. (Check out this New Yorker article  for more on that.) The possibility of a new, fast-acting, antidepressant drug is enticing indeed.
With the advent of Spravato, instead of paying out of pocket for IV ketamine infusions, some people with depression will be able to get their ketamine treatments reimbursed by insurance. (They will need it – the drug will reportedly cost several thousand dollars for the first month.)
Ketamine infusions certainly fit the bill for one woman with treatment-resistant depression who’d unsuccessfully tried dozens of drugs. She described the positive mind-altering changes she experienced while on ketamine :
“It feels like your body rises up, like you’re on a very peaceful roller coaster, and you’re riding a wave into a different dimension… During treatments, I feel like I learn about myself. Because I feel safe and positive, I’m able to confront things that I typically fear or that give me anxiety, like death. Because I’m able to face negative things during treatment, I’m better able to face them and cope with them outside treatment.
“After the first treatment, I felt a weight lift off me within hours. After three to four treatments, I could hear birds chirping and see vibrant colors again; I could walk out of the house without making a million excuses for why I couldn’t. I had hope again. It was the first time in 20 years that I’d felt relief. And the results just kept getting better and better with each treatment.”
Another young man’s inconsolable grief was rapidly ameliorated by ketamine . The death of his young wife left him so grief-stricken that he refused food, spoke in a tiny voice, broke out in crying spells, was borderline catatonic and ultimately ended up in the hospital.
After some brief hallucinations upon receiving ketamine, he began to communicate, was cheerful and started taking food orally. Three months later he was continuing to do well.
Studies are underway to identify how ketamine does what it does in depression. Ketamine, a glutaminergic enhancer , got its start when studies in the 1990’s began indicating that glutaminergic neurotransmission was affected in depression.
Ketamine prods the brain into producing more glutamate, an excitatory neurotransmitter that several studies suggest is elevated in fibromyalgia, depression, and neurodegenerative diseases. It’s not clear why ketamine might be helpful in diseases like fibromyalgia and depression, but researchers have some ideas.
One hypothesis suggests that ketamine triggers a quick burst of glutamate which, via activation of the mTOR pathway, stimulates the formation of new synapses . Interestingly, only lower doses of the drug appear to do this.
A study recently published in Science  using a new microscopic imaging technique found that ketamine infusions restored the small “dendritic spines” which allow signals to pass to and from the dendrites found on neurons in the brain. Ketamine, at least temporarily, restored the connectivity between the prefrontal cortex and other parts of the brain.
It’s interesting that dramatic oscillations in glucocorticoid levels (in particular high levels of glucocorticoids, which some believe may occur early in ME/CFS) are able to eliminate these spines, thus hampering the prefrontal cortex’s ability to communicate to other parts of the brain.
The authors noted that the loss of these spine-like projections on the dendrites – the small branches coming off the main nerve cells – may also be occurring in the hippocampus, nucleus accumbens and amygdala, all of which are possibly implicated in fibromyalgia and ME/CFS.
It’s still very early, but the ability of ketamine to increase neuroplasticity in the brain and restore broken connections suggests, as one MD on Medpage noted, that it could have wide applicability, including in diseases like Parkinson’s.
“If we are seeing these changes in neuroplasticity and these changes in the way that the neurons are talking to each other and the way the circuits in the brain are actually talking to each other, this could have wide variability.” Dr. Sanacora 
The down side with ketamine infusions is that half of the new dendritic spines are immediately lost when the treatment is stopped. It’s possible, though, that once those spines are renewed, other therapies, including neurostimulatory techniques like rTMS, may be able sustain them.
The woman who got the great results from ketamine – she just keeps doing the infusions.
Ketamine, Fibromyalgia and Pain
The evidence for the use of ketamine in pain has been mixed. One large study found that half of headache participants  experienced pain relief lasting weeks. A recent meta-analysis found “robust evidence” for the use of ketamine for relieving pain,  but noted that results were “modest” – about a 25% reduction in pain. They suggested that ketamine was probably most useful for people who cannot use opioids or other pain medications or who need particularly rapid relief.
Ketamine use was considered in fibromyalgia as far back as 1995 when a study reported  IV ketamine decreased pain intensity and increased endurance in FM patients. A 1997 study  reported pain reductions in FM and a 2000 study suggested  it might be getting at core issues in the disease.
A 2002 review recommended ketamine be used in combination with low-dose opioids  in FM. A small 2007 fibromyalgia study found an approximately two-thirds response rate and suggested that ketamine increased blood flow to the brain . A 2011 fibromyalgia study using S(+)-ketamine  found that about a third of FM patients immediately experienced a 50% reduction in pain, but the effects did not last.
Ginerva Liptan, an MD focused on fibromyalgia called IV ketamine for pain  experimental but noted that “it could be big”. Dr. Podell, an ME/CFS/FM doctor, reported that ketamine reduced pain in about 50% of his fibromyalgia patients. 
Ketamine was also a key component of Dr. Jay Goldstein’s (now retired) “resurrection cocktail  for chronic fatigue syndrome’. (The resurrection cocktail often included ascorbate, lidocaine and thyrotropin-releasing hormone. Goldstein administered Ketamine intravenously or through a gel.
Ketamine, interestingly, also can have positive circulatory effects. Subanesthetic doses of s-ketamine actually increased cerebral blood flows  in one study. Reduced cerebral blood flows appear to be universally present throughout the different kinds of orthostatic intolerance.
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The Wild, Wild West
Because ketamine is a generic drug, its use is not well-regulated by the FDA. Over the past ten years, the number of centers using intravenous (IV) ketamine infusions to treat chronic pain  and/or depression has skyrocketed. Some, like the Cleveland Clinic , Yale University, the University of California at San Diego, and the Mayo Clinic are reputable; others are not.
The kind of wild west approach to ketamine infusions prompted the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists to produce the first ever guidelines for the use of ketamine in chronic pain .
The groups concluded that, “Evidence supports the use of ketamine for chronic pain,” but described the many small, uncontrolled, unblinded (or improperly blinded) studies. A better understanding of dosing is needed. Larger, more rigorous studies (something we frequently hear) are needed.
The need for better studies is more acute in the case of ketamine because it’s being used in so many clinics, and the introduction of pill and nasal forms of the drug will undoubtedly increase its popularity.
It’s important to note that, while studies provide the more rigorous evidence for or against treatment, they’re just one part of a treatment decision-making process.
Florinef (fludrocortisone acetate)  provides an excellent example. It failed in not one but two ME/CFS trials, including one 100 person, double-blinded, placebo-controlled trial which ended up being published in the prestigious JAMA journal. No doctor reading the results of those trials would ever prescribe Florinef for their ME/CFS patients.
Yet Peter Rowe, the leader of the JAMA trial, uses the drug regularly. Rowe later pointed out that the trial had a number of significant issues.  The patients in the trial did not increase their sodium intake – a key part of Rowe’s protocol – and one which could have boosted the drug’s effects. The dose (0.1 mg/day) was also set low in order to ensure that the patients didn’t know if they were taking a placebo or the actual drug. Most of the patients in the study had also had ME/CFS for longer than 3 years, and Rowe apparently has found that shorter duration patients tend to do better.
The ketamine studies face similar issues. They tend to assess low amounts of the drug in single-doses. Clinics, on the other hand, often use higher doses repeated over time.
Studies can provide powerful assessments of drugs, but they often take place in a kind of artificial vacuum that does not reflect the clinical environment. They provide an important piece, but only one piece, of the puzzle regarding treatments – and can be misleading. Andrew Miller PhD, for instance, believes that ketamine may be especially useful in depressed patients with increased inflammation and that anti-inflammatory drugs may be useful in sustaining the response to ketamine. Miller also believes ketamine may be down regulating the activity of the kynurenine which some believe is upregulated in ME/CFS.
Other NMDAR-Affecting Drugs
Because the NMDAR (N-methyl-d-aspartate) receptors are involved in the transmission of sensory and pain signals, they’ve been considered possible drug targets for FM  and other pain disorders. Ketamine is the strongest NMDAR receptor antagonist on the market. Two other NMDAR antagonists, memantine and dextromethorphan, have, however, been assessed in FM.
Dextromethorphan, which has milder NMDAR blocking properties (and is found in cough syrup), has shown some efficacy in a subset of FM patients. The conclusion of the 2005 study proved the point that drugs often aren’t taken in isolation and their effectiveness shouldn’t be judged solely in isolation.
“Our results provide evidence that dextromethorphan could be clinically effective for FM, particularly in combination with other agents that act peripherally to reduce sensitization of nociceptors,” Staud 2005 
As with ketamine, at high doses, dextromethorphan can make one decidedly loopy (it’s another dissociative agent). Jarred Younger is currently trialing dextromethorphan – a potential microglial inhibiting agent – in fibromyalgia. Like LDN, Younger’s planning to use it in low doses (30 mg/day). Unlike LDN, dextromethorphan has the added benefit of being safe for people using opioids.
Memantine , another type of NMDAR blocker, has shown modest efficacy in FM and chronic pain.
A review of NMDAR blockers in FM concluded that, despite the role the NMDAR system appears to play, results have not been particularly good. Studies of NMDAR blockers, however, tend to be small, of short duration, and employ a limited range of doses; i.e., they’re the typical, poorly done drug trials that are common, and more work is needed to truly assess their effectiveness.
The Prefrontal Cortex Connection in Fibromyalgia and ME/CFS
Ketamine is also the first drug approved for depression that appears to be able to restore glutamate neurotransmission  in the prefrontal cortex . That’s intriguing, given that the prefrontal cortex is the seat of “executive functioning “. Executive functioning refers to a wide variety of behaviors (concentration, organization, judgement, reasoning, decision-making, creativity, emotional regulation, social–relational abilities, and abstract thinking), some of which are impaired in both fibromyalgia  and ME/CFS. 
It’s possible that cognition is not the end of the story with the prefrontal cortex and ME/CFS and FM. The Japanese believe that damage to the prefrontal cortex in chronic fatigue syndrome is contributing to the problems with movement and exercise as well. This is because one part of the prefrontal cortex connects to and regulates parts of the brain which generate movement (premotor cortex, supplementary motor area, cerebellum, and basal ganglia.)
That’s a potentially interesting connection given that ketamine so substantially alleviated fatigue  in patients with bipolar depression, that they suggested that ketamine and other glutamate affecting drugs be tried in other fatiguing disorders. They apparently suggested this because ketamine’s fatigue effects were not dependent on its ability to relieve depression.
Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders.
It should be emphasized that ketamine is an evolving field. While known primarily as an NMDAR antagonist, ketamine also affects other brain pathways involved in pain and mood (nicotinic and muscarinic cholinergic receptors, sodium/potassium channels, dopamine receptors, and others.)
Ketamine’s metabolites  may offer more efficacy and fewer side effects and are an active area of exploration. A 2019 study found that a ketamine metabolite had superior acute and chronic pain reducing properties in laboratory animals, and a 2018 report indicated that two ketamine derivatives  lasted longer, provided better effects, and produced fewer side effects than the current drug.
There is still much to learn about ketamine, including dosing, which patients benefit and why, and the very real concern regarding its long-term effects. As yet, the evidence for ketamine’s effectiveness is greater for depression (where ketamine appears to be able to spur the development of new synapses  that counteract the effects of chronic stress) than for pain. The FDA’s recent approval of the first ketamine-derived drug, Spravato (esketamine) brings the first entirely new approach to depression in decades to the market.
In fact, given the NMDAR’s central role in regulating pain levels, why ketamine and similar drugs have not proven more effective with pain seems puzzling. Studies using single, low dose protocols that are out of sync with clinical use may (or may not) provide one answer to that question.
In the meantime, work on producing more potent forms of ketamine are underway, and several potential metabolites which may boost ketamine’s effectiveness and duration have been identified. Dextromethorphan, another NMDAR antagonist, is being tested in fibromyalgia.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising .