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Sleep Relief

Calming magnesium, amino acids and herbs. Sleep Relief contains magnesium, a gentler muscle relaxer. The amino acids L-Tryptophan, L-Theanine, glycine and GABA and herbs such as Hops (Humulus lupulus) and Skullcap (Scutellaria lateriflora) all contribute to the calming effects of Sleep Relief by targeting different neurological and biochemical pathways.

  • L-Tryptophan is converted to serotonin and melatonin. Serotonin is a mood-elevating hormone and melatonin is a circadian modulator that helps regulate your body’s day and night cycle. 
  • L-Theanine promotes alpha wave brain activity, which is associated with alert relaxation.
  • Glycine and GABA are nutrients that acts as naturally calming neurotransmitters that promote relaxation.
  • Hops and Skullcap are ancient plants that have long histories of use in traditional healing systems. Native Americans relied on them for a wide variety of medicinal purposes, and extensive research has validated many of their traditional applications, including promoting healthy sleep.   

Adaptogenic herbs like Ashwagandha (Withania somnifera) and Jujube (Ziziphus jujuba). Adaptogens are a unique class of healing plants. They help balance, restore and protect the body. Ashwagandha and Jujube are ancient plants that have been used in traditional Asian medicine for thousands of years and can promote a healthy stress response.

Nutritional Biochemistry, Inc. (NBI) formulates and manufactures products that give results. Started by John Neustadt, ND, in 2006 when he couldn’t find formulas he needed to help his patients and family, NBI products solve 2 problems he was having. Existing products didn’t contain the dose or combination of nutrients used in clinical trials and actually shown to work. Equally frustrating, other companies would cite studies on their websites, but then use lower amounts of nutrients than what was used in the study, or use entirely different nutrients that weren’t supported by the research.

Neustadt’s latest creation is Sleep Relief [3]. NBI’s Sleep Relief is a breakthrough in sleep technology. Its bi-phasic, time-release technology delivers NBI’s proprietary formula with clinically validated nutrients in two stages—a quick-release first stage and a slow-release second stage to help you gently fall asleep, stay asleep and wake refreshed and ready for your day. NBI’s Osteo-K [5] delivers the clinical dose of nutrients shown in more than 25 clinical trials to grow stronger bones and reduce fractures more than 80%.

NBI is and always has been a family-owned company. We don’t manufacture anything we wouldn’t take ourselves or give to our own family. No matter what we do, our promise to physicians using our products is to help their patients, and to customers purchasing directly from NBI, is uncompromising quality.

NBI is a name you can trust. But don’t take our word for it. Spend some time on our website [6], learn about our products, and educate yourself on the hundreds of research citations and studies that they’re based on.

Transcript

Karolyn Gazella: Hello. I’m Karolyn Gazella, publisher of the Natural Medicine Journal. Thank you so much for joining me. Today, our topic is the integrative approach to insomnia. During this interview, we will learn that insomnia is a significant problem for many patients that can have far reaching physical, mental and emotional health ramifications. We will also learn how to successfully treat this condition by using a combination of diet, lifestyle recommendations, and dietary supplements.

My expert guest today is Dr. John Neustadt. Dr. Neustadt received his naturopathic doctorate from Bastyr University and he was the founder and medical director of Montana Integrative Health.

Before we begin, I’d like to thank the sponsor of this topic who is Nutritional Biochemistry Incorporated, or NBI, manufacturers of high-quality dietary supplements for health care professionals.

Dr. Neustadt, thank you so much for joining me today.

John Neustadt, ND: Thank you for having me on.

Gazella: Well, so the Centers of Disease Control and Prevention calls lack of sleep a public health epidemic. Now, that seems pretty significant so today we’re going to talk specifically about insomnia. How common is insomnia in particular?

Neustadt: Well, the CDC is absolutely correct. It is a public health epidemic. Up to 80% of people struggle at some point with what’s considered transient insomnia, less than two weeks of duration and insomnia effects 10 to 15 percent of the general population.

In primary care settings, it’s estimated that up to almost 70 percent of primary care patients have insomnia so it is incredibly common.

Gazella: Oh, yeah that is. So how does lack of sleep impact a patient’s overall health from like a physical, mental, emotional standpoint?

Neustadt: It has devastating impacts. There are two ways to think of it. One is short-term impacts and the other are the long-term impacts. So, short term it can impact decreased job performance, impact social and family life by creating greater fatigue. I mean, just you’re more tired during the day. Decreased mood and depression, increases in anxiety and stress. Decreased vigor and just not being able to cope with the demands of daily life and be able to complete tasks. That’s only short term. Devastating just in the short term.

But in the long term, it can be a killer. There, if people are sleeping an average of less than six hours per night, it can increase the … or decrease the quality of life at the same magnitude of a similar condition such as congestive heart failure and major depressive disorder. It’s an early symptom for Alzheimer’s Disease and Parkinson’s Disease and Huntington’s Disease and there’s a sweet spot for sleeping of about eight hours. That research shows is the healthiest, and if you’re sleeping less than six, or longer than nine hours, it increases your risk for diabetes, metabolic syndrome, and death and, in fact, for metabolic syndrome, there’s a 45 percent increase in risk compared to people who are sleeping seven to eight hours a night.

Gazella: Wow, so yeah, so this is a very important topic for clinicians to have on their radar. So, when you’re evaluating a patient with a sleep disorder such as insomnia, how do you approach the work up?

Neustadt: Well, insomnia’s really a qualitative diagnosis. It’s how are they … how do they feel that they’re sleeping? How do they feel that it’s impacting their health? Now the DSM official diagnosis, there is a quantitative or a couple of quantitative aspects to that and that is it’s occurring at least three nights per week, and present for at least three months. So understand the difference between transient insomnia, less than two weeks, versus the diagnosis, official diagnosis, needs to be going on for greater than three months.

So there’s a huge discrepancy there and in time periods and clinically it’s important to be aware of that because these detrimental and dangerous effects of insomnia and sleep deprivation definitely are occurring in shorter than three months period of time. They’re happening pretty quickly if someone’s not getting enough sleep and even over a few days the short term consequences.

And so what I ask people about is how many hours, on average, do they think they’re sleeping a night? Do they have any difficulty with falling asleep or staying asleep called sleep phase delay or sleep phase advance? Are they waking refreshed in the morning? What’s going on with them psychosocially? Are there any stresses going on at work or in relationships or financially that’s increasing their anxiety and could be impacting their sleep? Are they are risk for any hormonal abnormalities or imbalances because the research is clear that low estrogen, low or high testosterone, elevated TSH, those are all things that can create insomnia. Abnormal progesterone, as well.

And then looking at medications because there are some medications that can impact sleep, as well.

Gazella: Yeah, let’s talk about the medications that can impact sleep. What are some of those medications that can impact sleep?

Neustadt: Well, prednisone, that can cause hyper-arousal, or can cause somebody to not sleep, not be able to fall asleep, or have fragmented sleep. Beta-blockers, very common heart medications, can decrease melatonin production. So we know what the mechanism of action … their interaction of sleep is they decrease melatonin and can cause poor sleep.

Some antidepressants, actually, can cause poor sleep. Antidepressants can, depending on the antidepressants, can either cause somebody to not be able to sleep enough or can cause hypersomnolence, somebody to be sleeping too much. So looking at those, looking up … it’s very easy to look up whatever medication they’re taking quickly and see, besides the ones that I mentioned, could it be potentially interfering and impacting with their sleep.

Gazella: So I’ve been hearing about hyperarousal, or the hyperarousal hypothesis, which I find quite fascinating. What is the hyperarousal hypothesis and how can it affect what is recommended to patients?

Neustadt: Great question. So the hyperarousal hypothesis I like to refer to as “wired-but-tired.” And it occurs to people typically who are under a lot of stress, they have elevated cortisol, and when they end up trying to fall asleep they just can’t turn their mind off, or even if their mind isn’t racing, they just can’t calm down. Their body can’t relax and settle into sleep. They’re staring at the ceiling, it can cause fragmented sleep. And that wired-but-tired, again, typically occurs in people who are under chronic stress.

Gazella: Yeah. And you know the other day when you and I were talking as it related to the hyperarousal hypothesis, you were telling me about something else that was new to me and it was called social jet lag. Talk a little bit about social jet lag and the research associated with social jet lag.

Neustadt: I’m so happy you brought this up because I love this as well. Fitbit, that maker of the wearable tracking devices, and tracking people’s sleep as well, they had access, because of their users, to over six billion data points of sleep. And they looked at those. And they looked at the data and determined that the biggest predictor of healthy sleep, restful sleep, is going to bed at about the same time every night. Basically training our body that it’s bedtime, getting that routine.

Social jet lag occurs when people are going to bed at about the same time every night during the week but then the weekend comes. Friday night they go out, hang out with friends, stay out late. Saturday night maybe do the same thing, and then Sunday comes around and they try to go to bed again at their weekday, or their work week time, and they can’t fall asleep. And essentially what they’ve done is it’s as if they’ve flown to another time zone and their body thinks that it’s not time to go to sleep yet. And they’ve induced their own jet lag called social jet lag.

And so one of the things that Fitbit found, and I think one of the most impactful things, is showing that getting that regular bedtime, being in that routine, going to bed at about the same time every night is one of the best things people can do for improving their sleep.

Gazella: And even on the weekend, and I’ll tell, you, when you put this on my radar I, of course, had to do a little research and there’s a lot of studies on this that actually show that the physical effects that you talked about with sleep deprivation earlier also occur with this social jet lag. So I think it’s really important for clinicians to be aware of that. So thank you for bringing this to my attention.

So now doctors often prescribe benzodiazepine or benzodiazepine-like drugs to help patients sleep. What are some of the potential risks of these particular medications?

Neustadt: Well, the potential risks are very well documented and they increase risk for falling, dizziness, light-headedness, those risks are increased in people who are 60 years or older because their ability to metabolize the drug tends to decrease. And so because it increases the risk for falls and dizziness and light-headedness, it then increases the risk for fall-related injuries, such as osteoporotic fractures, such as concussions, such as death, even. But even beyond those risks associated with increased risks for falling, the research has shown that cancer risk is actually increased in people who take over about 132 doses of benzodiazepine a year. So that’s even … that’s less than half of a year worth.

And in fact some of these risks are increased with very small and limited exposure. So you know from half a dose to 18 doses per year, the hazard risk for death is increased 3.6 times. 18 to 132 doses, the hazard risk for death increased 4.43 times in a study that looked at this. And for greater than 132 doses, it increases 5.32 times. That’s 532 percent greater than somebody not taking these medications for death. And the research has shown to actually get one benefit, the number needed to treat, to have one patient benefit is 13 patients. But the number to treat to create harm is only 6 patients.

Gazella: Yeah, that’s problematic. So what about the newer class of medications, like the orexin receptor antagonist Belsomra?

Neustadt: Belsomra came on the market in 2015, it’s a schedule 4 drug and it’s a CNS depressant. So, like other CNS depressants, like benzodiazepine, it can have similar adverse effects. Some of the benzodiazepine drugs like Lunesta or Ambien can also cause, like Belsomra, can cause daytime impairment including impaired driving skills, risk of falling asleep while driving, abnormal thinking and behavioral changes are part of the adverse events spectrum, including amnesia, anxiety, hallucinations, other neuropsychiatric symptoms, even complex behaviors like sleep-driving. I mean, you’re driving while not fully awake, after taking the hypnotic. Or other complex behaviors have been documented, like preparing and eating food, making phone calls, or even having sex, without remembering it.

And so the drug has some serious risks, including worsening of depression and suicidal ideation, and the benefits of that, it can increase … or the benefits of the medication, because all medication, it’s a risk-reward calculation … it can decrease sleep latency, that is, the amount of time to fall asleep by about eight to 10 minutes and increase sleep duration by 17 to 20 minutes.

So at the most beneficial end of that, maybe it’s 30 extra minutes of sleep. But you get all of those risks associated with it.

Gazella: And are patients getting good sleep when they’re on these prescription and over-counter medications? Are they getting good quality sleep?

Neustadt: Well, you raise a great point. That’s one of the problems with all of these medications is they tend to increase sleep duration, sleep quantity, but they’re not increasing sleep quality. They’re not getting patients into that deep, restorative phrases of sleep, the slow-wave sleep, phase 3 and into phase 4, to get that good, restorative sleep.

So the quantity of the sleep may be increased but the quality has not been shown to be increased.

Gazella: So you’ve made a pretty compelling case that a more integrated, holistic approach is needed. And integrative practitioners often recommend melatonin for insomnia with their patients. Can you talk a little bit about melatonin and why for some patients, many even many patients, it may not be enough?

Neustadt: Melatonin is one of the first things I find that people with whom I speak, they’ve tried. They’ve reached for that. If they’re going to try a natural product, they’ve reached for the melatonin, you know, first, almost universally.

The challenge with melatonin is that it’s got a very short half life, 40 to 50 minutes. And so while melatonin is considered a circadian modulator, meaning it helps the body recognize day from night, and it is a natural hormone, a natural product that our body uses to help us fall asleep, it’s not really used for sleep maintenance. And so when somebody takes melatonin to help them fall asleep, because it’s got such a short half life, well 50 percent of the melatonin is eliminated from the body in less than an hour, so let’s just be generous and say an hour for easy calculations. So common doses out there is a 3 mg dose. So in an hour, they’ve got a one and a half milligrams left. An hour later they’ve got .75 milligrams left. And on down.

And so 3, 4 hours later, essentially most of that melatonin is out of their body and they wake up again. I hear so often people who take melatonin, they end up waking up in the middle of the night, still. And so what do they do? Well, they might need more melatonin. And so they keep taking higher and higher doses until they’re sleeping through the night and then they wake up feeling drugged in the morning. Groggy, hungover and it takes them hours to actually feel fully awake.

So the natural rhythm of melatonin in our body is that the rise in melatonin occurs around 10 PM and then it peaks at about 2 AM in the morning, and it declines at approximately 6 AM, it’s declined back to baseline. And that makes sense because that’s sort of the rhythm of when we start to fall asleep and when our body then starts to wake up. Of course melatonin is balanced with other hormones as well that the body is producing during sleep, but the immediate release of melatonin that people are taking is not mimicking the body’s cycle of melatonin production during the night. And it’s also not a complete solution because it’s not dealing with the other phases of sleep, we’re looking at the other hormones in sleep, GABA for example. Or the other variables that can impact sleep such as poor blood sugar. When blood sugar can drop, hormones are secreted like cortisol and epinephrine to increase the body’s blood sugar and we wake up.

And so that’s why melatonin for a lot of people doesn’t work, because it’s just not a complete enough solution.

Gazella: I think that’s a really good point, that it’s not a complete solution for many people and that’s why you use such an integrative approach. So I’d like to really dig into your integrative approach, I’d like to talk about dietary supplements, diet, and other lifestyle factors. So as long as we’re talking about melatonin, let’s keep on that subject and talk about dietary supplements. Are there specific dietary supplements that you use in your clinical practice specifically for insomnia?

Neustadt: There are and it depends typically on the clinical picture. So for example if somebody has muscle aches or tight muscles that’s keeping them from sleeping, magnesium can help, that can be a gentle muscle relaxant. If there’s some anxiety that may keep them from sleep, well, glycine is an amino acid that’s also an inhibitory neurotransmitter, that can be helpful. GABA also an inhibitory neurotransmitter used in the body available as a dietary supplement. That can be helpful. Botanical extracts such as alphianine increases alpha-wave production in the brain which is associated with calming, alert calmness. Then there are some sedative botanicals that can be helpful such as hops or skullcap, also called Scutellaria. And others.

So that’s part of it and for potential, looking at decreasing the response to stress, I like using, if they’re under a lot of stress, some adaptogenic herbs like ashwagandha, or jujube, magnolia bark extract. If there is vaso … if there’s an issue with hot flashes and perimenopause, pine back extract. There’s a clinical trial on that showing that it improved sleep quality and sleep quantity.

And so I typically, you know, this monotherapy approach of one symptom, 1 pill, it really doesn’t work when we’re looking at complex pathologies like insomnia or many other chronic issues. And so I tend to like products that combine those different nutrients shown in clinical trials to work that target the underlying pathology, the underlying biochemical pathways at work and sleep and affected by insomnia in a time release or a biphasic time release delivery system because it more closely mimics the body’s natural rhythm of the 2 major categories of your sleep. One is helping somebody fall asleep, you know how do we do that, and the other, over … you know, the subsequent 6, 7 hours later after they’ve fallen asleep, how do we help them stay asleep?

And so that’s how I conceptualize it and that’s the overall approach with dietary supplements when they’re indicated.

Gazella: So before I move on to diet, I know that you helped formulate and create a specific sleep supplement. I want you to tell me the name of that supplement but I also want you to tell me why you created it, because let’s face it, there are a lot of sleep supplements in the market. So why did you want to create the supplement that you created?

Neustadt: So the name of the product is NBI’s, my company, NBI’s Sleep Relief is the name of the product. And I created it for a couple reasons.

One, just like all the products that I’ve created in NBI and formulated, I couldn’t find the combination of nutrients or the dose and form of nutrients in a product shown in clinical trials to actually work. And I personally suffered from insomnia for years and years. And I tried a lot of different things. It wasn’t helping me. I’d work with a lot of my patients trying to different things, having to dispense different bottles of products, in addition of course to working with diet and lifestyle and other psychosocial factors involved. And I couldn’t find something that worked consistently.

And so I started digging into the sleep research, the pathophysiology of sleep, the clinical trials, what are the underlying mechanisms affecting sleep. And after over a year of research and formulating and working, trying over a dozen different combinations and doses, that’s when I created Sleep Relief.

Gazella: Okay perfect, Sleep Relief. So now let’s talk a little bit about diet. What are some of the things that you recommend to your patients when it comes to sleep, associated with diet that may not be on the radar of some practitioners?

Neustadt: So one of the big things that I see over and over is a lot of people have, may have acid reflux and they don’t know about it. And because maybe it’s not … maybe they have a cough when they lay down, maybe they are just not aware that that’s going on. And so evaluating for that because that can wake people up.

The other thing that I find with diet that’s very important, and with acid reflux, you know, that can be diet related. There are 5 most common foods that can contribute to that and interrupt sleep, that’s raw garlic and onion, chocolate, coffee, and citrus. Although other things can do it for other people. An infection can do that, H. Pylori can cause that as well. And then if they have a hernia, a hiatal hernia, that can cause it as well. So looking at that, looking at those underlying potential causes if that is involved.

The other thing is poor blood sugar control which I already mentioned. And one of the things I like to ask that can indicate if they might have poor blood sugar control is if they get that afternoon, postprandial tiredness. You know, about 3, 4 o’clock in the afternoon, a couple hours after lunch do they just get that energy slump. And that can be an indication that they’re having a little bit of blood sugar control issues. Or are they waking up at the same time every night. Both of those questions can give clues.

And if that does seem to be involved, one thing that I love to try with patients … it doesn’t work very often but when it does, it’s really a home run, and that is ask them to eat 8 to 10 grams of protein before bed. Protein’s one of the best ways to regulate blood sugar. And so if they do that and it stabilizes their blood sugar and they then are sleeping through the night, well, again, it’s a home run. I mean, there are no pills, no powders, it’s just natural doing it with food and it also opens the door for even more discussions with helping them understand how they can improve their diet during the day to help, to eat, to promote … to help them understand how they can eat, changes they can make to eat, the promote their health for the rest of their life.

Gazella: Yeah, those are some great suggestions when it comes to diet. Now let’s talk a little bit about lifestyle. What are some things that may not be on the radar of some practitioners when it comes to lifestyle aspects?

Neustadt: So we talked about going to sleep at about the same time every night, that’s really important. The other thing is … and most practitioners, or hopefully all of them have heard of sleep hygiene. The research shows that about the 69 to 70 degrees for most people is the ideal temperature for sleep. Some people who, if they’re in a relationship with their partner, they may like different temperatures may be most comfortable for them.

So there are wonderful things out there now, it’s call the ChiliPad, that you can get, it’s a pad you can put on your bed, where you can control the temperature on each side of the bed. So that can be really helpful.

Stress of course is a big issue in our society, a lot of people are under chronic stress, so anything that we can do to help people decrease their stress or better deal with stress is really important. And a fantastic study came out recently that showed that a lot of the impact of stress is not the actual event happening to us, it’s how we view it. So if people view stress as a good thing, meaning “I gotta learn something from it and what can I take from this,” the health impacts from stress are mitigated. If somebody sees a stressful event and they’re internalizing it and they’re not seeing it as a growth opportunity, then it magnifies the negative stress impacts.

So, A) getting them to just understand that mindset is really important, just when it comes to stress happening, and then what can they do to have more control over those events that may be causing them stress to decrease that stress. And that could mean creating healthy boundaries for themselves. That could mean doing any yoga or mind-body techniques. You know there’s lots of things that we can offer to patients that can be incredibly, incredibly helpful.

Gazella: Yeah, I would agree. And now your approach focuses on diet, lifestyle, and dietary supplements. How important is it to focus on all 3? So some practitioners might be really focused on the person’s diet, or some might be looking at their stress level, and some might be focused on just melatonin. Why is it so important to look at this from an integrative standpoint?

Neustadt: Well I think if we want to do the best job we possibly can for our patients and give them the best results, looking at it through a more integrative approach is important. And I like the approach of trying dietary supplements to give people benefit quickly. So if somebody is sleep deprived, it’s gonna increase their tendency to reach for those comfort foods. I think we’ve probably all experienced that. And especially because what happens with insomnia and sleep deprivation, it decreases mood. It can cause depression. And sugary foods, for example, when we reach for those, it can increase our serotonin production and temporarily lift mood. But it causes this rollercoaster of insulin and blood sugar that’s hard to get off of.

So just getting people sleep can help improve their mood. So I like the dietary supplement approach for triage to get them feeling better so they can make healthier decisions, have a more present mindset, be more proactive instead of reactive, while I’m working with them also on improving their diet. Transitioning to a healthier way of eating, which, the research has shown, unambiguously is the Mediterranean pattern of eating. And also stress reduction and exercise and those things as well.

Gazella: Yeah, I mean that all makes a lot of sense. And this is a very important topic and I want to thank you, Dr. Neustadt for a very interesting conversation and once again, I’d also thank today’s sponsor, Nutritional Biochemistry Incorporated, or NBI. Thanks again, Dr. Neustadt, for joining me.

Neustadt: Thank you for the opportunity.

The above was from: https://www.naturalmedicinejournal.com/journal/2019-02/insomnia-integrative-approach

Naltrexone could alleviate depression symptoms in patients who relapsed while taking antidepressants

The drug naltrexone is approved for use in the treatment of opioid use disorders and alcohol use disorders, but preliminary research suggests it could also aid the treatment of depression.

The double-blind, randomized study found that low dose naltrexone reduced depression severity in 12 depressed subjects who had relapsed on dopamine-enhancing antidepressants. The study will be published in the January 2017 issue of the Journal of Affective Disorders.

Mischoulon: Our group studies a wide variety of treatments for depression. We are especially interested in the underlying biology of antidepressants and mechanisms by which depression develops. This study of low dose naltrexone (LDN) was based on a model proposed by Bear and Kessler, originally for restless leg syndrome for which it was patented. During treatment of patients with RLS, they observed anecdotally that LDN seemed to benefit depression as well.

Because one of the apparent mechanisms of low dose naltrexone is through dopamine, which is a neurotransmitter associated with mood regulation, Dr Bear’s company, PharmoRx, was interested in funding a pilot study on this agent for people with depression who had relapsed on dopaminergic antidepressants. They spoke with us about running such a study at MGH, and we agreed to do it.

What should the average person take away from your study?

The main finding is that if you have depression and relapsed while taking a previously effective antidepressant that works primarily by dopaminergic mechanisms, addition of LDN could potentially alleviate the depression in combination with the original antidepressant.

PsyPost interviewed the study’s corresponding author, David Mischoulon of Massachusetts General Hospital/Harvard Medical School. Read his explanation of the research below:

he main limitation of this work is the small patient sample. We only treated 12 patients and this is too few to draw firm conclusions. We need to replicate this work in a larger group of patients. The study included only antidepressants that work by dopaminergic mechanisms, and so we don’t know how well it would work with other types of antidepressants, such as those that are primarily serotonergic (e.g. SSRIs) or noradrenergic (e.g. tricyclic antidepressants).

Also, LDN may involve a range of different doses that are defined as “low,” and so a dose-finding study to determine the optimal “low” dose would also be valuable to do. Clinicians who wish to prescribe LDN for depressive relapse should realize that this is considered an experimental therapy, and should inform their patients about the risks of trying a relatively unproven therapy.

Is there anything else you would like to add?

While LDN is obtainable by prescription from a licensed physician, it cannot be bought in most drugstores, because commercially available forms of naltrexone come in much higher doses. To obtain LDN you will need to take your prescription to a compounding pharmacy where they can prepare it for you in the appropriate dosage form. Most insurance plans will cover it, however, so LDN should be accessible to most people.

In addition to Mischoulon, the study “Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants” was co-authored by Lindsay Hylek, Albert S. Yeung, Alisabet J. Clain, Lee Baer, Cristina Cusin, Dawn Flosnik Ionescu, Jonathan E. Alpert, David P. Soskin and Maurizio Fava.

Kresser Institute

Clinicians are increasingly using low-dose naltrexone to treat challenging illnesses such as autoimmune conditions and neurodegenerative disease. LDN is extremely safe and well tolerated, especially compared to the drugs typically used to treat these conditions, making LDN a valuable tool for clinicians and an important focus for ongoing research.


naltrexone
istock.com/baona

As a practitioner, you may be familiar with the drug naltrexone, which was approved by the FDA in 1984 for treating addiction patients. In doses of 50 to 100 milligrams, naltrexone completely blocks opioid receptors in the brain, preventing patients from experiencing a high when they take opioid drugs.

Soon after the drug’s initial approval, Dr. Bernard Bihari discovered a potential alternate application for naltrexone. He noticed that in AIDS and cancer patients, a much lower dose of naltrexone (about 3 milligrams) had beneficial immune-modulating effects. This discovery gave rise to a grassroots movement of patients and practitioners who had seen LDN work and were calling for additional research and mainstream attention.

Despite the promise of this new treatment, formal research on LDN has been slow to happen, likely because LDN is off patent and therefore not as profitable to drug companies. Even so, our understanding of the mechanisms behind LDN’s effectiveness in various conditions continues to progress, and results from preliminary clinical trials are slowly being published.

In this article, I’ll describe our current understanding of LDN’s mechanisms and review the clinical trials that have been conducted thus far. I’ll also give you a more practical take on LDN from my perspective as a clinician and cover concerns that might be relevant for other clinicians who want to prescribe LDN to their patients.

How Does LDN Work?

As research on LDN progresses, it appears more and more likely that it functions through a variety of different mechanisms and that the most relevant mechanism might differ depending on the disease that is being treated. But at this point, the two most well-characterized functions of LDN are as an opioid antagonist and an anti-inflammatory.

Increasing Endogenous Opioid Activity

Like its full-dose counterpart, low-dose naltrexone blocks opioid receptors in the brain, the major difference being that LDN is cleared from the system after only a few hours. Most researchers believe that this temporary opioid receptor blockade creates a “rebound effect,” resulting in up-regulated production of the endogenous opioids beta-endorphin and met-enkephalin, as well as increased expression of opioid receptors (1).

How these adaptive changes affect the disease processes that LDN influences is less established. However, several mechanisms have been proposed. First, endogenous opioids are known to have analgesic and stress-relieving effects, which alone could account for some of the symptom relief seen with LDN.

What the latest research says about low-dose naltrexone

Second, we know that immune cells possess opioid receptors, and both endogenous and exogenous opioids have long been considered important immune modulators (2, 3). The exact effects of endogenous opioids on the immune system, however, remain unclear; both increases and decreases in immune cell activity and proliferation have been observed in response to LDN, as well as beta-endorphin and met-enkephalin (4, 5, 6).

These endogenous opioids may also exert therapeutic benefits based on their regulation of cellular proliferation. Met-enkephalin, also known as opioid growth factor (OGF), has been found to regulate the cell cycle by suppressing DNA synthesis via its action on the OGF receptor (7, 8). This so-called “OGF–OGFr axis” is the focus of research on LDN for treating cancer and may also be another mechanism by which LDN modulates immune function.

Reducing Inflammation in the CNS

LDN appears to have a second mechanism of action that is independent from the opiate-antagonist pathway described above: suppression of microglial activity. Microglia are the primary immune cells in the central nervous system and are responsible for creating inflammation in response to pathogens or injury. When activated, microglia secrete factors such as pro-inflammatory cytokines, prostaglandins, nitric oxide, and excitatory amino acids (9).

The activation of the microglia and the subsequent release of cytokines—though essential to protecting the brain and CNS—cause symptoms such as fatigue, reduced pain tolerance, sleep and mood disturbances, cognitive disruption, and general malaise, all classically referred to as “sickness behaviors” (10). While these adaptive symptoms may make sense in the short term for promoting rest and recovery, ongoing CNS inflammation is maladaptive and can contribute to a wide range of diseases and syndromes.

Evidence indicates that LDN can suppress microglial activation, likely via its antagonistic effect on toll-like receptor 4 (TLR4), a non-opioid receptor that is found on macrophages such as microglia (11). This mechanism may explain LDN’s effectiveness for conditions like fibromyalgia and other chronic pain disorders, which involve chronic activation of microglial cells.

LDN in the Scientific Literature

Unfortunately, research on LDN as a treatment for human disease is still extremely sparse. Most of the trials that have been conducted thus far were primarily intended to test the tolerability and safety of LDN, rather than the efficacy, so keep that in mind, but the initial research does show promise. I’ve summarized the existing studies below, and hopefully additional research won’t be far behind.

Crohn’s Disease

A small open-label pilot study from 2007 had remarkable results, reporting that 89 percent of participants responded to LDN, and a whopping 67 percent achieved remission (12). This was the first published LDN trial in humans.

Results from two subsequent randomized controlled trials were less dramatic, but still extremely promising. One study from 2011 reported significant improvement in 88 percent of the participants in the LDN group, compared to 40 percent in the placebo group (13). And 33 percent of participants in the LDN group achieved remission, compared to 8 percent in the placebo group, although this difference was not statistically significant.

The second RCT was published in 2013 and looked at the effectiveness of LDN in children with Crohn’s disease (14). They found that of those treated with LDN, 67 percent exhibited improvement, and 25 percent went into remission. In all of these studies, LDN was very well tolerated with no significant difference in side effects compared to placebo.

Fibromyalgia and Other Conditions

In 2009, a pilot study involving 10 fibromyalgia patients reported a greater than 30 percent reduction in symptoms over placebo in those taking LDN (15). Interestingly, they found that patients with a higher erythrocyte sedimentation rate (ESR) at baseline had greater symptom reduction in response to LDN treatment. ESR is a marker for inflammation, so this observation lends credence to the theory that LDN works by reducing inflammation in the central nervous system.

The second study, a randomized controlled trial involving 31 fibromyalgia patients, was published in 2013. They reported significant improvements in pain, mood, and general satisfaction with life in the LDN group compared to placebo (16). And again, LDN was well tolerated in these studies.

LDN has also been studied in and shown potential efficacy for autism (17), pain (18, 19), depression (20), multiple sclerosis (21, 22, 23), systemic sclerosis (24), and complex regional pain syndrome (25). Additionally, preliminary evidence in vitro and in animal models indicates that LDN may be an effective treatment for cancer, including ovarian cancer and pancreatic cancer (26, 27).

Clinical Success Using LDN for Autoimmune and Neurodegenerative Diseases

As I mentioned at the beginning of this article, LDN is unusual in that its use has spread as a result of grassroots efforts by patients themselves, rather than the typical top-down marketing of new drugs by pharmaceutical companies. Because of this, clinical and anecdotal evidence for the drug’s effectiveness in a wide variety of conditions still vastly outpaces the scientific literature.

This is initially a cause for concern because we obviously want any treatment we use on patients to be as evidence based and extensively studied as possible. But we do have ample safety data from the approval process of full-dose naltrexone, and all of the evidence we have so far on LDN shows that it is extremely safe and well tolerated. It’s still a judgment call, but the fact that existing treatments for many of these illnesses are demonstrably toxic with significant side effects certainly makes LDN an attractive option.

Conditions that have clinically responded well to LDN but have not been formally studied include autoimmune diseases such as Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, lupus, psoriasis, and ulcerative colitis, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s, and other conditions like chronic fatigue syndrome and even infertility. Because these conditions share the same underlying disease processes of immune dysregulation and inflammation, it’s not a huge surprise that LDN can be an effective treatment, despite the differences in disease presentation.

Practical Concerns for Prescribing LDN

LDN is generally very well tolerated, but patients may experience insomnia, headaches, or unusually vivid dreams when first starting the medication. These side effects are usually minor and dissipate after a week or two of taking LDN.  

Because naltrexone is only produced in 50-milligram tablets, prescriptions for LDN do need to be filled at a compounding pharmacy. And, because LDN is off label, it’s unlikely that insurance companies will cover it, but the out-of-pocket cost of LDN is only about $40 per month, making it more affordable than many drugs on the market.

One downside of LDN is that there’s not a standardized dose, and the most effective dose for a given patient may be anywhere from 1.25 to 4.5 milligrams. We typically start patients on 1 to 1.5 milligrams, then gradually increase to 4.5 milligrams and see how they do. From my experience, I’ve seen most people end up around 2.5 to 3 milligrams.

Note that in patients with Hashimoto’s or Graves’, their previous dose of thyroid medication could suddenly be too high as their thyroid function improves on LDN. It may be necessary to reduce their normal thyroid medication to prevent them from becoming hypo- or hyperthyroid.

Finally, be aware that while LDN can be miraculous for some patients, others may see no benefits at all. Unfortunately we don’t know enough yet to determine if there’s a subset of patients that LDN is most likely to help, so the best we can do is try and hope for the best. It can sometimes take a little while for patients to notice improvement on LDN, so we typically allow about three months as a trial period before deciding whether to continue treatment.

Ketamine – Psycom

8 herbs and supplements for depression

Depression is a serious mood disorder with symptoms that range from mild to debilitating and potentially life-threatening. Some people look to manage depression with herbal remedies, rather than with medication a doctor prescribes.

The most recent data from the National Institute of Mental Health suggest that in the United States, 6.7 percent of people experienced a major depressive episode in 2016.

Medications and counseling are conventional ways to alleviate the symptoms of depression. However, some herbs and supplements may also help.

In this article, we look at the common herbs and supplements with links to the treatment of depression and discuss their safety and effectiveness.

Herbs and supplements

herbs for depression

Some herbs, essential oils, and supplements have shown promising effects for people with depression.

The use of complementary therapies continues to gain popularity, as people look for more natural methods of managing their health.

However, herbal does not always mean safe or effective, and knowing which products to choose can save a lot of time and money.

In the United States, the Food and Drug Administration (FDA) do not monitor herbs in the same way as food and drugs. As a result, manufacturers are not always 100 percent clear about the quality or purity of their product.

Research suggests promise for some supplements in treating mild-to-moderate depression. These are some of the supplements that people most widely use:

1. St. John’s wort

St. John’s wort is also known as Hypericum perforatum. This plant has been a common herbal mental health treatment for hundreds of years. However, people must use caution if they chose to try it as a potential treatment for depression.

2016 systematic review found that St. John’s wort was more effective than a placebo for treating mild to moderate depression and worked almost as well as antidepressant medications.

However, this review of eligible studies did not find research on the long-term effects of St. John’s wort on severe depression.

The authors also advised caution against accepting the results wholesale, as the herb has adverse effects that many of the studies did not consider.

St John’s wort can also interfere with the effects of antidepressant medication, meaning that it may make symptoms worse or reduce the effectiveness of conventional treatment.

While St. John’s wort might help some people, it does not show consistently beneficial effects.

For these reasons, people should not use St. John’s wort instead of conventional treatment. Neither should they try St. John’s wort to treat moderate to severe depression.St. John’s Wort: Should I use it?Should I take St. John’s wort? Click here to find out more.READ NOW

2. Ginseng

This supplement comes from the gnarled root of the American or Asian ginseng plant. Siberian, Asian, and Eleuthero ginseng are different plants with different active ingredients.

Practitioners of Chinese medicine have used ginseng for thousands of years to help people improve mental clarity and energy and reduce the effects of stress.

Some people associate these properties of ginseng with potential solutions for the low energy and motivation that can occur with depression.

However, the National Center for Complementary and Integrative Health (NCCIH) advise that none of the many studies that people have conducted on ginseng have been of sufficient quality to form health recommendations.

3. Chamomile

study in 2012 reviewed data about chamomile, which comes from the Matricaria recutita plant, and its role in helping to manage depression and anxiety.

The results show that chamomile produced more significant relief from depressive symptoms than a placebo. However, further studies are necessary to confirm the health benefits of chamomile in treating depressive symptoms.

4. Lavender

Lavender oil is a popular essential oil. People typically use lavender oil for relaxation and reducing anxiety and mood disturbances.

2013 review of various studies suggested that lavender might have significant potential in reducing anxiety and improving sleep.

Lavender has mixed results in studies that assess its impact on anxiety. However, its effectiveness as a treatment for ongoing depression has little high-quality evidence in support at the current time.

5. Saffron

Some studies cite using saffron as a safe and effective measure for controlling the symptoms of depression, such as this non-systematic review from 2018.

However, more research would help confirm the possible benefits of saffron for people with depression. Scientists also need to understand any possible adverse effects better.

6. SAMe

man looks at drugs

Some supplements have shown promising effects on depression symptoms. However, many investigations confirming their benefits are low quality.

SAMe is short for S-adenosyl methionine. It is a synthetic form of a chemical that occurs naturally in the body.

In 2016, researchers reviewed all the randomized controlled trials on record for the use of SAMe to treat depression in adults. They found no significant difference between the effects of SAMe on depression symptoms and those of a placebo.

However, they also found that SAMe had about the same effectiveness as the common antidepressants imipramine or escitalopram. Furthermore, it was better than a placebo when the researchers mixed SAMe with selective serotonin reuptake inhibitor medications.

As with many other studies into herbs and supplements, the investigations into the safety and efficacy of SAMe are of low quality. More research is necessary to determine its exact effect.

People use the supplement in Europe as a prescription antidepressant. However, the FDA have not yet approved this for use in the U.S.

7. Omega-3 fatty acids

In a 2015 systematic review, researchers concluded that omega-3 fatty acid supplements are not useful across the board as a depression treatment.

While the study authors reported no serious side effects from the supplement, they also advised that it would only be an effective measure in treatment for depression that was due to omega-3 deficiency.

8. 5-HTP

Also known as 5-hydroxytryptophan, this supplement may be useful in regulating and improving levels of serotonin in the brain. Serotonin is the neurotransmitter that affects a person’s mood.

5-HTP has undergone a number of animal studies, and some, such as this review from 2016, cite its potential as an antidepressant therapy. However, evidence of its effects in human subjects is limited.

5-HTP is available as an over-the-counter (OTC) supplement in the U.S. but may require a prescription in other countries.

More research is necessary, especially regarding concerns that it may cause serotonin syndrome, a serious neurological complication if a person takes 5-HTP in excess.

Supplement manufacturers do not have to prove that their product is consistent. The dose on the bottle may also be inaccurate.

People should ensure they purchase herbs and supplements from a trusted manufacturer.

FOODS for Depression:

https://www.medicalnewstoday.com/articles/318428.php

Important foods and nutrients

The following foods and nutrients may play a role in reducing the symptoms of depression.

Selenium

Selenium can be a part of reducing symptoms of depression in many people. Low selenium levels have been linked to poor moods.

Selenium can be found in supplement form or a variety of foods, including whole grains, Brazil nuts, and some seafood. Organ meats, such as liver, are also high in selenium.

Vitamin D

Vitamin D deficiency is associated with many mood disorders, including depression. It is important to get enough vitamin D to help in the fight against depression.

This vitamin is obtained easily through full body exposure to the sun, and there are also many high-quality supplements on the market that contain vitamin D.

Food sources of vitamin D include fatty fish such as salmon, tuna, and mackerel.

Omega-3 fatty acids

Nuts and seeds are a source of omega fats

Nuts and seeds are sources of omega fats, which can help treat mood disorders and improve cognitive function.

In a study posted to the Indian Journal of Psychiatry, researchers observed that populations that do not eat enough omega-3fatty acids might have higher rates of depressive disorders.

Good sources of omega-3s may include:

  • cold water fish, such as salmon, sardines, tuna, and mackerel
  • flaxseed, flaxseed oil, and chia seeds
  • nuts, such as walnuts and almonds

The quality of these foods can affect the levels of omega-3s they contain.

Eating omega-3 fatty acids may increase the level of healthful fats available to the brain, preserve the myelin sheath that protects nerve cells, and keep the brain working at the highest level. In turn, this can reduce the risk of mood disorders and brain diseases occurring.

Antioxidants

Antioxidants have become popular as they fight free radicals. Free radicals are damaged molecules that can build up in different cells in the body and cause problems, such as inflammation, premature aging, and cell death.

The brain may be more prone to this type of damage than other areas of the body. As a result, it needs a good way to get rid of these free radicals and avoid problems. Foods rich in antioxidants are believed to help reduce or reverse the damage caused by free radicals.

Everyday antioxidants found in a variety of whole foods include:

These nutrients may help reduce stress-related symptoms of psychiatric disorders.

B vitamins

Some B vitamins are also key in mood disorders such as depression. Vitamin B12 and folate, or vitamin B9, have both been linked to a reduced risk of mood disorders.

Sources of B vitamins include:

  • eggs
  • meat
  • poultry
  • fish
  • oysters
  • milk
  • whole grains

Fortified cereals may also contain vitamins B12 and folate. Other foods that have folate in them include:

  • dark leafy vegetables
  • fruit and fruit juices
  • nuts
  • beans
  • whole grains
  • dairy products
  • meat and poultry
  • seafood
  • eggs

Eating a varied diet is an easy way to ensure there is enough folate in the diet.

Zinc

Zinc helps the body perceive taste, boosts the immune system, and may also influence depression. Zinc levels may be lower in people with clinical depression, and zinc supplementation may also improve the effectiveness of antidepressants.

Zinc is found in supplements. Foods, including whole grains, oysters, beans, and nuts, are also good sources of zinc.

Protein-rich foods

High-quality proteins are the building blocks of life. Getting adequate protein is essential for everyone, but some forms of protein, in particular, may be more helpful for people with depression.

Foods such as tuna, turkey, and chickpeas have good levels of tryptophan, which is needed to form serotonin.

Serotonin deficiency was once thought to be a major cause of depression. We now know that the link between serotonin and depression is very complex, but it does seem to influence depression in many people. Including foods rich in tryptophan in a diet may help relieve symptoms.

Foods to avoid

Just as certain foods and nutrients may be of benefit to people with depression, there are also some that should be avoided.

Caffeine

For people with depression that is linked to anxiety, it may be important to avoid caffeine. Caffeine can make it difficult to sleep and may trigger symptoms of anxiety in many people.

Caffeine also affects the system for hours after it is consumed. It is best for people with depression to avoid caffeine if possible, or reduce consumption and stop consuming it after noon.

Alcohol

Though occasional alcohol drinking is seen as an acceptable distraction, it may make depression symptoms worse.

Excessive alcohol consumption may increase the risk of panic attacks or depressed episodes. Alcohol also alters a person’s mood and may turn into a habit, which could influence depression symptoms.

Refined foods

High-calorie foods with few nutrients in them may also influence depression symptoms. Foods high in sugar and refined carbs can promote a crash, as the energy from them is depleted. This can make a person feel mood swings or energy swings.

Nutrient-dense whole foods are a much better approach to balancing mood and energy levels.

Processed oils

Highly processed or refined oils, such as safflower and corn oil, are very high in omega-6 fatty acids. Having too many omega-6s in the diet can cause an imbalance in the body that may promote inflammation in the brain and influence depression symptoms.

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Other factors in depression

Woman walking.

Regular physical activity and spending time outdoors are proven ways to help improve the symptoms of depression.

There are other factors that link to both diet and depression and play a role in this mental healthillness.

Emerging research has shown gut bacteria to play an integral role in major mood disorders, including depression and bipolar disease. A 2016 meta-analysis reported that probiotics, in both supplement form and in fermented foods such as yogurt and kefir, resulted in significant reductions in depression.

More research is needed to identify the therapeutic value of specific strains, but so far Lactobacillus and Bifidobacterium show potential.

Obese people may be more likely to be depressed, and depressed people are more likely to become obese. This may be due to hormone changes and immune system imbalances that come with depression.

Spending time outdoors and at least 150 minutes of physical activity weekly have been shown to improve mood and depressive symptoms.

Some people with depression also have substance abuse problems. Alcohol or other drugs can interfere with sleep patterns, decrease motivation, and alter a person’s mood.

Sleep may also play a role in depression. The body’s natural sleep cycle creates mood-altering chemicals to match the time of day. Altering this natural cycle may affect how well the body can use these chemicals.

Most adults respond well when they get 7 to 8 hours of sleep, though the number varies from person to person. It may also help to reduce exposure to blue light, during the hours leading up to sleep. Blue light is emitted by electronic devices and low-energy light bulbs.

LDN for psychiatric disorders:LDN-for-psychoactive-disordersDownload

LDn Information

When I have to describe my patient population, I often say that “my patients are normal people with some problems.” A significant number of my patients also have a chronic medical illness, such as an autoimmune disorder. Since I added it to my prescribing armamentarium many years ago, LDN has become a frequently used tool that I offer to my patients along with the other therapeutic strategies.

…LDN has become a frequently used tool that I offer to my patients along with the other therapeutic strategies.

For what kinds of conditions do you prescribe LDN?

In my practice, I use LDN for these conditions because I see it work:

  • Some subtypes of depression (subtypes that seem to be triggered by inflammation, seasonal type, postpartum, or related to deficiency of dopamine or endorphins);
  • Some subtypes of anxiety (for example, that come with obsessive ruminations or intrusive thoughts);
  • Obsessive-compulsive disorder and OCD-spectrum disorders;
  • Post Traumatic Stress Disorder (PTSD);
  • Modulation of sleep architecture;
  • A variety of sexual problems, including problems of desire, performance and satisfaction;
  • What I call “LDN assisted psychotherapy”. (I think I found how to use it to help extinguish unwanted behaviors and reinforce wanted alternative behaviors. This work is done with therapists I teach and then collaborate with);
  • Appetite control;
  • Addiction to internet, sex, gambling;
  • Alcohol and drug dependence. (While we probably need a “traditional dose” of naltrexone for treatment of alcohol dependence, some other types are doing great on LDN);
  • Helping patients stop opioids and then recover quicker from the prolonged post-opioid use problems, or just decreasing the amount of pain pills they are taking.

You mention prescribing LDN for certain subtypes of depression/anxiety. What subtypes are you referring to?

In my opinion, depression is not a single disorder. It is rather a generic name that was chosen to describe a number of diverse conditions, just because they share a few common symptoms. There were many attempts in academic psychiatry to separate the clearly heterogeneous group of disorders collectively called “depression” into subtypes. Unfortunately, for a long time, this work had no impetus, as most of the medications that came to market during the last 20-30 years were inspired by the same theory – that depression is related to the imbalance in one or more principal neurotransmitters in the brain – serotonin, norepinephrine and dopamine. In my view, in the nearest future, we will see that new medications will seek approval to treat specific symptoms of depression, such as sadness, racing thoughts, obsessive ruminations and changes in energy, rather than for the generic indication “depression”.Which subtypes of depression are more responsive to LDN?

Although not always, patients whose depression comes with tiredness, inability to feel any excitement, no motivation, no enthusiasm, slowed movements and thinking, decreased appetite, etc. are more likely to respond to LDN. This is compared to patients who describe their depression as “painful”, who feel discontent, antsy, and/or pessimistic. There are no strict rules; some of the depression types can overlap in their symptoms. I also want to add that it is very uncommon for LDN to worsen depression.

Although not always, patients whose depression comes with tiredness, inability to feel any excitement, no motivation, no enthusiasm, slowed movements and thinking, decreased appetite, etc. are more likely to respond to LDN.

What effects did you see LDN providing?

Since the majority of my patients are already taking at least a few, if not more, medications, I do not have a luxury to stop all their medications suddenly and switch them only to LDN. I usually start by adding LDN, along with making some other changes to the cocktail of their medications. I can only say that the result of adding LDN is sometimes spectacular and sometimes there is no obvious change.In your experience, who can benefit from LDN?

LDN works on opioid receptors. Everybody who has opioid receptors can benefit from LDN. Although at this point there are no recommendations to take LDN prophylactically, knowing how much LDN can do, and how many autoimmune conditions remain undetected for long time, a trial of LDN is probably warranted for most of the cases of “vague symptoms”, for the cases of incomplete resolution of an illness, etc.What do you advise your patients about the timing of taking their LDN?

In psychiatry, we frequently adjust dosages and schedules. Of course, I am aware of the traditional way to take low dose naltrexone before bed and I always recommend that patients start taking it this way. If, however, we do not get a desirable result – and, in the case of psychiatry, the patient, not the lab value is the best judge of the result – the dosage can be changed or the timing can be changed. I have patients who take LDN once a day and others who sip an LDN solution throughout the day. In some cases of addiction, or if my goal is to modify an unwanted behavior, I might instruct the patient to take naltrexone every time they think they might find themselves engaged in the behavior they want to extinguish.Have you observed long-term effects of LDN yet?

As far as I understand, there is no official information related to the long term use of LDN. A lot of patients feel that they “returned back to step one” when they stopped taking LDN. Because of this, especially taking in consideration practically negligible side effects, the risk-benefit ratio of LDN is clearly supporting long-term use. Even when I treat illnesses with episodic courses, such as depression, I still recommend that patients continue taking LDN because of the high risk of recurrence. On the other hand, I had patients who felt strongly about stopping all medications as soon as they improved; it made no sense, but they had strong philosophical disagreement with taking any medications in general. In their cases, I just made sure that they have a strategic supply of LDN which can be started when the next episode begins. Unfortunately, this kind of patient is not always able to catch the first signs of the illness and start the treatment before it becomes severe.

…especially taking in consideration practically negligible side effects, the risk-benefit ratio of LDN is clearly supporting long-term use.

Do you think there is a risk of receptors becoming adjusted to LDN and creating the potential for either tolerance or addiction to it?

Some of my patients who say, “If I forget to take my LDN, I feel it” wonder the same. They feel they are “missing something”, and they might become more irritable, tired, have difficulty concentrating, and complain of “brain fog”. This makes sense because LDN works on the opioid receptors, after all. At the same time, I do not know a case when a patient could not stop LDN or had unbearable withdrawal, even after a prolonged use. Based on what I understand now, this “dependence” on LDN does not look like dependence to opioids or benzodiazepines (Xanax®, Ativan®, Valium®, etc.). It looks more like dependence to coffee. Some people who drink coffee every day and stop abruptly also complain of withdrawals – they have no energy, no concentration, they start having headaches, etc. These symptoms, however, are more of a nuisance than a tragedy. As a rule, they subside in a few days. Based on what I know now and what I read, I would not stop LDN because of the fear of dependence.

…I do not know a case when a patient could not stop LDN or had unbearable withdrawal, even after a prolonged use.

Have you seen any side effects from LDN?

The patients I treat are probably more vulnerable to vivid dreams and their dreams might become unpleasant. Additionally, after a couple of surprises, I do not forget to tell my female patients to be more careful about pregnancy precautions, because they might become unexpectedly more fertile.What kind of research on LDN for sexual dysfunction are you interested in?

There is a tight connection between autoimmune conditions and hormone imbalance; there is even an opinion that autoimmune conditions are caused by hormone imbalance. Sexual dysfunctions (not only disorders of performance, but also disorders of desire and satisfaction) are only a small part of the consequences of the hormone imbalance. My most recent project is focusing on post-coital dysphoria or “post-sex blues”. Basically, it describes a phenomenon when people become dysphoric (tearful, depressed, or, possibly, argumentative) after they have an orgasm, even though they had satisfying sex with a person they loved. The phenomenon is most likely related to the skyrocketing and then sudden dropping of the dopamine level. The mechanism is somewhat similar to the crash following cocaine use. A few years ago, I came up with the idea of using LDN prior to sex to normalize this dopamine/endorphin response. In essence, taking LDN prior to sex can fix the problem, and the only question left is the timing and the amount of LDN.

In essence, taking LDN prior to sex can fix the problem, and the only question left is the timing and the amount of LDN.

What dose and timing do you recommend for this kind of sexual dysfunction condition?

In practice, I recommend LDN as a part of a stimulant-vitamin-drug combination. At this point, I need a little more data to announce the magic combination, dose and timing. I would like to invite the readers, whether you are on LDN currently or not, openly or anonymously, to share your experience about using LDN for this condition.

LDN can → ↑ BDNF as well as: exercise caloric restriction glutamate, cucurmin

To boost endorphins, use LDN with: ● high-protein food ● vitamins: B, C, Omega-3 with vit D, E, Zink; ● avoiding sugar, flour, coffee – (“exorphins”) ● exercise, massage, acupuncture, sunlight ● guided imagery, music, romance, nature

BDNF – norbuprenorphine, kratom, cannabidiol (Epidiolex), THC (Marinol) – inhibited by trazodone, buprenorphine

Naltrexone Alcoholism Medication

Naltrexone is a medication that can be used for the treatment of opioid violations and alcohol addiction. The research that was conducted in order to study the action of this drug showed that naltrexone can also be taken within the patients suffering from severe depression.

As a result of the research, it was found that taking the drug naltrexone can help to reduce depression. The patients participating in the research were people, who had depression and took antidepressants. It was set up that the severity of depression was reduced within the patients taking naltrexone. The results of the research were published in the Journal of Affective Disorders in January 2017.

The author of this study was David Mischoulon, a medical specialist of the Massachusetts Hospital and one of the specialists of the Harvard Medical School. He was the leader of the group that studied a variety of ways to treat severe depression. The group studied the action mechanism and the effect of antidepressant medications, as well as the mechanisms that contribute to the development of depression. Initially, the LDN drug was patented as the drug indicated for the treatment of restless legs syndrome (RLS), but during the treatment of patients with RLS taking LDN, it was found that LDN also positively affects suppression of depression.

One of the mechanisms of the low dose naltrexone medication is dopamine. It is a neurotransmitter, which is associated with the regulation of human mood and helps to reduce depression.

The studies, connected with LDN, have also shown that if a patient suffers from depression and takes antidepressants that work with dopaminergic mechanisms, the additional use of LDN in combination with the antidepressant drugs can help to cope with depression in a shorter period of time.

There was also a disadvantage of the research. It is connected with the fact that there were just 12 patients who participated in the study. This number of the participants is too small to make exact conclusions, concerning the LDN action mechanisms and taking it in order to treat depression. To be sure about the action of this drug during treating depression, more studies should be done, involving larger groups of participants. In the study described above, the patients used just the antidepressants, acting through dopaminergic mechanisms. This fact does not give any confidence that LDN will act positively in combination with other antidepressants, for example, with serotonergic and noradrenergic antidepressants.

Moreover, it would be useful to conduct an optimal LDN study, as the LDN medication includes a number of different dosages and they are all defined as low doses. Such a study has not previously been conducted. Therefore, some medical specialists who prescribe LDN should inform their patients about this drug and warn the patients that the therapy associated with LDN while treating depression is experimental. The patients should be aware of the potential risks before taking this medication, as the drug is not accepted in medicine, regarding the treatment of depression.

LDN can’t be bought at most pharmacies, although it can be obtained by prescription from a licensed doctor. The commercially available forms of naltrexone come in much higher doses. To get LDN, you need to bring a prescription from your doctor to the pharmacy and there the appropriate dosage form will be prepared for you. In general, LDN is available for the majority of people.Treatment-of-Complex-Regional-Pain-Syndrome-CRPS-Using-Low-Dose-Naltrexone-LDNDownloadAssociation-of-Combined-Naltrexone-and-Ketamine-With-Depressive-Symptoms-in-a-Case-series-of-Patients-With-Depression-and-Alcohol-Use-DisorderDownload

Ketamine has rapid and robust antidepressant effects. However, there are concerns about the abuse liability of ketamine.1This concern was heightened recently owing to a preliminary report suggesting that antidepressant effects of ketamine might be dependent on opiate receptor stimulation.2 Below, we present pilot data that indicate that the antidepressant effects of ketamine are not attenuated by naltrexone pretreatment. As a result, the combination of opiate receptor antagonism with ketamine might be a strategy to reduce addiction risk among patients with depression at risk for substance abuse.Methods

We recruited and obtained written informed consent from 5 patients with current major depressive disorder and alcohol use disorder. In this 8-week open-label pilot study, which recieved institutional review board approval by the VA Connecticut Healthcare System Human Subjects Subcommittee, patients received injectable naltrexone (380 mg once 2-6 days prior to the first ketamine infusion) and repeated intravenous ketamine treatment (0.5 mg/kg once a week for 4 weeks; a total of 4 ketamine infusions). The study had 2 phases: (1) a 4-week ketamine treatment phase and (2) a 4-week follow-up phase. All patients were abstinent from alcohol for 5 days or longer prior to the first ketamine infusion. The primary outcome measure was clinical response defined as a 50% or higher improvement from baseline in the Montgomery-Åsberg Depression Rating Scale scores at 4 hours postinfusion.Results

The combination of naltrexone and ketamine was associated with reduced depressive symptoms. The Figure shows that 60% (3 of 5) of patients met response criteria after their initial ketamine dose and 100% (5 of 5) met response criteria by their fourth dose, although 1 patient left the trial after receiving 2 ketamine infusions. The Table shows that depressive symptoms improved about 57% to 92%. Also, 80% (4 of 5) of patients reported improvement in alcohol craving and consumption as measured by the Obsessive Compulsive Drinking Scale. The combination treatment was safe and well tolerated in all participants. No serious adverse effects were reported in the trial.Discussion

Our pilot data suggest that naltrexone pretreatment did not interfere with the antidepressant effects of ketamine and might enhance the treatment of comorbid alcohol use disorder. This result conflicts with that reported by Williams et al2 in which pretreatment with 50 mg of naltrexone reduced the rate of clinical response to ketamine from 71% (5 of 7 individuals) to 0% (0 of 7 individuals). Their data and an editorial by George,3 although preliminary, make a case for a central role for opiate agonism in the antidepressant effects of ketamine. Although our pilot data were collected under somewhat different conditions than those of Williams et al2 (eg, different primary outcome time of 4 hours vs 1 day postinfusion, presence vs absence of alcohol use disorder, injectable vs oral naltrexone), they do not support the hypothesis that opiate receptor stimulation mediates the antidepressant effects of ketamine. Since Williams et al2 did not provide depression ratings over a 4-hour period postinfusion, we cannot examine whether 50 mg of oral naltrexone blunted ketamine response in this early 4-hour period. Our findings are consistent with an earlier study in healthy individuals showing that the behavioral effects of an antidepressant dose of ketamine were not altered by pretreatment with 25 mg of naltrexone,4 and some preclinical evidence that ketamine isomers may be weak partial agonists at μ opiate receptors.5

The initial report by Williams et al2 and our preliminary data should be interpreted with great caution. Larger randomized clinical trials are needed to better understand whether opiate receptor stimulation contributes to the antidepressant effects of ketamine. If so, then preclinical research will be needed to help us to understand this role for opiates and its implications for future rapid-acting antidepressant treatments.

Unique Drug Combo Promising for Severe, Intractable Pain

 Low doses of the hormone oxytocin along with the anestheticketamine may provide a unique and effective therapeutic approach to some patients with severe, intractable pain

This therapeutic approach is “incredibly unique” and is safe and effective in some patients with intractable pain. “If you put these two together, you could replace any short-acting opiate,” Caron Pedersen, FNP-C, DC, BSN, BS-PT, a nurse practitioner, chiropractor, and physical therapist specializing in patients with spinal pain, told Medscape Medical News.

Dr Caron Pedersen

Dr Pedersen has been working with pain management expert, Forest Tennant, MD, DPH, Veract Intractable Pain Clinic, West Covina, California, to find better ways to treat patients with very severe pain.

Such patients, said Dr Pedersen, “are pretty much opioid-dependent and have been for long time, and are not getting relief.”

Dr Pedersen presented some of her research here at the Academy of Integrative Pain Management (AIPM) 28th Annual Meeting.

Alternative to Opioids?

A variety of antiseizure, antidepressant, and anti-inflammatory agents, as well as muscle relaxants and adrenergic blocking agents, provide mild to moderate pain relief. But these approaches are not always a substitute for opioids in patients with severe pain.

Both oxytocin and ketamine provide analgesia by mechanisms other than stimulating opioid receptors.

Produced in the hypothalamus, oxytocin is a potent natural pain reliever. The hormone is released in pregnant women during labor and also in other painful conditions or stressful events.

It has been reported to relieve pain in patients with headache, chronic back pain, and fibromyalgia, and there is “a mountain of research” on oxytocin’s complex production, release, and receptor system, said Dr Pedersen.

Dr Tennant explained that some of the hormone is released into the peripheral circulation via the posterior pituitary and some into the central nervous system, including the spinal fluid.

Oxytocin receptors are found at multiple sites in the brain and throughout the spinal cord, said Dr Tennant. In addition to activating its own receptors and decreasing pain signals, oxytocin binds to opioid receptors and stimulates endogenous opioid release in the brain.

In addition to relieving pain, oxytocin lowers serum cortisol and can produce a calming effect and improve mood.

“It has the effect of making people happy, making them feel a little less anxious,” said Dr Pedersen. “It changes the central nervous system; it makes the hypothalamus pump out chemicals that are telling the body it’s okay, calm down.”

Oxytocin can block “anticipatory pain,” added Dr Pedersen. Patients with intractable pain are constantly waiting for “the next burse of pain” so are “in constant stress,” she said.

However, when they take oxytocin, “they may actually get a lot of relief based on the fact that they are no longer having that anticipation.”

Pain Free, No Side Effects

The investigators are working to determine optimal doses and routes of administration for oxytocin. They have experimented with combining oxytocin with low-dose naltrexone, benzodiazepines, neuropathic agents, opioids, and now ketamine, an N-methyl-D-aspartic acid receptor antagonist.

There has been a resurgence of interest in ketamine as a possible therapy for chronic pain conditions, including neuropathic pain, complex regional pain syndrome, fibromyalgia, postherpetic neuralgia, migraines, and spinal cord injury

At relatively high doses, ketamine has significant psychomimetic and euphoric properties that have led to abuse. Oral ketamine, sometimes called Special K, has become a popular nightclub drug.

Dr Tennant and Dr Pedersen have been experimenting with low-dose ketamine added to oxytocin in patients with the most severe intractable pain.

The study they presented at the AIPM meeting included five such patients (mean age, about 40 years) who had used oxycodonemorphinehydrocodone, or hydromorphone for over a year.

Patients had not taken their short-acting opiate for several hours when they received 0.5 mL (2 mg — half of a syringe, or 20 units) of liquid oxytocin sublingually. Within 10 minutes, all five patients reported varying degrees of pain relief.

About 15 minutes after receiving the oxytocin, patients then received 0.25 to 0.50 mL (12.5 to 25 mg) of liquid ketamine, also sublingually.

The ketamine enhanced the pain relief. With the combination, two patients became completely pain free. These patients would “positively not” have been pain free with opioids, said Dr Pedersen.

The pain relief lasted about 4 hours with no side effects.

The Worst of the Worst

Dr Pedersen said the study patients were “the very worst” of pain patients. In her clinic, many patients suffer intractable pain — pain that never completely goes away with surgery or with drugs. “Some have had, say, seven or eight back surgeries and they have so much inflammation in their spine.”

Some are battling an autoimmune disease, such as lupus. Others have arachnoiditis, an incurable inflammatory condition of the arachnoid mater, the middle layer of the meninges.

Because oxytocin is a hormone, its pain-relieving ability varies from patient to patient and its effectiveness is related, among other things, to blood levels, pain severity, and sex. 

In her experience, Dr Pedersen has found that men tend to have a better response to the combination of oxytocin and ketamine than women.

But women also respond “fabulously,” she said. She described one 38-year-old female patient in her practice with a disc herniation who had been taking opioids, which were not helping her much. “She stopped taking them when she started using this combination therapy.”

Other patients have been able to cut back on opioids “significantly enough that if they had to stop taking them, they would be okay,” said Dr Pedersen.

The combination therapy may also address the issue of addiction, said Dr Pedersen. Some of her patients had become addicted to opioids, but after using the oxytocin-ketamine regimen, they’re not craving or abusing opioids.

The liquid form taken sublingually provides “the best delivery system” and is much more effective than pills, said Dr Pedersen.

Although liquid oxytocin typically has a shelf life of only about 10 days, Dr Pedersen has found pharmacies that put the hormone in a suspension that lasts for 3 months.

Intriguing Results

Commenting on the research for Medscape Medical News, Charles E. Argoff, MD, professor of neurology, and director, Comprehensive Pain Center, Albany Medical College, New York, said it “provides intriguing results.”

However, he said, a single-center open-label study of only five patients “is insufficient to draw any conclusions.”

While the use of oxytocin as an analgesic is supported by basic science, “this study does not add significantly to the human studies already completed, given its size and design,” said Dr Argoff.

Adding ketamine “dampens enthusiasm” for this therapeutic approach because of concerns about dependency and side effects, said Dr Argoff.

Adverse effects of ketamine can include nausea, headaches, fatigue, and dysphoria.

The authors have disclosed no relevant financial relationships.

Academy of Integrative Pain Management (AIPM) 28th Annual Meeting. Abstract 24. Presented October 21, 2017. About Nancy L Sajben MD

Pain Sand Diego

Web Blog Pain management LinkWelcome to my Weblog on Pain Management! Thanks for stopping by.

patients to use at home as a nasal spray or sublingual:
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Do not use it with opioids.Opioids cause inflammation, ketamine does the opposite. It modulates (reduces) inflammation.
Never use it alone. It is a glial modulator, it is not only an NMDA receptor inhibitor.
For intractable, treatment resistant cases, use as many glial modulators as you can.
Ultra low dose naltrexone (20 micrograms TID) can profoundly reduce tolerance in patients on opioids: they may now need 1/2 to 1/8th the dose of opioid that simply had never quite done enough. Naltrexone not only relieves pain, it may profoundly improve function.
Opioids stimulate glia to produce pro-inflammatory cytokines -> pain. Stop opioids if you can. You are likely to get far better results with glial modulators, especially if you have CRPS.
Pain specialists should be offering a trial of glial modulators before they choose opioids for life.
Use glial modulators as needed: ketamine, oxytocin (a hormone), tricyclic antidepressants (weaker than the others but can be profound for some), metformin.
Metformin, a glial modulator!  for pain! in people who do not have diabetes. I will be posting on it this coming week — inshallah
 Use it sparingly. Whether ketamine or opioids, use sparingly because of tolerance.
If it is a good day, use less and use sparingly. If pain spikes, use higher dose, use sparingly.
 When tolerance develops to ketamine, what then?
Is it possible that a drug holiday would work? Should that be in months or years? we may never find out.
Use ketamine and/or opioids sparingly. Prevent tolerance. You may not always need the same dose on a good day or when pain spikes.
Make sure you are doing other things to relieve pain, not just ketamine or opioids.
 Dextromethorphan helps, a sigma I receptor antagonist that reduces the excitotoxic glutamate
Try as much as you can to exercise.
Lift the mind to positive things. Learn to block thoughts of pain, dissociate from that. Choose life and doing and being.
Develop momentum. Try never to judge; that includes being hard on yourself and others.
Expand your spiritual life. Find your path if you don’t already have one. It may begin for all sorts of reasons, but figure it out. It’s real. Spiritual giants from all paths have had direct perception of the infinite in many ways and forms. Direct perception.
S-ketamine clinical trials are now ongoing in the US. I was very disturbed to hear the side effects of S-ketamine infusion related last week. S-ketamine deeply disturbing. It is wrong to give everyone the same dose of ketamine. Not once have I ever heard anyone recount similar side effects from ketamine infusions. I got the impression from her they were not inclined to attribute it to S-ketamine, but it would be disturbing if they did not. Ketamine’s dose no matter how you give it is idiosyncratic, meaning some respond to 2 mg, some to 400 mg. It is wrong and should be unethical to subject someone to doses 200 times the dose they may need. It is dangerous and promotes tolerance .


Metformin & Pain

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A diabetes drug used for many who have no diabetes. Recent discussion on metformin here and here.

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Metformin “can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification.” [ref below]

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References:

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A successful case of pain management using metformin in a patient with adiposis dolorosa.

International Journal of Clinical Pharmacology and Therapeutics [2013], from Medical University of Silesia, Katowice, Poland

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This is a very rare condition that has no known treatment.

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Abstract:

In this case report, we describe a patient with Dercum’s disease who was successfully managed with metformin. The administration of metformin reduced pain intensity from 9/10 to 3/10 and favorably affected the profile of inflammatory cytokines (i.e., TNF a, IL-1β, IL-6, and IL-10), adipokines (i.e., adiponectin, leptin, and resistin), and β-endorphin. Because each variable was affected moderately by the drug, in the range of 20 – 30%, it follows that these effects are additive, i.e., they act independently of each other. However, taking into account advances in the pharmacology of metformin, it seems that other phenomena, such as modulation of synaptic plasticity, activation of microglia, and autophagy of the afferents supplying painful lipomas should be taken into consideration. Nonetheless, metformin deserves further exploration in the biology of pain.

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The use of metformin is associated with decreased lumbar radiculopathy pain

Journal of pain [2013], from University of Arizona Tucson, Ted Price’s lab, and USC

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Abstract:

Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK) as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of “pain now,” by −1.85 (confidence interval: −3.6 to −0.08) on a 0–10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease of −1.36 (credible interval: −2.6 to −0.03). Additionally, patients on metformin showed a non-statistically significant trend toward decreased pain on a variety of other pain descriptors. Our proof-of-concept findings suggest that metformin use is associated with a decrease in lumbar radiculopathy pain, providing a rational for larger retrospective trials in different pain populations and for prospective trials, to test the effectiveness of metformin in reducing neuropathic pain.

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The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

PLoS One [2014] from MD Anderson Cancer Center

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metforminprotects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

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Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment

from Mol Pain [2013], from University of Arizona

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Abstract

BACKGROUND:

Peripheral nerve injury (PNI) results in a fundamental reorganization of the translational machinery in the injured peripheral nerve such that protein synthesis is increased in a manner linked to enhanced mTOR and ERK activity. We have shown that metformin treatment, which activates adenosine monophosphate-activated protein kinase (AMPK), reverses tactile allodynia and enhanced translation following PNI. To gain a better understanding of how PNI changes the proteome of the sciatic nerve and ascertain how metformin treatment may cause further change, we conducted a range of unbiased proteomic studies followed by biochemical experiments to confirm key results.

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CONCLUSIONS:

These proteomic findings support the hypothesis that PNI leads to a fundamental reorganization of gene expression within the injured nerve. Our data identify a key association of ApoE with PNI that is regulated by metformin treatment. We conclude from the known functions of ApoE in the nervous system that ApoE may be an intrinsic factor linked to nerve regeneration after PNI, an effect that is further enhanced by metformin treatment.

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Targeting AMPK for the Alleviation of Pathological Pain

Volume 107 of the series Experientia Supplementum [2016] from University of Texas Dallas

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Abstract:

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

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Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain.

Mol Pain [2011] from University of Arizona

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Abstract

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

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Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice.

Age [20124, from University of Arizona

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Abstract:

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.

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Two Weeks of Metformin Treatment Enhances Mitochondrial Respiration in Skeletal Muscle of AMPK Kinase Dead but Not Wild Type Mice

.PLoS One from University of Copenhagen [2013].

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Abstract:

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.

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We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.

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Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries

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Journal of the American College of Cardiology [2006], from University of Glasgow Cardiovascular Research Centre
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Abstract:

We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 women with a prior history of normal coronary angiography but 2 consecutive positive (ST-segment depression ≥1 mm) exercise tolerance tests.Women randomized to metformin (n = 16) showed significant improvements in endothelium-dependent microvascular function (p < 0.0001) and maximal ST-segment depression (p = 0.013), and a trend (p = 0.056) toward reductions in chest pain incidence relative to placebo recipients. Hence, metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Metformin Targets Aging – no lactic acidosis, no significant hypoglycemia in 18,000 patients-years of follow-up

03/15/2017 — Nancy Sajben MD      Rate This

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Metformin targets multiple pathways affected by aging (pdf)

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Authors Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland from aging research centers at Albert Einstein Medical School and Wake Forest Medical School, Cell Metabolism June 2016

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….in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time 20% of the cohort was age 70 or older (mean age 64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Pro- gram Research Group, 2012). Mild anemia occurred in 12% of metformin-treated participants versus 8% in the placebo group (p = 0.04). Vitamin B12 deficiency occurred in 7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990). Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).

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B12 deficiency is related to MTHFR. I prescribe the doses of B vitamins to take daily, as published by University of Oxford for seniors. Their work shows it prevents 90% of brain atrophy in those areas that are known to involve Alzheimers Disease [avoid toxic B6 doses that damage brain].

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When time permits, I will be adding more on metformin.

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If low blood sugar (hypoglycemia) occurs, juice works quickly but rapidly disappears and then blood sugar is low again in minutes. Use good diet practices, and use plenty of small protein snacks if needed. Protein lasts longer and does not trigger sugar spikes like juice.

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Common side effects, if present at all, are mostly GI such as diarrhea, nausea, gas, distension of the belly with discomfort, indigestion, anorexia, headache, asthenia. If present, stop the drug, wait till all resolve, and very slowly, increase only as tolerated. This is not a speed test.

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Lactic Acidosis potential rare side effect

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The potentially serious side effect of concern is lactic acidosis. I advise patients to review its list of potential side effects.

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http://www.medsafe.govt.nz/profs/PUarticles/5.htm

.https://www.healthgrades.com/conditions/lactic-acidosis–symptoms

Introduction

Symptoms

Causes

Treatments

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What are the symptoms of lactic acidosis?

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Symptoms of lactic acidosis may include nausea and vomiting, abdominal pain, weakness, rapid breathing, rapid heart rate or irregular heart rhythm, and mental status changes.

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Common symptoms of lactic acidosis

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If you experience lactic acidosis, it may be accompanied by symptoms that include:

Abdominal pain

Anxiety

Fatigue

Irregular heart rate (arrhythmia)

Lethargy

Nausea with or without vomiting

Rapid breathing (tachypnea)

Rapid heart rate (tachycardia)

Shortness of breath

Weakness

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Serious symptoms that might indicate a life-threatening condition

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In some cases, lactic acidosis can be life threatening.

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Seek immediate medical care (call 911) if you, or someone you are with, have any of these life-threatening symptoms including:

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Bluish coloration of the lips or fingernails

Change in level of consciousness or alertness, such as passing out or unresponsiveness

Chest pain, chest tightness, chest pressure, palpitations

High fever (higher than 101 degrees Fahrenheit)

Not producing any urine, or an infant who does not produce the usual amount of wet diapers

Rapid heart rate (tachycardia)

Respiratory or breathing problems, such as shortness of breath, difficulty breathing, labored breathing, rapid breathing, or not breathing

Severe abdominal pain

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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METFORMIN for Nerve Pain

03/06/2017 — Nancy Sajben MD      2 Votes

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Is metformin the new wonder pill or snake oil? Based on one man’s response to metformin and recent exciting research on the drug, I am looking forward to finding out how it works clinically for my patients with intractable pain (and possibly treatment resistant depression). Hopefully most will confirm it is well tolerated. I am just beginning to trial it after learning this one man’s amazing story:

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50% relief of nerve pain &

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musculoskeletal pain

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after 2nd week on metformin

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One Man’s Story

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A few days ago I spoke with a man, not my patient, who had 50% relief of pain after the second week on metformin. He’s taken it for 3 months now, but the big change came dramatically after the second week when he had been on the 2,000 mg dose a full week. In 2013, he was on the side of the freeway median lane, and had crawled into the engine of his disabled Ford F350 reaching in with his left hand when his vehicle was hit by a Lexus SUV going 70 mph and he was thrown. He doesn’t talk about his pain. Ever. He needs total knee replacement in the next few weeks, and has had four surgeries on his left wrist, mangled in that engine, now with a long steel plate in the wrist. He broke the titanium plate and it wasn’t healing. Since metformin, the skin and surgical scar is healing. He’s one of these quiet guys who don’t ever talk about pain. His wife simply said these days he’s sleeping since on metformin.

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But no one had asked him about pain since on metformin or for years either. It took 30 minutes to get one little bit of information from him on pain, like pulling teeth: Since metformin, he’s had 50% relief including the nerve pain at his wrist.

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She said he used to sit up all night in pain for years and was very irritable. Irritability is what happens with no sleep; pain is worse with no sleep. I could not get him to rate his pain. Stoic. Bright man, stoic. Devilish sense of humor. Severe pain for so many years he would never talk about. His surgeon had him stop the Vicodin 5/325 weeks before his last surgery “to help it heal.”

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Some of his relief may have also been influenced by blood sugar dropping from 170 to 90, no more excessive thirst and urination keeping him awake, but the neuropathic pain at his wrist had been nasty a few years. Pain had kept him up for months. He had no side effects.

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Metformin

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Metformin is a medication approved in Canada in 1972 and in the United States by the FDA in 1994 for type 2 diabetes. It is well tolerated when prescribed for people who do not have diabetes but who have other conditions such as PCOS (polycystic ovary syndrome), infertility; and it is the focus of intense activity being studied for its

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(1) anti-aging (PDF from Wake Forest University or the Albert Einstein Medical School Longevity study clinicaltrials.gov), 

(2) anti-cancer (it “has become the focus of intense research as a potential anticancer agent” per Cancer Treat. Res. publication 2014) and now recently being studied for

(3) anti-inflammatory analgesic effects.

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“Metformin increases the number of oxygen molecules released into a cell, which appears to boost robustness and longevity. It works by suppressing glucose production in the liver and increasing insulin sensitivity, therefore benefiting patients with type 2 diabetes.”

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I am very interested by all the new research being done on an old drug, metformin, that has suddenly turned heads in just the last few months as we learn its mechanisms involving the pain matrix. Is this metformin some miracle drug, another hot trendy bandwagon people jump on in medicine? It’s an old drug already FDA approved, now repurposed, with excellent safety, and four months ago a publication shows it to be a glial modulator and anti-inflammatory, centrally active. Best of all, it was dramatically potent in the setting of this man’s intractable nerve and musculoskeletal pain.

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But how do we get from 1994 to 2017, through the Decade of Pain, seeing patients who have astonishing pain relief without asking a single patient, millions of patients if it helped pain? A recent past president of the American Endocrine Society said: “No good data on metformin to treat pain. Everything else, but not pain.” He also said, “Safe. We do it all the time for people with PCOS, infertility, cancer, etc. The anti-aging people use it all the time. No risk of hypoglycemia. Just be sure their GFR is above 40.” So ask your doctor who may not know it’s hot research right now.

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When was it first mentioned for pain?

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Less than one year ago, a report on metformin’s use for pain was a 2016 poster presentation at the annual meeting of the American Pain Society from Ted Price’s lab at University Texas Dallas. “The AMPK activator metformin has been shown by our lab to reverse the effects of chronic neuropathic pain in various short term studies….The treatment successfully decreased the hypersensitivity and cold allodynia associated with neuropathic pain, and showed persistent relief for several weeks post-injection. Metformin also decreased the activation of microglia in the spinal cord.”

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I have cautiously held back prescribing it for pain until I heard this man’s story a few days ago, and days later I am still astonished at the relief he had. I immediately suspected metformin must be a strong glial modulator and that mechanism was confirmed in a publication four months ago, in animal (discussed at end).

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 SIDE EFFECTS

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If some develop side effects, stop the medication until all side effects are zero. Then at your own body’s rate, as slowly as needed, increase if needed to 1000 mg twice daily.

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If you again have side effects, again stop til all are zero. Maybe your top dose with no side effects is less than 2,000 mg/day.

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More information on potential side effects  are on the next metformin post – almost none in 18,000 patient years, and not a single case of lactic acidosis.

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STUDIES NEEDED

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It would be extremely helpful to see a study on metformin’s use for pain in a major cancer center, including the range of all underlying diagnoses of those patients who may not be in best of health.  What are % of side effects?

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INFLAMMATION

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Metformin helps inflammation. Inflammation is the cause of 90% mortality. Almost all disease in the body begins with inflammation including atherosclerosis that leads to plaque, heart attacks, stroke. And the same risk factors for heart disease are same for Alzheimers. Inflammation manifests differently in each of us, but to relieve pain, major depression, bipolar disease, PTSD, it can be very dynamic to see response in a few hours once you have the right dose and combination of glial modulators. If this one can relieve 50% of severe chronic pain in two weeks, with few or no side effects, then millions can benefit now. It is an old generic drug repurposed for pain, that is anti-inflammatory. Best of all anti-inflammatory up there in the brain where the inflammatory cytokines produced by glia make you feel like you have the flu:  difficulty thinking, fatigue, drowsy, achey, irritable, needing sleep. That is inflammation. The innate immune system going into gear to attack a virus or…..damage.

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Studies reported about 2001, NIMH showed brain atrophy and memory loss in chronic depression, and about 2009 others showed the same in chronic low back pain.

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My focus for years has been on inflammation in the CNS (brain, spinal cord) because NSAIDs like ibuprofen, Aleve, do not reach the CNS and do not interact on the cells of interest: glia, the cells of the innate immune system that produce a balance of anti-inflammatory and pro-inflammatory chemicals called cytokines. BALANCE.

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Tolerance is a big issue in treating pain or major depression. I strongly recommend reading yesterday’s post on tolerance, i.e. when the body stops responding to ketamine or morphine or an antidepressant after several days or weeks or years. Inflammation may be one cause.

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A publication four months ago shows metformin has both immune and glial suppressive effects that can relieve tolerance to morphine.  It’s a centrally acting analgesic because that’s where chronic pain or major depression is, in the CNS.

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MECHANISM of PAIN RELIEF

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It has both immune and glial suppressive effects: J Neuroinflammation. 2016 Nov 17;13(1):294.

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Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

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ABSTRACT

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BACKGROUND:

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Tolerance [see post on this subject yesterday] seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

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RESULTS:

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We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin.Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore,systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

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CONCLUSIONS:

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Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

Metformin-as-a-Tool-to-Target-AgingDownloadMetformin-reduces-morphine-tolerance-by-inhibiting-microglial-mediated-neuroinflammationDownload

BACKGROUND:

Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

METHODS:

The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.

RESULTS:

We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

CONCLUSIONS:

Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.Perioperative-Immunosuppression-and-Risk-of-Cancer-Progression-The-Impact-of-Opioids-on-Pain-Management.DownloadCRPSLDNLDN AND KETAMINELOW DOSE NALTREXONEMETFORMINMETFORMIN AND PAINNBIORAL KETAMINEOXYTOCINPAIN ALCOHOL ABUSEPSYCOMSLEEP

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Link

Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases

Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.Ketamine-Infusion-Combined-With-Magnesium-as-a-Therapy-for-Intractable-Chronic-Cluster-Headache-Report-of-Two-CasesDownload

Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases

September 1, 2017 by CHSG Admin

Authors: Xavier Moisset MD, PhD, Pierre Clavelou MD, PhD, Michel Lauxerois MD, Radhouane Dallel DDS, PhD, Pascale Picard MD
Source: Headache, Vol. 57, Issue 8, September 2017: 1261–1264. 

Abstract

Background

Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.

Case reports

Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases.

Conclusion

The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment.

Ketamine Infusions for Treatment Refractory Headache

December 27, 2016

Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractable population.

Ketamine Infusions for Treatment Refractory Headache

December 27, 2016 by CHSG Admin

Authors: Jared L. Pomeroy MD, MPH, Michael J. Marmura MD, Stephanie J. Nahas MD, MSEd, Eugene R. Viscusi MD
Source: Headache, Dec. 27, 2016

Abstract

Background

Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractablepopulation.

Methods

This is a retrospective review of 77 patients who underwent administration of intravenous, subanesthetic ketamine for CM or NDPH. All patients had previously failed aggressive outpatient and inpatient treatments. Records were reviewed for patients treated between January 2006 and December 2014.

Results

The mean headache pain rating using a 0-10 pain scale was an average of 7.1 at admission and 3.8 on discharge (P < .0001). The majority (55/77, 71.4%) of patients were classified as acute responders defined as at least 2-point improvement in headache pain at discharge. Some (15/77, 27.3%) acute responders maintained this benefit at their follow-up office visit but sustained response did not achieve statistical significance. The mean length of infusion was 4.8 days. Most patients tolerated ketamine well. A number of adverse events were observed, but very few were serious.

Conclusions

Subanesthetic ketamine infusions may be beneficial in individuals with CM or NDPH who have failed other aggressive treatments. Controlled trials may confirm this, and further studies may be useful in elucidating more robust benefit in a less refractory patient population.Ketamine-Infusions-for-Treatment-Refractory-HeadacheDownload

Ketamine i. v. for the treatment of cluster headaches: An observational study

April 11, 2016

Cluster headaches have an incidence of 1–3 per 10,000 with a 2.5:1 male-to-female gender ratio. Although not life threatening, the impact of the attacks on the individual patient can result in tremendous pain and disability. The pathophysiology of the disease is unclear, but it is known that the hypothalamus, the brainstem, and genetic factors, such as the G1246A polymorphism, play a role. A distinction is made between episodic and chronic cluster headaches. In a controlled setting, we treated 29 patients with cluster headaches (13 with chronic cluster and 16 with the episodic form), who had been refractory to conventional treatments, with a low dose of ketamine (an NMDA receptor antagonist) i.v. over 40 min to one hour every 2 weeks or sooner for up to four times. It was observed that the attacks were completely aborted in 100 % of patients with episodic headaches and in 54 % of patients with chronic cluster headaches for a period of 3–18 months. We postulated neuroplastic brain repair and remodulation as possible mechanisms.Ketamin-i.-v.-zur-Behandlung-vonDownloadIntravenous-Therapies-in-the-Management-of-Neuropathic-PainDownload

Safety and Efficacy of Prolonged Outpatient Ketamine Infusions for Neuropathic Pain

July 1, 2006

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients.

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.Safety-and-Efficacy-of-Prolonged-Outpatient-Ketamine-for-neuropathic-painDownload

Intranasal Ketamine for the Relief of Cluster Headache

Ketamine’s Mechanism of Action

Ketamine (2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride), a human and veterinary anesthetic agent, has an extremely varied set of pharmacologic actions depending on the dosage used.1 A selective uncompetitive N-Methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, the drug has been in legitimate clinical use since 1963.

When administered as an appropriate pharmacologic agent, ketamine has been shown to serve as a safe anesthetic agent. At sub-anesthetic doses, ketamine acts as an uncompetitive antagonist at ionotropic NMDA-type glutamate receptors, binding to a site on the receptor while it is open. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the mammalian brain. Based on their pharmacology, there are three main classes of glutamate-activated channels:

  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
  • kainate receptors
  • N-methyl-d-aspartate receptors (NMDAR).

Among ion-gated receptor subtypes (iGluRs), NMDAR are exceptional in their high unitary conductance, high Ca2+ permeability, and remarkably slow gating kinetics.

Ketamine has relatively specific effects on other glutamate subtypes. Several families of these receptors also include AMPA-type and kainate receptors, and the metabotropic family of receptors, of which many exist. NMDARs, in particular, are glutamate-gated ion channels primarily for calcium ions and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.1 Interest and research is growing and abounds in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity.In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after ketamine infusion.

Use in Migraine, Cluster Headache, and Neuropathic Pain Disorders

In more recent years, a very small number of clinicians, including the author, have used ketamine intravenously (IV), and in some cases, via intramuscular injection, to treat migraine, cluster headache, and various other chronic pain disorders, including mixed headache and neuropathic pain clinical syndromes.3-21 In the author’s clinic specifically, ketamine has been used via IV administration for more than 20 years to treat nearly 1,000 patients with various headache and pain disorders. These include: migraine and cluster headache flare-ups; headaches associated with orofacial pain disorders, such as trigeminal neuralgia (TN); atypical face pain; temporomandibular joint disorder (TMD); and neck pain.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after a ketamine infusion.

The focus of this paper is to provide a summary of specific retrospective cases in which intranasal ketamine was used for the rescue of cluster headache in patients who had previously experienced a positive outcome from IV ketamine in the author’s outpatient clinic. Cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home. Table I outlines the outpatient clinic’s treatment of various migraine and headache types. As shown, cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home.

Retrospective Case Summaries

The dose of intranasal ketamine prescribed to patients ranged between 7.5 mg and 15 mg per 0.1 cc nasal spray (75 and 150 mg of ketamine per cc compounded in normal saline by a pharmacy). Patients were instructed to use one spray in the nostril of the affected side and wait 10 to 15 minutes to feel any effects, including side effects. They were to use the spray when they felt a cluster attack coming on. Patients were asked to use another spray of ketamine in the same nostril at 10- to 15-minute intervals until a sufficient degree of relief (at least 60 to 75%) was obtained for that cluster attack. If the attack still came on after about one hour, the instructions were for the patient to repeat the procedure. All patients were instructed not to drive after taking the medication and signed off on this agreement. Patients were also instructed to keep the nasal spray refrigerated when not in use; no efficacy loss was reported. Of the 17 patients who trialed the nasal spray, 11 elected not to have the intranasal ketamine compounded, or were lost to follow-up, leaving six case scenarios which are summarized herein.

Case 1

A 38-year-old male, with a 16-year history of cluster headache, including a family history of the same, had tried a number of acute and prophylactic agents with, at best, a shortening of the cluster episode. His attacks tended to flare in the spring and lasted up to three months at a time with 4 to 6 episodes per day. The attacks prevented him from working and he came to the outpatient clinic for IV treatment with ketamine, which resulted in a complete cessation after three days, with resolution of allodynia on the right side as well. He elected to try intranasal ketamine (15 mg) at the first onset of his next cluster episode. He reported pain relief and a feeling of calm after 2 to 3 sprays, with no adverse effects. Sometimes, he had to repeat the dosing regimen the next day.

Case 2

A 25-year-old woman was thrown from a horse during a competition and fractured her cervical spine, requiring surgery. The injury included syringomyelia between C3 and C7-T1 and left her with left-sided dystonia of the upper and lower body, abdomen, and chest wall, together with left-sided migraines, which she reported as new. Several times a year, she would awaken every night with left-sided cluster headache episodes, with facial allodynia, tearing, eyelid drooping, and increased dystonia and neck spasm; these occurred primarily in the winter season, with several up to six episodes in per night for a period of three to six weeks.

IV ketamine relieved most of her dystonic, cluster headache, and migraine symptoms, when complemented by IV and oral baclofen and tizanidine, as well as rescue opioids. Nasal spray ketamine was compounded, as well as buccal troches; both allowed her to continue working full-time in her hair salon. She reported no side effects while using the nasal spray ketamine. Liver function tests conducted every three to six months were unremarkable.

Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. (Source: 123RF)

Case 3

A 55-year-old woman with episodic cluster headache and migraine (3 to 4 attacks per week) also experienced chronic neck pain and had diagnosed TN on the right side. Her cluster headache attacks started at age 27, with tearing, allodynia, and facial numbness. On occasion, her migraine would evolve into a cluster episode that came on during sleep and was seasonal as well, lasting about 2 months on average. She was not a smoker and had no family history of cluster headache but did have a family history of migraine.

She was treated successfully for migraine, right TN, and neck pain with botulinum toxin-A injections (Botox) every 3 to 5 months, supplemented by prophylactic neuropathically active medications, but no opioids. The Botox did not affect her cluster headache, except when they evolved from a migraine, and only to a slight extent (15 to 20%). Multiple acute and prophylactic therapies were attempted to resolve the cluster headache episodes to no significant avail.

IV ketamine was tried on one occasion over a period of 4 days during a cluster headache episode. As a result, the attacks were reduced from 5 per day to 1 per day, and only 1 cluster attack the following week, which was resolved with additional oral oxcarbazepine (600 mg).

The patient agreed to trial nasal spray ketamine which was compounded at 10 mg per 0.1 cc spray with the suggestion that she spray the right nostril every 10 to 15 minutes upon attack to give the medicine time to absorb from the nasal mucosa and to repeat the process until at least 75% relief was obtained. She reported being happy with this approach as it gave her control of her hardest-to-treat symptom. She also reported that her cluster episodes became less frequent over about 1 year and that her migraine and TN also improved; her Botox injection intervals grew longer over time.

Case 4

A 70-old-male, with a 40-plus year history of right-sided cluster attacks with eyelid drooping, tearing, allodynia, neck pain, and other symptoms was treated for these symptoms for many years. Opioids provided him with partial relief, at best. He had a chronic cluster headache that typically awoke him from a sound sleep at 1 or 2 am. These episodes were especially bad in the winter and during weather changes. He had a history of facial and other traumas before the headaches started, including a car accident, but no family history of cluster headache. He also had occasional migraine, about three per month, as well as chronic neck and back pain. He was treated with IV medications, including ketamine, up to 200 mg over 5 hours, with relief of his symptoms in the clinic.

He agreed to trial a compounded nasal spray of ketamine [12.5 mg per 0.1 cc] to use at each bedtime. Two sprays were indicated before each bedtime and at the first onset of any cluster headache at night. Sprays were repeated every 10 minutes until 50 to 65% relief was achieved. He took tizanidine before bedtime for neck spasm and sleep. The patient would, on occasion, repeat one or two ketamine sprays in the morning or during the day if he felt the next cluster attack coming on. As he was on frequent IV and nasal spray ketamine, his liver functions tests were routinely monitored over the course of several years; there was no observed impact.

Case 5

A 34-year-old male who worked in construction began having episodic cluster headache episodes at age 22. He had a family history of migraine and cluster headache. His attacks were season-specific, occurring mostly in the early summer of each or every other year. He described the attacks as very disabling and often awoke from a sound sleep for several weeks at a time as a result of them. He had tried several oral medications, including opioids, for suppression of symptoms without any real benefit and many side effects. When he first presented to the clinic, he trialed IV lidocaine, IV valproate sodium, and IV magnesium sulfate with only partial success in shutting down the episode.

IV ketamine was also offered at the beginning of one of his episodes, and it proved to work more effectively than other treatments. Specifically, the patient’s cluster episode duration was reduced by more than two-thirds (6 to 7 weeks to 7 to 10 days). Based on this result, he was prescribed compounded nasal spray ketamine (7.5 mg per 0.1cc spray) and instructed to use the spray once at bedtime, with additional sprays in one nostril (the affected side of the cluster headache) every 10 minutes until relief was obtained to at least 75%. The patient was also instructed to use the same approach during the day if the cluster headache returned. He used nasal spray ketamine for several years and his overall pattern became easier to treat successfully. His episodes grew further apart and he has reported only one short cluster headache episode in the past four years.

She got extinction of the cluster episode or at least 75% reductions in the cluster headache severity with up to 4-5 nasal sprays of ketamine at the dose described above, and has also noticed a shortening and diminution of the cluster headache episodes as time has gone by.

Case 6

A 51-year-old male, with a family history of cluster headache began having episodic attacks at age 18 with strong occurrences in the spring. He was a smoker. He had tried a calcium channel blocker, lithium, and other medications to little or no avail over the years. He found that triptans taken early in the course of a cluster attack, at several doses, would sometimes abort or lighten the burden of that particular cluster series.

A 3-day course of IV ketamine at the onset of one of his episodes nearly eradicated the episode, and since he lived a great distance (6 hours each way) from the clinic, he wanted to try the nasal spray form of ketamine for at-home application. He reported that a daily dose of 1500 mg of Depakote-ER often softened the arrival of his next cluster headache episode, as did prescribed triptans. However, he did not experience an end to the attack until IV ketamine had been administered.

15 mg per 0.1cc of nasal spray ketamine were compounded for this patient. He reported some nasal burning with the nasal ketamine formulation, so was advised by his pharmacist to use one drop of 2% lidocaine and orange oil as part of the prescription. This addition alleviated the side effect. The patient has successfully used this approach for many years to date. He requires 5 to 6 nasal sprays of ketamine per day, and his episodic cluster headache pattern has markedly softened and shortened in the past few years. He has reduced his dosage of Depakote-ER to 1 or 2 per day as well and attempted to stop smoking several times.

Discussion and Recommendation

The specificity of the ketamine speaks to a unique mechanism of action primarily through the blockade of the NMDA-glutamate and other close-related receptors. This treatment approach may provide insight into the distinctive involvement of this receptor family in the generation and maintenance of this and perhaps other, more rare trigeminal autonomic cephalalgias, or TACs.21

Based on this anecdotal evidence, observed retrospectively in the author’s outpatient clinic over a period of 20 years, intranasal ketamine seems to offer a legitimate, safe pharmacologic treatment for cluster headache rescue. The medication adds a new dimension to managing out-of-control cluster headache and mixed headache/pain disorders in an outpatient setting with no monitoring. Double-blind, placebo-controlled studies are needed to confirm these primarily open-label observations. It should be noted that a small number of patients (5) were given sham nasal treatment and their cluster headache did not respond.

The author found sub-anesthetic doses of intranasal ketamine to be very useful in the control of episodic and chronic cluster headache attacks, as well as in managing certain trigeminal neuralgia symptoms. On a 0 to 10 visual analog scale, pain scores were below 60 to 65% from initial baseline pain score after the use of the intranasal ketamine spray. Efficacy, as well as safety, and tolerability, of low dose IV ketamine were seen consistently in the outpatient clinic, without significant adverse effects. In the author’s opinion, therefore, ketamine may be considered when treating this clinically disabling condition. When used under controlled conditions, ketamine in a nasal spray form may offer a safe and more effective option to patients than emergency room visits and may also serve as a substitute for more standard IV-based rescue cluster headache medications.

About Cluster Headache:Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. A series of cluster headaches can take place over several weeks to months, and may occur once or twice per year. Several of the following related symptoms may occur: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration may present as well. Attacks usually recur on the same side of the head. Cluster headaches afflict males more than females by a 2.5 to 1 ratio and have an overall prevalence of 0.4%. Onset of clusters is usually between ages 20 and 45. There is often no family history of cluster headache.

  1. Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
  2. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
  3. Virginia Scott-Krusz, Jeanne Belanger, RN, Jane Cagle, LVN, Krusz, JC, Effectiveness of IV therapy in the headache clinic for refractory migraine, poster at 9th EFNS meeting Athens, Greece. 2005.
  4. Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
  5. Krusz JC, Cagle J, Belanger J, Scott-Krusz, V. Effectiveness of IV therapy for pain in the clinic, Poster P183 presented at 2nd International Congress on Neuropathic Pain Berlin, Germany. 2007
  6. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  7. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine in treating refractory migraines in the clinic (poster 218). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  8. Krusz JC, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic (poster 219). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  9. Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
  10. Krusz JC, Cagle J, Scott-Krusz VB. Ketamine for treating multiple types of headaches (poster). 14th Congress International Headache Society. Cephalalgia. 2009;29(Suppl 1)163.
  11. Krusz JC. Difficult Migraine Patient. Pract Pain Manage. 2011;11(4):16.
  12. Krusz JC, Cagle J. IV Ketamine: Rapid Treatment for All TAC Subtypes in the Clinic, Abstract Poster #72, 15th Congress of the International Headache Society, Berlin, Germany, 2011.
  13. Krusz JC, Cagle J. IM ketamine for intractable headaches and migraines (poster abstract). American Headache Society Annual Meeting, Los Angeles, CA, 2012.
  14. Krusz JC. Traumatic Brain Injury: Treatment of Post-traumatic Headaches. Pract Pain Manage. 2013;13(5):57-68.
  15. Krusz JC, Cagle J, Belanger J, Scott-Krusz V. Effectiveness of IV therapy for pain in the clinic, Poster P183. European J Pain:11, Suppl 1, pS80, presented at 2nd Int’l Congress on Neuropathic Pain, Berlin, Germany. 2007.
  16. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain, 9: Suppl 2, P30, 27th Annual Scientific. American Pain Society. 2008.
  17. Krusz JC. Ketamine IV in an outpatient setting: effective treatment for neuropathic pain syndromes (poster #378). 32nd Annual Scientific Meeting, American Pain Society, New Orleans, 2013.
  18. Krusz JC. Ketamine IV – for CRPS, TN/TMD and other neuropathic pain in the outpatient clinic (poster #524). 4th International Congress on Neuropathic Pain, Toronto, Ontario, 2013.
  19. Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
  20. Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalalgias: Diagnosis and Management. In: Silberstein SD, Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York, NY: Oxford Univ Press; 2008:379-430.
  21. Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63. 
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Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

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Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients << Article link 

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

 

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study  << Article in Clinical Psychiatry

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial Article link for below:

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. 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.”

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “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.”

Ketamine for Rapid Reduction of Suicidal Thoughts in major depression – A midazolam controlled trial PDF article

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Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

Abstract
Objective To review the published literature on the efficacy
of ketamine for the treatment of suicidal ideation (SI).
Methods The PubMed and Cochrane databases were
searched up to January 2015 for clinical trials and case
reports describing therapeutic ketamine administration to
patients presenting with SI/suicidality. Searches were also
conducted for relevant background material regarding the
pharmacological function of ketamine.
Results Nine publications (six studies and three case
reports) met the search criteria for assessing SI after
administration of subanesthetic ketamine. There were no
studies examining the effect on suicide attempts or death
by suicide. Each study demonstrated a rapid and clinically
significant reduction in SI, with results similar to previously
described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been
reported in the literature as receiving therapeutic ketamine.
Seven studies delivered a dose of 0.5 mg/kg intravenously
over 40 min, while one study administered a 0.2 mg/kg
intravenous bolus and another study administered a liquid
suspension. The earliest significant results were seen after
40 min, and the longest results were observed up to
10 days postinfusion.
Conclusion Consistent with clinical research on ketamine
as a rapid and effective treatment for depression, ketamine
has shown early preliminary evidence of a reduction in
depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to
further investigate its mechanism of action, long-term
outcomes, and long-term adverse effects (including abuse)
and benefits. In addition, ketamine could potentially be
used as a prototype for further development of rapid-acting
antisuicidal medication with a practical route of administration
and the most favorable risk/benefit ratio.
Key Points
Preliminary data from randomized controlled trials
have demonstrated that ketamine may rapidly and
effectively control treatment-resistant depression,
though the effects are transient.
A small subset of studies has demonstrated similar
results in the effects of ketamine on suicidal ideation.
Ketamine has potential as a rapid treatment for
suicidal ideation and/or a possible model compound
for future drug development.

4 Discussion
With an estimated prevalence of mood disorders ranging
from 3.3 to 21.4 % and the substantially increased risk of
suicide among patients with mood disorders, treatment is
certainly warranted [19]. Current treatment options for
suicidality are limited. They include brain stimulation
therapeutics, such as ECT, and pharmacological intervention
(lithium, clozapine). The efficacy of lithium in treating
suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48
studies [22]. Clozapine has also been shown to reduce
suicide risk in patients with schizophrenia [23, 24]. The
limitations of both lithium and clozapine include a longer
time to efficacy in this psychiatric emergency/urgency,
compared with the early response to ketamine [25]. Ketamine
seems to be gaining substantial evidence as a pharmacological
option for depression with a fast onset of
action, but its long-term effects need further investigation.
In addition, ketamine probably offers a faster onset of
action in terms of SI, but further work is certainly needed
in this area. Given the risk of suicide and even the
increasing rates of suicide in certain subgroups, such as
soldiers and veterans [26, 27], there is an urgent need for
faster therapeutics for SI and TRD. Importantly, suicidality
and suicide pose a high global burden of patient suffering
to families and society. Although several small-to-moderate
sized studies, in addition to several reviews, have been
published that have examined the efficacy of ketamine in
TRD, there are considerably fewer published data
specifically examining ketamine in patients presenting with
SI. Notably, only three studies have directly examined SI
as the primary outcome [11, 16, 17], while the rest
examined SI as the secondary outcome [4, 15, 18], not
including case reports. This review summarizes the current
published literature regarding ketamine as a treatment for
SI. The data so far show promising trends of ketamine
being an effective and rapid treatment with minimal side
effects.
Pharmacologically, ketamine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It has been used for anesthesia
in the USA since the 1970s. At subanesthetic doses,
ketamine has been shown to increase glutamate levels [3].
This mechanism is relevant, as glutamate regulation and
expression are altered in patients with major depressive
disorder (MDD). Studies have also demonstrated an
abnormal glutamate–glutamine–gamma-aminobutyric acid
cycle in patients with suicidality [28]. Furthermore, ketamine
has also been shown to work on nicotinic and opioid
receptors [29]. No other class of antidepressant medication
works to modulate the glutamatergic system, and research
continues into this, with the goal of characterizing the full
mechanism of action of ketamine and perhaps developing
other compounds that would have similar effects. Thus,
even if the approval and marketing of ketamine as a rapidacting
antisuicidal and antidepressant medication is not
realized, it could well be a prototype for development of
other medication(s) that retain the mechanism of action
with more favorable qualities and a lesser adverse effect
profile (such as a longer duration of action or less or no
addictive potential). Although the mechanisms explaining
the antisuicidal effect and the NMDA receptor antagonism
of ketamine are still unclear, some of the initial evidence
points to an anti-inflammatory action via the kynurenic
acid pathway. Strong suggestions as to the causal relationship
between inflammation and depression/suicidality
has come from studies demonstrating that cytokines [30,
31] and interferon-b [32] induce depression and suicidality.
Other recent studies have added to the notion of implicating
brain immune activation in the pathogenesis of suicidality.
For instance, one study showed microglial
activation of postmortem brain tissue in suicide victims
[33]. Another study found increased levels of the cytokine
interleukin-6 in cerebrospinal fluid from patients who had
attempted suicide [34]. Higher levels of inflammatory
markers have been shown in suicidal patients than in nonsuicidal
depressed patients [33, 35]. Inflammation leads to
production of both quinolinic acid (an NMDA agonist) and
kynurenic acid (a NMDA antagonist). An increased
quinolinic acid to kynurenic acid ratio leads to NMDA
receptor stimulation. The correlation between quinolinic
acid and Suicide Intent Scale scores indicates that changes
in glutamatergic neurotransmission could be specifically
linked to suicidality [36].
Small randomized controlled trials have demonstrated
the efficacy of ketamine in rapidly treating patients with
both TRD and/or bipolar depression [4, 8, 9, 11, 16–18].
Some studies have also examined suicide items as a secondary
measure in their depression rating scales [4, 7]. In
total, the studies examining ketamine and TRD have nearly
consistently demonstrated that ketamine provides relief
from depressive and suicidal symptoms, starting at 40 min
and lasting for as long as 5 days. Questions still remain as
to the long-term effects of this treatment, how much should
be administered and how often, any serious adverse effects,
and the mechanism of action.
Pharmacologically, ketamine has poor bioavailability
and is best administered via injection [37]. In their landmark
study, Berman et al. [4] found that a subanesthetic
dose (0.5 mg/kg) rapidly improved depressive symptoms.
Most of the subsequent studies have delivered ketamine as
a constant infusion for 40 min at a rate of 0.5 mg/kg.
Others have examined its efficacy after multiple infusions
and observed similar results [8, 13, 16, 38]. Currently, it is
recommended that ketamine be administered in a hospital
setting [39].

______________________________________

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:

 

Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic
modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after
ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI
response to ketamine.
Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with
DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic
(0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture
modeling to generate SI response classes, and class membership predictors were evaluated using multinomial
logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.
Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders
(44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1.
Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for
Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated
with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to
Remitters rather than Responders.
Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma,
rather than CSF, markers were used.
Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence
from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic
SI were less likely to respond or remit post-ketamine.

1. Introduction
Suicide poses a serious threat to public health. Worldwide, suicide
accounts for approximately 1 million deaths, and 10 million suicide
attempts are reported annually (World Health Organization, 2014). In
the United States, the national suicide rate has increased by approximately
28% over the last 15 years (Curtin et al., 2016). At the same
time, relatively few interventions for suicide risk exist. While treatments
such as clozapine and lithium have demonstrated effects on
suicidal behavior over weeks to months, these effects may be limited to
specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently,
no FDA-approved medications exist to treat suicidal ideation
(SI), leaving those who experience a suicidal crisis with limited options
for a reprieve of symptoms. Consequently, a critical need exists for
rapid-acting treatments that can be used in emergency settings.
A promising off-label agent for this purpose is the rapid-acting antidepressant
ketamine, which past studies have suggested reduces suicidal
thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price
et al., 2009). A recent meta-analysis of 167 patients with a range of
mood disorder diagnoses found that ketamine reduced suicidal
thoughts compared to placebo as rapidly as within a few hours, with
effects lasting as long as seven days (Wilkinson et al., 2017). These
results are reinforced by newer findings of reduced active suicidal
ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era
of personalized medicine, two important issues must be addressed.
First, little is known about the acute course of SI following ketamine.
The speed with which antidepressant response occurs, and how much
improvement can be expected on average, has been documented for
single administrations of ketamine (Mathew et al., 2012; Sanacora
et al., 2017); in the limited available literature, researchers have
emulated previous studies examining antidepressant effect, where a
cutoff of 50% improvement demarcated response (Nierenberg and
DeCecco, 2001). Nevertheless, it remains unknown whether this categorization
accurately reflects the phenomenon of suicidal thoughts.
Empirically-derived approaches to the description of SI trajectory after
ketamine may be useful in operationalizing “response” in future clinical
trials.
Second, identifying demographic, clinical, or biological predictors
of SI response to ketamine would allow researchers and clinicians to
determine who is most likely to exhibit an SI response to ketamine. A
broad literature describes clinical and demographic predictors for suicide
risk (Franklin et al., 2017), and a smaller literature connects suicidal
thoughts and behaviors to plasma markers such as brain-derived
neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015;
Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini
et al., 2013). However, no biomarkers have been shown to predict SI/
behavior response to intervention, a finding reinforced by the National
Action Alliance for Suicide Prevention’s Research Prioritization Task
Force’s Portfolio Analysis (National Action Alliance for Suicide
Prevention: Research Prioritization Task Force, 2015). Notably, predictor
analyses have the potential to reveal insights into personalized
treatments for suicidal individuals, as well as the neurobiology of SI
response. With respect to antidepressant response, for example, this
approach yielded the observation that individuals with a family history
of alcohol dependence may be more likely to exhibit an antidepressant
response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip
et al., 2014).
The goals of this study were to elucidate trajectories of SI response
and identify predictors of that response, with the ultimate goal of
adding to the growing literature surrounding ketamine’s specific effects
on SI. In particular, we sought to determine whether the heterogeneous
patterns of change in SI after ketamine administration were better explained
by a model with two or more latent groups of trajectories rather
than a single average trajectory, using secondary analyses from previously
published clinical trials. These classes were then used to evaluate
potential clinical, demographic, and plasma biomarker predictors
of SI response to ketamine in order to generate hypotheses.. Discussion
This analysis used a data-driven approach to characterize SI response
to ketamine. The data were best explained by three trajectory
classes: one with severe average baseline SI and little to no response to
ketamine (Non-Responders), one with moderate average baseline levels
of SI and significant response to ketamine (Responders), and a third
with moderate average baseline levels of SI and complete remission of
SI by two days post-ketamine (Remitters). These findings suggest a
diversity of post-ketamine changes in SI that may not be captured under
traditional methods of categorizing response to treatment.
Furthermore, we found evidence that SI response and antidepressant
response could be distinguished from each other; one subset of participants
experienced improvement in SI that was partially explained by
improvements in Depressed Mood, while the other group’s improvements
in SI occurred independently of antidepressant response. With
regard to predictors of SI response trajectory, preliminary results suggest
the individuals least likely to experience improvement in SI postketamine
were those with the most severe SI and a history of self-injury.
Few plasma markers emerged as predictors of SI response in this study,
highlighting the limitations of connecting SI ratings of response with
biological markers.
The growth mixture modeling approach used here underscored the
heterogeneity of SI response to ketamine, which would not have been
captured by simply calculating the average trajectory. The class assignment
from this approach also differed from the definition of response
(50% reduction in symptoms) traditionally used in the antidepressant
literature, which often focuses on a specific timepoint rather
than the entire symptom trajectory. In comparing classification using a
50% response at Day 1 and Day 3 with the latent trajectory classes, we
found representation of almost every SI class across each responder
group, highlighting the potential limitations of the 50% response approach.
Further study is needed to determine which of these approaches
will prove more fruitful. Complete remission of SI has previously been
used as an outcome measure in clinical trials and in a meta-analysis of
ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018;
Wilkinson et al., 2017), as well as in a study examining the relationship
between SI response to ketamine and changes in nocturnal wakefulness
(Vande Voort et al., 2017). One strength of the present study is that this
data-driven approach provides classifications that directly reflect the
phenomena under study as they are, as opposed to what they should be.
Especially when used in larger samples than the current study, this
approach is particularly promising in its ability to provide a more
nuanced understanding of the nature of SI response to ketamine.
Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable
by baseline Depressed Mood scores; patients with the most
severe SI did not differ meaningfully in Depressed Mood scores from
those with the mildest SI. Second, while previous analyses of these data
documented that BMI and family history of alcohol dependence predicted
antidepressant response (Niciu et al., 2014), SI response was not
associated with these variables in the current analysis. Third, the antidepressant
response profiles of the SI classes suggest that SI response
and antidepressant response are not wholly redundant. This aligns with
previous clinical trials and meta-analytic reviews of the literature suggesting
that SI response to ketamine occurs partially independently of
antidepressant response (Grunebaum et al., 2018; Wilkinson et al.,
2017). Nevertheless, this independence did not hold true across both SI
response groups. Specifically, antidepressant and SI response were
clearly linked in Remitters, with depression accounting for half of the
changes in SI; however, in Responders, improvements in SI occurred
independently from improvements in Depressed Mood. These discrepancies
could be related to ketamine’s complex neurobiological
mechanisms or to the potentially low levels of clinical severity observed
in the Remitters.
Interestingly, the current analyses found no baseline demographic
variables that reliably distinguished Responders from Remitters. Some
phenotypic characteristics were uniquely associated with belonging to
the Non-Responder group, suggesting that a long-standing history of
self-injury or SI may indicate resistance to rapid changes in SI.
Relatedly, a recent, randomized clinical trial of repeat-dose ketamine
compared to placebo found that ketamine had no effect on SI in a
sample of patients selected for their longstanding, chronic history of SI
(Ionescu, 2017). These results highlight the importance of patient selection,
particularly for suicide risk. It should be stressed, however, that
SI does not necessarily translate to suicidal attempts or deaths; to our
knowledge, no study has yet linked ketamine with reduced risk of
suicidal behavior. Indeed, in the present study the SI Non-Responders
experienced limited antidepressant effects in response to ketamine, but
may nevertheless have improved on other, unmeasured symptoms that
could provide important benefit and relief. As the ketamine literature
develops, it will be important to identify which clinical symptom profiles
are most likely to have a robust anti-SI and anti-suicidal behavior
response to ketamine and which ones may benefit from other interventions.
While we evaluated a range of potential plasma markers previously
linked to suicidal ideation and behavior, in the present analysis only IL5
was associated with the SI Responder subgroup. Ketamine is known to
have anti-inflammatory effects (Zunszain et al., 2013), but the relationship
between antidepressant response and change in cytokine
levels remains unclear (Park et al., 2017). Cytokines have been linked
to suicidal behavior in the past; a recent meta-analysis found that lower
levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated
with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large
number of comparisons and lack of precedent in the literature, this
result may have been spurious and should be interpreted with caution.
A number of other results may reflect meaningful relationships, but the
high degree of variability—and the associated wide confidence intervals—suggests
that larger sample sizes are needed to better elucidate
the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13,
p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly,
plasma BDNF levels were not associated with responder class.
Previous studies of bipolar, but not MDD, samples found that plasma
BDNF levels were associated with SI response after ketamine
(Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed
diagnostic composition of this study may explain differences from
previous work. Studies exploring the relationship between BDNF and
antidepressant response to ketamine have also yielded mixed findings
(Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven
approaches have considered both biological and behavioral variables in
characterizing depression (Drysdale et al., 2017); a similar approach
might prove useful for predicting SI response.
The present study is associated with several strengths as well as
limitations. Strengths include the relatively large sample size of participants
who received ketamine, the use of composite SI scores from
previous exploratory factor analyses as opposed to individual items,
and the combination of clinical and biological markers as potential
predictors of class membership. Limitations include patient selection
methods, as these patients were part of an antidepressant trial and were
not selected for active suicidal thoughts, as well as the exploratory
nature of the analysis. As stated above, suicidal thoughts do not necessarily
equate to suicidal behavior, and class membership would thus
not necessarily correspond with an overall reduction in suicide risk.
Another limitation is that results were collapsed across several clinical
trials with slight variations in study design, and findings were thus only
extended to Day 3 rather than a week after ketamine administration. As
a result, only a subset of the sample could be used for predictive analyses.
In addition, plasma—rather than CSF—markers were used, and
the latter might better indicate underlying biology due to proximity to
the brain, though certain markers such as plasma BDNF may be related
to platelet storage, rather than the brain (Chacón-Fernández et al.,
2016). Comparison of results to trajectories of suicide-specific measures,
such as the Scale for Suicide Ideation (Beck et al., 1979), may also
give further insight into specific SI content. Finally, many clinical
predictors were collected upon hospital admission; future analyses
could use formal assessments, such as the Childhood Traumatic Questionnaire
(Bernstein et al., 1994), assessment of personality disorders,
or diagnoses such as post-traumatic stress disorder (PTSD) as potential
indicators of response.
Despite these limitations, the study demonstrates the utility of a
data-driven approach for characterizing the heterogeneity of SI response
to a rapid-acting intervention. This allows for a more finegrained
analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at
50% reduction in symptoms. This study identified several findings of
note. These included distinguishing at least three patterns of SI response
to ketamine and finding that subjects who exhibited more severe SI at
baseline were not likely to experience an SI response to ketamine.

 

____________________________________

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CAll 703-844-0184 for a Ketamine treatment evaluation for depression, PTSD, bipolar, CRPS, or pain.

FACEBOOK page – NOVA Health Recovery Ketamine services

NOVA Health Recovery – Ketamine treatment for depression

 

Ketamine: Key Predictor of Treatment Response for MDD Identified

 

 

I am going to link into a few articles that discuss a phenomena that I have observed in the office setting at NOVA Health Recovery (Alexandria, Va 703-844-0184) for our Ketamine infusions in depressed and PTSD patients. The best long term results seem to occur when the individual has a slightly more dissociative experience during the infusion.  A lot of times I will give an initial boost to the medication at the start to get that state of mind going. Studies below have hinted that the slight dissociation actually improves outcomes:

Ketamine: Key Predictor of Treatment Response for MDD Identified  < Medscape article

 

Ketamine: Key Predictor of Treatment Response for MDD Identified

Nancy A. Melville

April 12, 2018

WASHINGTON — More intense dissociative symptoms exhibited during ketamine infusion for severe depression, particularly depersonalization, may be key predictors of treatment response. In addition, new safety and efficacy data for off-label use of the drug are encouraging.

Mark Niciu, MD, PhD, of the National Institute of Mental Health (NIMH), and colleagues analyzed three studies involving 126 patients with treatment-resistant depression. They found a significant association between dissociative symptoms experienced during infusion and reductions in depressive symptoms, as reflected in some, but not all, dissociation subscale measures.

“The findings suggest that mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded,” Niciu told delegates attending the Anxiety and Depression Association of America (ADAA) Conference 2018.

The results were also published in the May issue of the Journal of Affective Disorders.

In another presentation at the ADAA conference, Samuel Wilkinson, MD, assistant director of the Depression Research Program at Yale University, New Haven, Connecticut, reported details from his institution’s experience with the use of ketamine during a period of more than 30 months in patients with severe and treatment-resistant mood disorders.

Among 50 patients who received one to four treatments, the response rate, defined as a 50% improvement in symptoms, was approximately 50%; the remission rate was 27.3%.

In a subset of 14 patients who received 12 to 45 total treatments during a period of 14 to 126 weeks, there was no evidence of cognitive decline or delusions, as measured with the CogState cognitive assessment tool, Wilkinson reported.

Soaring Interest

Because conventional antidepressants can take weeks if not months to reach full effect and are completely ineffective in many patients, interest in ketamine, an N-methyl-d-aspartate receptor antagonist, as a rapid-acting treatment for severe mood disorders has soared in recent years, noted Niciu.

Previous studies have reported significant improvements in depression following a single ketamine infusion, with improvements lasting from several days to a week. However, not everyone responds to ketamine.

In the new study, 84 of the 126 participants had major depressive disorder, and 42 had bipolar depression. All were treated with the standard ketamine treatment for depression, consisting of a single subanesthetic dose (0.5 mg/kg) delivered by infusion over 40 minutes.

Patients were followed for at least 1 week post infusion and, in one of the three studies that were assessed, for up to 28 days.

In one of the studies, dissociative effects, measured using the Clinician-Administered Dissociative States Scale (CADSS) at baseline and at the end of infusion, were associated with symptoms of depression, as measured with the Hamilton Depression Rating Scale (HDRS-17), at day 7 following the infusion (P = .04).

Scores on the depersonalization subscale of the CADSS were related to percentage change in HDRS-17 score in all three studies and at all time points (P = .04).

Scores on the subscale of derealization were associated with percentage change in HDRS score on day 7 post infusion in one study (P = .01).

No association was observed between amnesia symptoms during infusion and reduction in depression, as reflected in percentage change in HDRS score.

Mechanistic Similarities

“What really jumped out at us was the depersonalization subscale,” Niciu said.

He speculated that depersonalization in particular may relate to some of the deeper aspects of depression, more so than derealization, which involves detachment from reality, or amnesia.

“There might be mechanistic similarities between depersonalization and an antidepressant response,” Niciu explained.

“These are people with a highly introspective disorder and are often focused on their inner self. If you can detach them from that for a period of time and disconnect them from the subjective sensations, then that may result in a better antidepressant response, but that’s a hypothesis,” he said.

The findings suggest that the use of the depersonalization scale could represent a relatively easy way to assess the possibility of the patient’s responding to ketamine.

“In the clinical setting, if someone is administering ketamine and doesn’t have much time and just wants to get a sense of how a patient might respond, the CADSS depersonalization subscale is something they might want to administer,” Niciu said.

“It is easy to administer — it’s only five items, and those who tend to score higher on that subscale may be more likely to be responders,” he added.

Relevance Questioned

The study was an extension of earlier research from the investigators linking the degree of dissociative symptoms with ketamine’s antidepressant effects.

On the basis of those findings, some clinicians already try to achieve the effects in order to evoke a better response, said Sanjay Mathew, MD, professor of psychiatry and behavioral sciences, Baylor College of Medicine and the Michael E. Debakey VA Medical Center, Houston, Texas, while commenting on the study at the meeting.

“Often, anesthesiologists and psychiatrists at ketamine clinics will start at 0.5 mg/kg and titrate the dose to mild dissociation,” said Matthew. “They often want the patient to feel buzzed, because that’s when they feel confident that they’ve hit the ‘sweet spot’ of NMDA modulation.”

He noted that another NIMH study of 99 patients, which is currently under review, showed that the best outcomes, as reflected in scores on depression scales, were achieved with the standard 0.5 mg/kg dose in comparison with the 1.0 mg/kg dose and the very low dose of 0.1 mg/kg, which were associated with a high degree of dissociation.

“Clearly, the message from that study is that you don’t need to dissociate to get better,” he said.

Nevertheless, “the issue is fascinating, with high clinical relevance in terms of how clinicians are using ketamine in the community,” Mathew said.

However, Wilkinson noted that he has not seen similar patterns in his patients who were treated with ketamine, and he questioned the use of the CADSS tool for determining dissociation symptoms in the study.

“We have not observed that the level of dissociation and depersonalization predict response,” he told Medscape Medical News.

“I am skeptical of this finding, as the CADSS instrument was not designed for use in ketamine studies and in my opinion does not do a great job at capturing this phenomenon related to ketamine,” he added.

Wilkinson noted that the dissociative symptoms that can occur with ketamine treatment do not appear to subside after multiple infusion sessions.

“In my experience treating patients, there seem to be a group of patients who always develop fairly significant symptoms, even though they have been treated 20 times or more with ketamine,” he said.

Longer-term Outcomes

During the presentation of his own study, Wilkinson reported that 21 participants (38%) were men and 96% were being treated with concomitant medications during the acute course. These medications included antidepressants (72.2%), antipsychotics (53.7%), mood stabilizers (37%), lithium (18.5%), and sedatives/hypnotics (50%).

Patients were initially treated intravenously with a single or double infusion of 0.5 mg/kg over 40 minutes. However, patients were later transitioned to a four-dose protocol administered twice per week over 2 weeks.

The response rate was about 50%, and the remission rate was 27.3% among 50 patients who received one to four treatments.

Although there was no evidence of cognitive decline or delusions, one person discontinued infusion because of intolerability, one discontinued because of hypertension, one experienced relapse of cannabis use disorder, and three required rehospitalization for suicidal ideation or suicide attempts.

There were two completed suicides, one occurring 10 months after last contact with the program, and one 4 months after last contact.

Wilkinson noted that the 50% response rate is somewhat lower than rates reported in clinical trials, which may reflect a real-world setting.

“This is sometimes called the ‘efficacy-effectiveness gap’ and is not really surprising, because clinical trials are usually done in ideal conditions, whereas community practice represents real-world conditions and the patients are generally sicker and have comorbidities,” he told Medscape Medical News.

He added that once patients have responded to several weeks of ketamine treatments, efforts are made to help them shift to other forms of management.

 

“For those patients who do well following a series of four to six ketamine infusions, we initially try and keep them well using a strategy that does not involve repeated use of ketamine,” said Wilkinson.

 

Concerns Remain

Despite the encouraging improvements in depression that have been reported, the increased popularity of ketamine without long-term safety or efficacy data has raised considerable concerns, as reflected in aconsensus statement issued by an American Psychiatric Association Task Force in 2017.

Wilkinson said he shares the task force’s concerns.

“Ketamine has tremendous potential, but this needs to be tempered with the potential risks. There needs to be a higher level of regulation than currently exists,” he said.

“Ketamine is very safe in the short term, but we need better long-term data, because the risks of long-term adverse effects with repeated use are not theoretical,” Wilkinson added.

“We know that too much ketamine is not good for the brain or bladder. We just don’t know how much is too much,” he said.

Dr Niciu has disclosed no relevant financial relationships. The senior author of the study is a coinventor on a patent for the use of ketamine and its metabolites in the treatment of major depression. Although he assigned his rights in the patent to the US Government, he will share a percentage of any royalties that may be received. Wilkinson has received funding, administered through Yale University, from Janssen to conduct clinical trials with esketamine. He has also received consulting fees of less than $5000 from Janssen.

Anxiety and Depression Association of America (ADAA) Conference 2018. Session 341R, presented April 7, 2018.

 

CADSS-test-for-PTSD  <<Clinician-Administered Dissociative States Scale (CADSS)  A test to see how dissociated an individual is – the more the better!

 

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Abstract

Background

The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.

Methods

Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7.

Results

Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.

Limitations

Secondary data analysis, combined diagnostic groups, potential unblinding.

Conclusions

Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

Highlights

  • Intra-infusion dissociation is associated with antidepressant response to ketamine.
  • Antidepressant response may be uniquely related to dissociative symptom clusters.
  • Depersonalization was globally associated with antidepressant response.
  • Derealization was discriminately associated with antidepressant response.

Abstract

Background

Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters.

Methods

Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response.

Results

Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change.

Limitations

Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine’s antidepressant efficacy; the possibility of Type I errors in secondary analyses.

Conclusions

From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

KETAMINE INFUSIONS |KETAMINE DEPRESSION | KETAMINE DOCTORS IN VIRGINIA | FAIRFAX KETAMINE | 703-844-0184 | KETAMINE AND DEPRESSION TREATMENT | 22308 |22305 | 22304 | 22191 |22192 |22193 | 20118 | 20104 | KETAMINE TREATMENT FOR DEPRESSION |CRPS |RSD |KETAMINE INFUSIONS FOR PAIN | SPRINGFIELD , VA KETAMINE | 22303 22307 22306 22309 22308 22311 22310 22312 22315 22003 20120 22015 22027 20121 22031 20124 22030 22033 22032 22035 22039 22041 22043 22042 22046 22044 22060 22066 20151 22079 20153 22101 22102 20171 20170 22124 22151 22150 22153 22152 20191 20190 22181 20192 22180 20194 22182

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Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

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Ketamine center in Fairfax, Virginia    << Ketamine infusions

NOVA Health Recovery – KETAMINE SYSTEMS<< Link

703-844-0184 NOVA Health Recovery Ketamine Infusion Center – Beat depression and Anxiety. https://novahealthrecovery.com/

Each year, 13 to 14 million people in America suffer from major depression. Of those numbers who seek treatment, about 30-40% don’t get any better or recover through using the standard depression medications prescribed by healthcare professionals.

Untreated depression puts someone at a greater risk of alcohol and drug abuse, hospitalization and attempted suicide. However, there’s a growing body of research which shows there is a new reason to hope, and it’s the anesthesia drug ketamine.

Ketamine is a popular illicit party drug because it provides the user with hallucinogenic effects. The medication is used in only a handful of clinics around the United States, people who weren’t helped by standard psychiatric treatments are receiving a series of ketamine infusions to help ease the effects of their depression. Ketamine has also been used in emergency rooms to help curb suicidal thoughts, which means the drug is a potential lifesaver.

Ketamine is a fast-acting drug, the effects peak, often within hours, and healthcare providers who give it to a patient at a therapeutic dose say its side effects are brief and mild in most people. The drug hasn’t been studied for long-term safety and effectiveness and the Food and Drug Administration hasn’t approved it to treat depression.

Medical experts do not yet fully understand all the ways ketamine works, but it does work differently than antidepressants such as Zoloft, Prozac and Effexor. The way the drug works might explain why people who don’t respond to traditional treatment methods respond so well to ketamine.

It’s important to remember that no matter how successful ketamine may prove to be, one single treatment isn’t enough to cure depression. To successfully treat depression, a medical professional will need to address all aspects of a person’s disease from the biological, psychological to social and environmental angles.

A Brief History of Ketamine
Ketamine is an anesthetic that has been used on both humans and animals for over 52 years.  Unlike other anesthetics, it doesn’t depress patients’ breathing or circulatory systems and it is very fast-acting.

How Is Ketamine Used
Because of its effectiveness and safety when delivered appropriately, ketamine is being used more in the following ways: treating depression and other mood disorders and pain conditions including Complex Regional Pain Syndrome (CPRS/RSD).  Leading institutions such as Yale University, The National Institute of Mental Health, and  Massachusetts General Hospital have completed research that demonstrates the efficacy and safety of ketamine infusion treatments for these conditions.

The Visit
The medicine is given very slowly over 40 minutes.  Most people can expect to be with us for about 90 minutes.  You will leave treatment without side effects and you should not experience side effects between treatments.​

In As Little As One Treatment
Ketamine treatments may free you from depression, OCD, PTSD, anxiety, CRPS/RSD, fibromyalgia & other chronic pain conditions.

Ketamine Infusion for Depression, Bipolar Disorder or PTSD?

Ketamine could be the bridge for somebody who is suicidal because if they are given the drug and it’s effective for 3 days, the person could be hooked up with outpatient resources, other medications and psychotherapy.

Not all cases of suicidal thoughts are linked to depression, post-traumatic stress disorder, borderline personality disorder and alcohol and other substance abuse issues can also account for some suicides. Further research is needed to determine how ketamine can be utilized for treatment of depression and other psychiatric disorders.

Does Ketamine Infusion Work for Depression?

Social Anxiety and Ketamine:

Approximately one-third to one-half of all people with Social Anxiety Disorder (SAD) do not experience adequate clinical benefits from using the current treatment methods for SAD. These treatments include conventional approaches like selective serotonin reuptake inhibitors or SSRIs or cognitive behavioral therapy. Failing to relieve anxiety in patients with social anxiety disorder is a source of distress, substantial morbidity and it decreases the quality of a person’s life over the long term.

Feeling shy or uncomfortable in certain public situations isn’t an indication of a social anxiety disorder, particularly if these emotions are present in young children. A person’s comfort level in social situations will vary and depend on the individual’s personality and life experiences. Some people are naturally reserved and other people are outgoing, some are a mixture of both.  In contrast to everyday nervousness, social anxiety disorder includes distress, avoidance and unease that interferes with one’s daily life, routine, work, school and other activities.

There’s been new evidence from neuroimaging and pharmacological studies which support the importance of glutamate abnormalities in the pathogenesis of social anxiety disorder. In a previous clinical study, an elevate glutamate to creatinine ratio was found in the anterior cortex of social anxiety disorder patients when compared with healthy control subjects.

Ketamine is a potent agonist of the N-methyl-D-aspartate receptor is a major glutamate receptor in the brain. The drug is normally used as an anesthetic because of its dissociative properties. In a multitude of controlled clinical studies, ketamine has proven to be an effective treatment for reducing symptoms of depression and anxiety. Ketamine has produced a rapid antidepressant effect in unipolar and bipolar depression and the effects peak 1-3 days following infusion and is observed long after the drug has been metabolized and excreted by the body.

The results of several studies involving ketamine infusion show the medication may have significant anxiolytic effects. For patients with major depressive disorders or social anxiety disorder, the drug has shown strong and significant reductions in co-morbid anxiety symptoms. If you want to find out more information about how ketamine infusion may work for you, please contact us at 703-844-0184 – NOVA Health Recovery

 

PTSD TREATMENT:

Ketamine is a drug that was developed more than 50 years ago to be used as anesthesia during surgery, and it has also been used as an illicit street drug. Recently, ketamine has been found to be a valuable and extremely effective treatment for depression, anxiety, PTSD, OCD and certain pain disorders, like fibromyalgia.

Our Ketamine treatment center in Bowie MD offer infusions on an outpatient basis and following a consultation with medical staff it can be determined if the medication is appropriate and safe for a person. A patient using ketamine infusion therapy is monitored during the process by a clinical coordinator to ensure a smooth, supportive and successful treatment process.

Because the effects of a ketamine infusion are short-lived, patients will usually receive a series of infusions over a series of 2-3 weeks. Ketamine infusions for PTSD is an off-label use and it means the Food and Drug Administration has not approved the drug for this particular use. However, the drug’s safety and effectiveness have been demonstrated in multiple research studies and off-label prescribing is a common and necessary practice in the medical world.

Unlike most of the common antidepressant medications that may take weeks or months before a patient and doctor can even determine if it works, ketamine infusions yield positive results within hours or days. Many patients will know within the first few hours or days if ketamine is working for them or not. The most common experience when using ketamine infusions is no side effects between treatments, so it is a good option for those with treatment-resistant depression or those who have troublesome side effects from other medications commonly prescribed.

Ketamine Safety and Tolerability In Clinical Trials For Treatment-resistant Depression

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in DepressionA preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department

Ketamine for Depression: Where Do We Go from Here?

A Systematic Review of Ketamine for Complex Regional Pain Syndrome

The Promise of Ketamine For Treatment-resistant Depression: Current Evidence and Future Directions

Ketamine-Induced Optimism: New Hope for the Development of Rapid-Acting Antidepressants

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

A review of ketamine in affective disorders:Current evidence of clinical efficacy,limitations of use and pre-clinical evidence on proposed mechanisms of action

Intravenous Ketamine for the Treatment of Mental Health Disorders: A Review of Clinical Effectiveness and Guidelines

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder​

Researchers find new ways of managing clinical and seasonal depression

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Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016

 

Northern Virginia:

McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304  Fairfax – 20191 – Reston – 22009 – Springfield – 22152  22015  Lorton 22199

Fairfax, Va

2303 –  22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312

22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 –  20124

22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043

22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101

22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153

22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 –  22182

Woodbridge – 22191 – 22192 -22193 -22194 – 22195

Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161

Front Royal 22630

Warren County 22610 22630 22642 22649

Fredericksburg Va 22401 22402 – 22403 – 22404 -22405 -22406 -22407 -22408 – 22412

Please call Sendi Hair Loss Center now at 703-574-0974 for quality Hair Restoration services in Alexandria, VA.

20105    Aldie      Loudoun County 20106  Amissville            Culpeper County 20107 Arcola   Loudoun County

20108    Manassas            Manassas City 20109       Sudley Springs   Prince William County

20109    Manassas            Prince William County 20110       Manassas            Manassas City

20111    Manassas            Prince William County 20111       Manassas Park  Prince William County

20112    Manassas            Prince William County 20113       Manassas Park  Manassas Park City

20115    Marshall               Fauquier County 20116  Marshall               Fauquier County

20117    Middleburg        Loudoun County 20118  Middleburg        Loudoun County

20119    Catlett  Fauquier County – 20120 Sully Station    Fairfax County

20120    Centreville          Fairfax County – 20121   Centreville          Fairfax County

20122    Centreville          Fairfax County – 20124   Clifton   Fairfax County

20128    Orlean  Fauquier County -20129                Paeonian Springs             Loudoun County

20130    Paris      Clarke County

20131    Philomont           Loudoun County 20132  Purcellville          Loudoun County

20134    Hillsboro              Loudoun County 20134  Purcellville          Loudoun County

20135    Bluemont            Clarke County 20136       Bristow Prince William County

20137    Broad Run           Fauquier County 20138  Calverton            Fauquier County

20139    Casanova             Fauquier County 20140  Rectortown        Fauquier County

20141    Round Hill            Loudoun County 20142  Round Hill            Loudoun County

20143    Catharpin            Prince William County

20144    Delaplane            Fauquier County20146   Ashburn               Loudoun County

20147    Ashburn               Loudoun County 20148  Brambleton        Loudoun County

20148    Ashburn               Loudoun County 20151  Chantilly               Fairfax County

20151    Fairfax  Fairfax County 20152      South Riding       Loudoun County

20152    Chantilly               Loudoun County 20152  Fairfax  Loudoun County

20153    Chantilly               Fairfax County 20153      Fairfax  Fairfax County

20155    Gainesville          Prince William County 20156       Gainesville          Prince William County

20158    Hamilton              Loudoun County 20159  Hamilton              Loudoun County

20160    Lincoln  Loudoun County 20160  Purcellville          Loudoun County

20163    Sterling Loudoun County 20164  Sterling Loudoun County

20165    Potomac Falls    Loudoun County 20165  Sterling Loudoun County

20166    Dulles    Loudoun County 20166  Sterling Loudoun County

20167    Sterling Loudoun County 20168  Haymarket          Prince William County

20169    Haymarket          Prince William County 20170       Herndon              Fairfax County

20171    Oak Hill Fairfax County 20171      Herndon              Fairfax County

20172    Herndon              Fairfax County 20175      Leesburg             Loudoun County

20176    Lansdowne         Loudoun County 20176  Leesburg             Loudoun County

20177    Leesburg             Loudoun County 20178  Leesburg             Loudoun County

20180    Lovettsville         Loudoun County 20181  Nokesville           Prince William County

20182    Nokesville           Prince William County 20184       Upperville           Fauquier County

20185    Upperville           Fauquier County 20186  Warrenton          Fauquier County

20187    New Baltimore  Fauquier County 20187  Vint Hill Farms   Fauquier County 20187  Warrenton          Fauquier County

20188    Vint Hill Farms   Fauquier County 20188  Warrenton          Fauquier County

20190    Reston  Fairfax County 20190      Herndon              Fairfax County

20191    Reston  Fairfax County 20191      Herndon              Fairfax County

20194    Reston  Fairfax County 20194      Herndon              Fairfax County

20195    Reston  Fairfax County 20195      Herndon              Fairfax County

20197    Waterford           Loudoun County 20198  The Plains            Fauquier County

Loudon County:

Loudoun County, VA – Standard ZIP Codes

20105 | 20117 | 20120 | 20129 | 20130 | 20132 | 20135 | 20141 | 20147 | 20148 | 20152 | 20158 | 20164 | 20165 | 20166 | 20175 | 20176 | 20180 | 20184 | 20189 | 20197 | 22066

Ashburn, VA – Standard ZIP Codes
20147 20148
Leesburg, VA – Standard ZIP Codes
20175 20176
Sterling, VA – Standard ZIP Codes
20164 20165 20166

Waterford, VA 20197

Dulles, VA – Standard ZIP Codes
20166 20189
Purcellville, VA – Standard ZIP Codes
20132
Chantilly, VA – Standard ZIP Codes
20151 20152

Mcclean, Va Zip codes: 220432204622066,221012210222207